bibliography.bib

@article{barrettNeurodegenerationDiabetesUK1995,
  title = {Neurodegeneration and Diabetes: {{UK}} Nationwide Study of {{Wolfram}} ({{DIDMOAD}}) Syndrome},
  volume = {346},
  journal = {The Lancet},
  author = {Barrett, Timothy and Bundey, Sarah and Macleod, Andrew},
  year = {1995},
  keywords = {Wolfram},
  pages = {1458--63},
  file = {/Users/k/Zotero/storage/NTBRR43Z/Barrett, Bundey, Macleod - 1995 - Neurodegeneration and diabetes UK nationwide study of Wolfram (DIDMOAD) syndrome.pdf;/Users/k/Zotero/storage/X4RVSFCZ/Barrett, Bundey, Macleod - 1995 - Neurodegeneration and diabetes UK nationwide study of Wolfram (DIDMOAD) syndrome.pdf}
}

@misc{centerforhistoryandnewmediaZoteroQuickStart,
  title = {Zotero {{Quick Start Guide}}},
  howpublished = {http://zotero.org/support/quick\_start\_guide},
  author = {{Center for History and New Media}}
}

@misc{harrellBayesianVsFrequentist2017,
  title = {Bayesian vs. {{Frequentist Statements About Treatment Efficacy}}},
  abstract = {To avoid ``false positives'' do away with ``positive''.
A good poker player plays the odds by thinking to herself ``The probability I can win with this hand is 0.91'' and not ``I'm going to win this game'' when deciding the next move.
State conclusions honestly, completely deferring judgments and actions to the ultimate decision makers. Just as it is better to make predictions than classifications in prognosis and diagnosis, use the word ``probably'' liberally, and avoid thinking ``the evidence against the null hypothesis is strong, so we conclude the treatment works'' which creates the opportunity of a false positive.},
  language = {en-us},
  journal = {Statistical Thinking},
  howpublished = {http://fharrell.com/post/bayes-freq-stmts/},
  author = {Harrell, Frank},
  month = oct,
  year = {2017},
  file = {/Users/k/Zotero/storage/UNEZ7BGF/bayes-freq-stmts.html}
}

@misc{harrellMusingsMultipleEndpoints2018,
  title = {Musings on {{Multiple Endpoints}} in {{RCTs}}},
  abstract = {Learning is more productive than avoiding mistakes. And if one wishes to just avoid mistakes, make sure the mistakes are real. Question whether labeling endpoints is productive, and whether type I error risks are valuable in quantifying evidence for effects and should interfere with asking questions. The NHLBI-funded ISCHEMIA multinational randomized clinical trial1 is designed to assess the effect of cardiac catheterization-guided coronary revascularization strategy (which includes optimal medical management) compared to optimal medical management alone (with cardiac cath reserved for failure of medical therapy) for patients with stable coronary artery disease.},
  language = {en-us},
  journal = {Statistical Thinking},
  howpublished = {http://fharrell.com/post/ymult/},
  author = {Harrell, Frank},
  month = mar,
  year = {2018},
  file = {/Users/k/Zotero/storage/4HMEN4CM/ymult.html}
}

@misc{harrellStatisticalErrorsMedical,
  title = {Statistical {{Errors}} in the {{Medical Literature}}},
  abstract = {Misinterpretation of P-values and Main Study Results  Dichotomania  Problems With Change Scores  Improper Subgrouping  Serial Data and Resp...},
  author = {Harrell, Frank},
  keywords = {BeBetterStatistician},
  file = {/Users/k/Zotero/storage/XVGACI2J/statistical-errors-in-medical-literature.html}
}

@misc{PembrolizumabNotNivolumab,
  title = {Pembrolizumab, but {{Not Nivolumab}}, {{Improves Outcomes}} in {{Front}}-{{Line Setting}} for {{PD}}-{{L1}}\textendash{{Positive Advanced NSCLC}} - {{The ASCO Post}}},
  howpublished = {http://www.ascopost.com/issues/november-10-2016/pembrolizumab-but-not-nivolumab-improves-outcomes-in-front-line-setting-for-pd-l1-positive-advanced-nsclc/},
  file = {/Users/k/Zotero/storage/NSWMNXVX/pembrolizumab-but-not-nivolumab-improves-outcomes-in-front-line-setting-for-pd-l1-positive-adva.html}
}

@article{vejbaesyaNIHPublicAccess2010,
  title = {{{NIH Public Access}}},
  volume = {199},
  issn = {1946-6242},
  doi = {10.1086/597422.Tumor},
  number = {2},
  author = {Vejbaesya, Sasijit and Luangtrakool, Panpimon and Luangtrakool, Komon and Vaughn, David W and Endy, Timothy P and Mammen, Mammen P and Libraty, Daniel H and Ennis, Francis A and Rothman, Alan L and Henry, A F},
  year = {2010},
  keywords = {Corneal,33447,44-207-794-0500 ext 35123 or,address correspondence to dr,centre for nephrology and,dengue,disease severity,e-mail,ethnic thais,genetic associations,henry stephens,hla,london nw3 2pf,lta,rowland hill street,royal free hospital campus,tel,the,the anthony nolan trust,tnf,uk,university college london},
  pages = {1442--1448},
  pmid = {20371490}
}

@article{millsDesignAnalysisPresentation2009,
  title = {Design, Analysis, and Presentation of Crossover Trials.},
  volume = {10},
  issn = {1745-6215},
  doi = {10.1186/1745-6215-10-27},
  abstract = {OBJECTIVE: Although crossover trials enjoy wide use, standards for analysis and reporting have not been established. We reviewed methodological aspects and quality of reporting in a representative sample of published crossover trials. METHODS: We searched MEDLINE for December 2000 and identified all randomized crossover trials. We abstracted data independently, in duplicate, on 14 design criteria, 13 analysis criteria, and 14 criteria assessing the data presentation. RESULTS: We identified 526 randomized controlled trials, of which 116 were crossover trials. Trials were drug efficacy (48\%), pharmacokinetic (28\%), and nonpharmacologic (30\%). The median sample size was 15 (interquartile range 8-38). Most (72\%) trials used 2 treatments and had 2 periods (64\%). Few trials reported allocation concealment (17\%) or sequence generation (7\%). Only 20\% of trials reported a sample size calculation and only 31\% of these considered pairing of data in the calculation. Carry-over issues were addressed in 29\% of trial's methods. Most trials reported and defended a washout period (70\%). Almost all trials (93\%) tested for treatment effects using paired data and also presented details on by-group results (95\%). Only 29\% presented CIs or SE so that data could be entered into a meta-analysis. CONCLUSION: Reports of crossover trials frequently omit important methodological issues in design, analysis, and presentation. Guidelines for the conduct and reporting of crossover trials might improve the conduct and reporting of studies using this important trial design.},
  journal = {Trials},
  author = {Mills, Edward J and Chan, An-Wen and Wu, Ping and Vail, Andy and Guyatt, Gordon H and Altman, Douglas G},
  year = {2009},
  keywords = {CrossoverTrials},
  pages = {27},
  file = {/Users/k/Zotero/storage/2YU9E8GH/Mills et al. - 2009 - Design, analysis, and presentation of crossover trials.pdf;/Users/k/Zotero/storage/RFC292X3/Mills et al. - 2009 - Design, analysis, and presentation of crossover trials.pdf},
  pmid = {19405975}
}

@article{heHHSPublicAccess2015,
  title = {{{HHS Public Access}}},
  volume = {33},
  issn = {1527-5418},
  number = {4},
  author = {He, Qiye and Johnston, Jeff and Zeitlinger, Julia and City, Kansas and City, Kansas},
  year = {2015},
  pages = {395--401},
  pmid = {24655651}
}

@misc{BayesianInferenceCompletely2016,
  title = {Bayesian Inference Completely Solves the Multiple Comparisons Problem},
  abstract = {I promised I wouldn't do any new blogging until January but I'm here at this conference and someone asked me a question about the above slide from my talk. The point of the story in that slide is that flat priors consistently give bad inferences. Or, to put it another way, the routine use of \ldots{}},
  language = {en-US},
  journal = {Statistical Modeling, Causal Inference, and Social Science},
  howpublished = {http://andrewgelman.com/2016/08/22/bayesian-inference-completely-solves-the-multiple-comparisons-problem/},
  month = aug,
  year = {2016},
  file = {/Users/k/Zotero/storage/NRKM3N8M/bayesian-inference-completely-solves-the-multiple-comparisons-problem.html}
}

@article{Lilenbaum2008,
  title = {Randomized Phase {{II}} Trial of Erlotinib or Standard Chemotherapy in Patients with Advanced Non-Small-Cell Lung Cancer and a Performance Status of 2.},
  volume = {26},
  issn = {1527-7755},
  doi = {10.1200/JCO.2007.13.2720},
  abstract = {PURPOSE: A multicenter randomized phase II trial to evaluate two treatment strategies in the first-line management of advanced non-small-cell lung cancer (NSCLC) patients with a performance status (PS) of 2. PATIENTS AND METHODS: Patients were assigned to erlotinib 150 mg orally daily until progression or to carboplatin (area under the curve [AUC] 6) and paclitaxel (200 mg/m(2) day 1 every 3 weeks) for up to four cycles. Patients who experienced progression or did not tolerate or refused further chemotherapy were allowed to cross over to erlotinib. The primary end point was progression-free survival (PFS). Secondary end points were response, survival, quality of life (QOL), and a retrospective molecular correlation. RESULTS: Fifty-two patients were randomly assigned to erlotinib and 51 to chemotherapy. Partial responses were 2\% and 12\%, respectively. Median PFS was 1.9 months in the erlotinib arm and 3.5 months in the chemotherapy arm (hazard ratio [HR] = 1.45; 95\% CI, 0.98 to 2.15; P = .06). Median survival times were 6.5 and 9.7 months, respectively (HR = 1.73; 95\% CI, 1.09 to 2.73; P = .018). Patients who crossed over to erlotinib had a median survival of 14.9 months. Sex, histology, skin rash, and smoking history predicted outcome with erlotinib. Rash and diarrhea were more common with erlotinib; emesis, alopecia, peripheral neuropathy, and fatigue were more common with chemotherapy. QOL was similar between the two arms. Molecular correlation was limited by available samples. CONCLUSION: Unselected patients with advanced NSCLC and PS 2 are best treated with combination chemotherapy as first-line therapy. Erlotinib may be considered in patients selected by clinical or molecular markers.},
  number = {6},
  journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology},
  author = {Lilenbaum, Rogerio and Axelrod, Rita and Thomas, Sachdev and Dowlati, Afshin and Seigel, Leonard and Albert, Donald and Witt, Karsten and Botkin, David},
  year = {2008},
  keywords = {NSCLC},
  pages = {863-869},
  file = {/Users/k/Zotero/storage/CUBJXU4C/Lilenbaum et al. - 2008 - Randomized phase II trial of erlotinib or standard chemotherapy in patients with advanced non-small-cell lung.pdf;/Users/k/Zotero/storage/JMHUP3PU/Lilenbaum et al. - 2008 - Randomized phase II trial of erlotinib or standard chemotherapy in patients with advanced non-small-cell lung.pdf},
  pmid = {18281658}
}

@article{Lilenbaum2005,
  title = {Single-Agent versus Combination Chemotherapy in Advanced Non-Small-Cell Lung Cancer: {{The Cancer}} and {{Leukemia Group B}} (Study 9730)},
  volume = {23},
  issn = {0732183X},
  doi = {10.1200/JCO.2005.07.172},
  abstract = {We compared the efficacy of combination chemotherapy versus single-agent therapy in patients with advanced non-small-cell lung cancer.},
  number = {1},
  journal = {Journal of Clinical Oncology},
  author = {Lilenbaum, Rogerio C. and Herndon, James E. and a. List, Marcy and Desch, Chris and Watson, Dorothy M. and a. Miller, Antonius and Graziano, Stephen L. and Perry, Michael C. and Saville, Wayne and Chahinian, Philippe and Weeks, Jane C. and Holland, Jimmie C. and Green, Mark R.},
  year = {2005},
  keywords = {NSCLC,PS2},
  pages = {190-196},
  file = {/Users/k/Zotero/storage/GP3ZXSEC/Lilenbaum et al. - 2005 - Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer The Cancer and Leukemia Gr.pdf},
  pmid = {15625373}
}

@article{Smith2015,
  title = {Early Experience of the Use of Fibrin Sealant in the Management of Children with Pilonidal Sinus Disease.},
  volume = {50},
  issn = {1531-5037},
  doi = {10.1016/j.jpedsurg.2014.11.022},
  abstract = {BACKGROUND: The use of fibrin sealant in the management of pilonidal sinus disease has not previously been described in children. We present our experience of primary pit excision and use of fibrin sealant (PEF) and compare outcomes with lateralising flap procedures (LFP).$\backslash$n$\backslash$nMETHODS: A single centre retrospective case note review of all children who had undergone a definitive procedure for pilonidal sinus from August 2006 to Dec 2013 was performed using data expressed as median (range) and compared using Fisher's exact test. P$<$0.05 was regarded as significant.$\backslash$n$\backslash$nRESULTS: Forty-one children were identified having undergone 49 procedures, with median age 15 (12-16 years) and follow up 32 (8-92) months. Groups were comparable for disease severity. Ten children underwent primary PEF and twenty-six LFP. Two children had recurrence following primary PEF and had repeat PEF which was curative. Overall recurrence rates following PEF procedure were comparable to LFP (17\% vs 21\%; P=1.0). There were no wound dehiscences in the PEF group and one wound infection. There was one wound dehiscence and one wound infection in the LFP group. Median operative time for PEF was lower than LFP (20 vs 60 min, P=0.001). 83\% of PEF procedures were performed as day cases. One child was lost to follow up, and two children progressed to adult services.$\backslash$n$\backslash$nCONCLUSIONS: We recommend PEF in children with pilonidal sinus disease as primary treatment and for recurrence. PEF has comparable recurrence and wound infection rates to LFPs, is performed as day case, has shorter anaesthetic times, and the risk of wound dehiscence is avoided.},
  number = {2},
  journal = {Journal of pediatric surgery},
  author = {Smith, Caroline Mary and Jones, Abigail and Dass, Dipankar and Murthi, Govind and Lindley, Richard},
  year = {2015},
  keywords = {Surgery,Fibrin,Fibrin glue,Fibrin sealant,Pilonidal,Pilonidal disease,Pilonidal sinus},
  pages = {320-2},
  file = {/Users/k/Zotero/storage/76KASK4U/Smith et al. - 2015 - Early experience of the use of fibrin sealant in the management of children with pilonidal sinus disease.pdf;/Users/k/Zotero/storage/HE4RLRM7/Smith et al. - 2015 - Early experience of the use of fibrin sealant in the management of children with pilonidal sinus disease.pdf},
  pmid = {25638628}
}

@article{Handmer2012,
  title = {Sticking to the Facts: A Systematic Review of Fibrin Glue for Pilonidal Disease},
  volume = {82},
  issn = {1445-2197; 1445-1433},
  doi = {http://dx.doi.org/10.1111/j.1445-2197.2011.05752.x},
  abstract = {BACKGROUND: Pilonidal disease occurs when hair invading the natal cleft causes inflammation and abscess formation. Opinions vary on best practice, and most procedures have considerable morbidity and high recurrence rates of 6-40\%. OBJECTIVES: This study systematically reviews the use of fibrin glue in the treatment of pilonidal disease. Outcomes measured were healing time and recurrence rate. DATA SOURCE: ScienceDirect and PubMed databases were searched for relevant literature, yielding seven papers including five small trials. The total number of patients receiving fibrin glue treatments across all trials was 85. There were no exclusion criteria in this review. RESULTS: Fibrin glue treatments had equivalent or better reported healing times than conventional therapies at an average of 2-6 weeks, and low recurrence rates between 0 and 17\% at follow-up periods between 4 and 28 months. Considerable heterogeneity in study methodologies and surgical techniques prevented statistical significance or aggregate figures from being determined. CONCLUSIONS: There appears to be early promise for the use of fibrin glue in the treatment of pilonidal disease and an impetus for definitive research.Copyright 2011 The Author. ANZ Journal of Surgery 2011 Royal Australasian College of Surgeons.},
  number = {4},
  journal = {ANZ Journal of Surgery},
  author = {Handmer, M},
  year = {2012},
  keywords = {Humans,Surgery,Fibrin,Pilonidal,Fibrin Tissue Adhesive/tu [Therapeutic Use],Index Medicus,Pilonidal Sinus/su [Surgery],Tissue Adhesives/tu [Therapeutic Use],Wound Healing},
  pages = {221-224},
  file = {/Users/k/Zotero/storage/HESHPMPH/Handmer - 2012 - Sticking to the facts a systematic review of fibrin glue for pilonidal disease.pdf;/Users/k/Zotero/storage/LN85LHWY/Handmer - 2012 - Sticking to the facts a systematic review of fibrin glue for pilonidal disease.pdf},
  pmid = {22510177}
}

@article{McCulloch2009,
  title = {No Surgical Innovation without Evaluation: The {{IDEAL}} Recommendations},
  volume = {374},
  issn = {01406736},
  doi = {10.1016/S0140-6736(09)61116-8},
  abstract = {Surgery and other invasive therapies are complex interventions, the assessment of which is challenged by factors that depend on operator, team, and setting, such as learning curves, quality variations, and perception of equipoise. We propose recommendations for the assessment of surgery based on a five-stage description of the surgical development process. We also encourage the widespread use of prospective databases and registries. Reports of new techniques should be registered as a professional duty, anonymously if necessary when outcomes are adverse. Case series studies should be replaced by prospective development studies for early technical modifications and by prospective research databases for later pre-trial evaluation. Protocols for these studies should be registered publicly. Statistical process control techniques can be useful in both early and late assessment. Randomised trials should be used whenever possible to investigate efficacy, but adequate pre-trial data are essential to allow power calculations, clarify the definition and indications of the intervention, and develop quality measures. Difficulties in doing randomised clinical trials should be addressed by measures to evaluate learning curves and alleviate equipoise problems. Alternative prospective designs, such as interrupted time series studies, should be used when randomised trials are not feasible. Established procedures should be monitored with prospective databases to analyse outcome variations and to identify late and rare events. Achievement of improved design, conduct, and reporting of surgical research will need concerted action by editors, funders of health care and research, regulatory bodies, and professional societies. \textcopyright{} 2009 Elsevier Ltd. All rights reserved.},
  number = {9695},
  journal = {The Lancet},
  author = {McCulloch, Peter and Altman, Douglas G. and Campbell, W. Bruce and Flum, David R. and Glasziou, Paul and Marshall, John C. and Nicholl, Jon},
  year = {2009},
  keywords = {Surgery,3,evaluation,no surgical innovation without,surgical innovation and evaluation,the ideal,IDEAL},
  pages = {1105-1112},
  file = {/Users/k/Zotero/storage/27FGJTQA/McCulloch et al. - 2009 - No surgical innovation without evaluation the IDEAL recommendations.pdf;/Users/k/Zotero/storage/3SR8FASW/McCulloch et al. - 2009 - No surgical innovation without evaluation the IDEAL recommendations.pdf},
  pmid = {19782876}
}

@article{jamesAdditionDocetaxelZoledronic2015,
  title = {Addition of Docetaxel, Zoledronic Acid, or Both to First-Line Long-Term Hormone Therapy in Prostate Cancer ({{STAMPEDE}}): Survival Results from an Adaptive, Multiarm, Multistage, Platform Randomised Controlled Trial},
  doi = {10.1016/S0140-6736(15)01037-5},
  abstract = {Articles www.thelancet.com Published online December 21, 2015 http://dx.doi.org/10.1016/S0140-6736(15)01037-5 1 Addition of docetaxel, zoledronic acid, or both to fi rst-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial Summary Background Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting fi rst-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone.},
  author = {James, Nicholas D and Sydes, Matthew R and Clarke, Noel W and Mason, Malcolm D and Dearnaley, David P and Spears, Melissa R and Ritchie, Alastair W S and Parker, Christopher C and Russell, J Martin and Attard, Gerhardt and De Bono, Johann and Cross, William and Jones, Rob J and Thalmann, George and Amos, Claire and Matheson, David and Millman, Robin and Alzouebi, Mymoona and Beesley, Sharon and Birtle, Alison J and Brock, Susannah and Cathomas, Richard and Chakraborti, Prabir and Chowdhury, Simon and Cook, Audrey and Elliott, Tony and Gale, Joanna and Gibbs, Stephanie and Graham, John D and Hetherington, John and Hughes, Robert and Laing, Robert and Mckinna, Fiona and Mclaren, Duncan B and O 'sullivan, Joe M and Parikh, Omi and Peedell, Clive and Protheroe, Andrew and Robinson, Angus J and Srihari, Narayanan and Srinivasan, Rajaguru and Staff, John and Sundar, Santhanam and Tolan, Shaun and Tsang, David and Wagstaff, John and Parmar, Mahesh K B},
  year = {2015},
  keywords = {MAMS},
  file = {/Users/k/Zotero/storage/F72ZYXGT/James et al. - 2015 - Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPE.pdf}
}

@article{Monahan1997,
  title = {Spherical-{{Radial Integration Rules}} for {{Bayesian Computation}}},
  volume = {92},
  number = {438},
  journal = {Journal of the American Statistical Association},
  author = {Monahan, John and Genz, Alan},
  year = {1997},
  keywords = {importance,monte carlo,NumericalIntegration,randomized numerical},
  pages = {664-674},
  file = {/Users/k/Zotero/storage/2AHS3Z24/Monahan, Genz - 1997 - Spherical-Radial Integration Rules for Bayesian Computation.pdf}
}

@article{Ludbrook2013,
  title = {Should We Use One-Sided or Two-Sided {{P}} Values in Tests of Significance?},
  volume = {40},
  issn = {03051870},
  doi = {10.1111/1440-1681.12086},
  number = {6},
  journal = {Clinical and Experimental Pharmacology and Physiology},
  author = {Ludbrook, John},
  year = {2013},
  keywords = {11,and new zealand,con fi dence interval,fisher,from a google scholar,google scholar,journal of surgery over,lehmann,neyman,p values were used,pearson,search of the australian,Stats,the decade 2002,type iii error},
  pages = {357-361},
  file = {/Users/k/Zotero/storage/VVZGCIGA/Ludbrook - 2013 - Should we use one-sided or two-sided P values in tests of significance.pdf;/Users/k/Zotero/storage/YXL92RCP/Ludbrook - 2013 - Should we use one-sided or two-sided P values in tests of significance.pdf}
}

@article{Zukin2013,
  title = {Randomized Phase {{III}} Trial of Single-Agent Pemetrexed versus Carboplatin and Pemetrexed in Patients with Advanced Non-Small-Cell Lung Cancer and {{Eastern Cooperative Oncology Group}} Performance Status of 2},
  volume = {31},
  issn = {0732183X},
  doi = {10.1200/JCO.2012.48.1911},
  abstract = {PURPOSETo compare single-agent pemetrexed (P) versus the combination of carboplatin and pemetrexed (CP) in first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC) with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2. PATIENTS AND METHODSIn a multicenter phase III randomized trial, patients with advanced NSCLC, ECOG PS of 2, any histology at first and later amended to nonsquamous only, no prior chemotherapy, and adequate organ function were randomly assigned to P alone (500 mg/m(2)) or CP (area under the curve of 5 and 500 mg/m(2), respectively) administered every 3 weeks for a total of four cycles. The primary end point was overall survival (OS).ResultsA total of 205 eligible patients were enrolled from eight centers in Brazil and one in the United States from April 2008 to July 2011. The response rates were 10.3\% for P and 23.8\% for CP (P = .032). In the intent-to-treat population, the median PFS was 2.8 months for P and 5.8 months for CP (hazard ratio [HR], 0.46; 95\% CI, 0.35 to 0.63; P $<$ .001), and the median OS was 5.3 months for P and 9.3 months for CP (HR, 0.62; 95\% CI, 0.46 to 0.83; P = .001). One-year survival rates were 21.9\% and 40.1\%, respectively. Similar results were seen when patients with squamous disease were excluded from the analysis. Anemia (grade 3, 3.9\%; grade 4, 11.7\%) and neutropenia (grade 3, 1\%; grade 4, 6.8\%) were more frequent with CP. There were four treatment-related deaths in the CP arm. CONCLUSIONCombination chemotherapy with CP significantly improves survival in patients with advanced NSCLC and ECOG PS of 2.},
  number = {23},
  journal = {Journal of Clinical Oncology},
  author = {Zukin, Mauro and Barrios, Carlos H. and Pereira, Jose Rodrigues and Ribeiro, Ronaldo De Albuquerque and Beato, Carlos Augusto De Mendon{\c c}a and Do Nascimento, Yeni Neron and Murad, Andre and a. Franke, Fabio and Precivale, Maristela and Araujo, Luiz Henrique De Lima and Baldotto, Clarissa Serodio Da Rocha and Vieira, Fernando Meton and a. Small, Isabele and Ferreira, Carlos G. and Lilenbaum, Rogerio C.},
  year = {2013},
  keywords = {NSCLC,PS2},
  pages = {2849-2853},
  file = {/Users/k/Zotero/storage/KDVA8PE3/Zukin et al. - 2013 - Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced.pdf;/Users/k/Zotero/storage/MECX83RZ/Zukin et al. - 2013 - Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanc(2).pdf;/Users/k/Zotero/storage/TD5ITQVK/Zukin et al. - 2013 - Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced.pdf},
  pmid = {23775961}
}

@article{Bosch2015,
  title = {Ibrutinib in {{CLL}}: 2 Sides of the Same Coin},
  volume = {126},
  issn = {0006-4971},
  doi = {10.1182/blood-2015-09-670653},
  number = {19},
  journal = {Blood},
  author = {Bosch, F. and Abrisqueta, P.},
  year = {2015},
  keywords = {CLL,Ibrutinib},
  pages = {2173-2174},
  file = {/Users/k/Zotero/storage/BIPVT3VU/Bosch, Abrisqueta - 2015 - Ibrutinib in CLL 2 sides of the same coin.pdf;/Users/k/Zotero/storage/MEMDEG7U/Bosch, Abrisqueta - 2015 - Ibrutinib in CLL 2 sides of the same coin.pdf},
  pmid = {26542251}
}

@article{Antoniou2015a,
  title = {Evaluating {{Statistical Characteristics}} of {{Biomarker}}-{{Guided Trial Designs Personalized Medicine}}},
  author = {Antoniou, Miranta},
  year = {2015},
  keywords = {Biomarkers,biomarkers},
  file = {/Users/k/Zotero/storage/CS6RQBCX/Antoniou - 2015 - Evaluating Statistical Characteristics of Biomarker-Guided Trial Designs Personalized Medicine.pdf;/Users/k/Zotero/storage/U2MUNSSK/Antoniou - 2015 - Evaluating Statistical Characteristics of Biomarker-Guided Trial Designs Personalized Medicine.pdf;/Users/k/Zotero/storage/ZWMBM989/Antoniou - 2015 - Evaluating Statistical Characteristics of Biomarker-Guided Trial Designs Personalized Medicine.pdf}
}

@article{Buyse2013,
  title = {Omics-Based Clinical Trial Designs},
  issn = {1040-8746},
  doi = {10.1097/CCO.0b013e32835ff2fe},
  journal = {Current Opinion in Oncology},
  author = {Buyse, Marc and Michiels, Stefan},
  year = {2013},
  keywords = {predictive biomarker,Genomics,clinical trials,prognostic biomarker,signature,genomics},
  pages = {1},
  file = {/Users/k/Zotero/storage/3UH2KAJD/Buyse, Michiels - 2013 - Omics-based clinical trial designs.pdf;/Users/k/Zotero/storage/R7PD9WPX/Buyse, Michiels - 2013 - Omics-based clinical trial designs.pdf}
}

@article{Hayes2015,
  title = {Lessons for Tumor Biomarker Trials: Vicious Cycles, Scientific Method \& Developing Guidelines.},
  volume = {15},
  issn = {1744-8352 (Electronic)},
  doi = {10.1586/14737159.2015.991893},
  abstract = {Interview with Daniel Hayes, by Claire Raison (Commissioning Editor) Daniel F Hayes, M.D. is the Stuart A Padnos Professor of Breast Cancer Research and co-Director of the Breast Oncology Program at the University of Michigan Comprehensive Cancer Center (Ann Arbor, MI, USA). Dr Hayes has extensive experience in clinical and translational breast cancer biomarker research, and in drug development and clinical trials. Around 30 years ago, he led the discovery of the circulating breast tumor biomarker, CA15-3, which started his career into further tumor biomarker work. The main thrust of his work since then has been in clinical trials, tumor biomarkers and trying to integrate the two. Dr Hayes is Chair of the Correlative Sciences Committee of the North American Breast Cancer Group (now called the Breast Cancer Steering Committee), and co-chairs the Expert Panel for Tumor Biomarker Practice Guidelines for the American Society of Clinical Oncology.},
  number = {2},
  journal = {Expert review of molecular diagnostics},
  author = {Hayes, Daniel and Raison, Claire},
  year = {2015},
  keywords = {Biomarkers,biomarkers},
  pages = {165-169},
  file = {/Users/k/Zotero/storage/QE9EMNMS/Hayes, Raison - 2015 - Lessons for tumor biomarker trials vicious cycles, scientific method & developing guidelines.pdf},
  pmid = {25548983}
}

@article{Buyse2011,
  title = {Integrating Biomarkers in Clinical Trials},
  volume = {11},
  issn = {1473-7159},
  doi = {10.1586/ERM.10.120},
  abstract = {Clinical trials have revolutionized medicine by providing reliable evidence on the efficacy and safety of new treatments. Until recently, clini-cal trials were designed and analyzed under the assumption that the effects of treatment were broadly similar in different individuals, and hence the goal of the clinical trial was primar-ily to provide precise and unbiased estimates of these common effects. Today, the advent of molecular biology has modified the funda mental tenet that the effect of treatment varies only ran-domly from patient to patient. There are indeed increasing numbers of treatments (especially targeted agents) whose effects vary widely as a function of individual molecular characteristics. When these characteristics are known early on in the course of developing of new treatments, clinical trials can be designed to target only those patients who are expected to benefit. However, more commonly, the exact molecular character-istics that drive a patient's response to a specific treatment are unknown and might only be dis-covered during the clinical development of the treatment or indeed following its approval. This fact has profound implications for clinical trials; it may indeed revolutionize the way in which tri-als are planned and executed [1\textendash{}3]. The purposes of this article are, first, to discuss the ways in which biomarkers (including, but not limited to, molecular characteristics) are validated in clini-cal trials, and second, to consider how they can be incorporated into clinical trial designs with the goal of optimizing the use of new therapies in biomarker-defined subgroups of patients. Our examples all come from the field of oncology, where efforts to develop new methodologies for clinical research have been most intense, but fur-ther examples abound in the other therapeutic areas [4]. We will focus our discussion on statisti-cal issues, leaving aside practical considerations related to the bio markers themselves, such as their accessibility in specific tissues (e.g., in fresh, frozen or formalin-fixed paraffin-embedded tis-sue) or the ease and reliability of their quantifica-tion (e.g., through reverse-transcriptase PCR or microarray), all of which greatly contribute to their potential for use in clinical practice.},
  number = {2},
  journal = {Expert Review of Molecular Diagnostics2},
  author = {Buyse, Marc and Michiels, Stefan and Sargent, Daniel J and Grothey, Axel and Matheson, Alastair and {de Gramont}, Aimery},
  year = {2011},
  keywords = {Biomarkers,biomarkers},
  pages = {171-182},
  file = {/Users/k/Zotero/storage/FDM5RJEU/Buyse et al. - 2011 - Integrating biomarkers in clinical trials.pdf}
}

@article{Middleton2015,
  title = {The {{National Lung Matrix Trial}}: Translating the Biology of Stratification in Advanced Non-Small-Cell Lung Cancer},
  issn = {0923-7534},
  doi = {10.1093/annonc/mdv394},
  journal = {Annals of Oncology},
  author = {Middleton, G. and Crack, L. R. and Popat, S. and Swanton, C. and Hollingsworth, S. J. and Buller, R. and Walker, I. and Carr, T. H. and Wherton, D. and Billingham, L. J.},
  year = {2015},
  keywords = {Adaptive trial design,National Lung Matrix Trial,Non-small-cell lung cancer,Stratified medicine,Umbrella Trial,strati fi ed medicine,adaptive trial design,national lung matrix trial,non-small-cell lung cancer,umbrella trial},
  pages = {mdv394},
  file = {/Users/k/Zotero/storage/29F6VGDM/Middleton et al. - 2015 - The National Lung Matrix Trial translating the biology of stratification in advanced non-small-cell lung cance.pdf;/Users/k/Zotero/storage/9469VFLQ/Middleton et al. - 2015 - The National Lung Matrix Trial Translating the biology of stratification in advanced non-small-cell lung ca(2).pdf;/Users/k/Zotero/storage/NZTDE59T/Middleton et al. - 2015 - The National Lung Matrix Trial translating the biology of stratification in advanced non-small-cell lung cance.pdf}
}

@article{Senchenkov2007,
  title = {Predictors of {{Survival}} and {{Recurrence}} in the {{Surgical Treatment}} of {{Merkel Cell Carcinoma}} of the {{Extremities}}},
  volume = {95},
  doi = {10.1002/jso},
  number = {3},
  journal = {Journal of surgical oncology},
  author = {Senchenkov, Alex and Barnes, Sunni and Moran, Steven},
  year = {2007},
  keywords = {MCC},
  pages = {148-155},
  file = {/Users/k/Zotero/storage/98W25SF3/Senchenkov, Barnes, Moran - 2007 - Predictors of Survival and Recurrence in the Surgical Treatment of Merkel Cell Carcinoma of the Extre.pdf;/Users/k/Zotero/storage/FUZ8TGK4/Senchenkov, Barnes, Moran - 2007 - Predictors of Survival and Recurrence in the Surgical Treatment of Merkel Cell Carcinoma of the Extre.pdf},
  pmid = {17323329}
}

@article{Harrington2014,
  title = {Outcomes of {{Merkel Cell Carcinoma Treated}} with {{Radiotherapy}} without {{Radical Surgical Excision}}},
  volume = {21},
  issn = {1068-9265},
  doi = {10.1245/s10434-014-3757-8},
  number = {11},
  journal = {Annals of Surgical Oncology},
  author = {Harrington, Chris and Kwan, Winkle},
  year = {2014},
  keywords = {MCC},
  pages = {3401-3405},
  file = {/Users/k/Zotero/storage/AZB3WBZA/Harrington, Kwan - 2014 - Outcomes of Merkel Cell Carcinoma Treated with Radiotherapy without Radical Surgical Excision.pdf;/Users/k/Zotero/storage/YR2ARUKW/Harrington, Kwan - 2014 - Outcomes of Merkel Cell Carcinoma Treated with Radiotherapy without Radical Surgical Excision.pdf}
}

@article{Pape2011,
  title = {Radiotherapy Alone for {{Merkel}} Cell Carcinoma: {{A}} Comparative and Retrospective Study of 25 Patients},
  volume = {65},
  issn = {01909622},
  doi = {10.1016/j.jaad.2010.07.043},
  abstract = {Background: Merkel cell carcinoma (MCC) is a rare skin cancer. Cumulative data from retrospective series support the notion that benefits are obtained by both wide excision and adjuvant radiation therapy. However, surgery may be difficult to perform with tumors located in the head and neck region and/or in elderly patients with comorbidities incompatible with general anesthesia. Objective: We assessed the benefit of treating MCC exclusively with radiation when conventional treatment (surgery followed by radiotherapy) is not possible. Methods: A total of 25 patients with primary MCC were treated at our institution exclusively with radiotherapy. Because there is no consensus about this specific approach, we compared the recurrence rate of the 25 patients receiving radiotherapy alone with that of 25 patients who received conventional treatment at our institution. Results: The median follow-up periods were 3 years (range: 5 months-11 years) for the group receiving only radiotherapy (group 1) and 9 years (range: 12 months-16 years) for the conventional therapy group (group 2). No local relapses were observed, but two locoregional relapses were observed in group 1, and 4 in group 2. No statistical differences were found in overall and disease-free survival between the two groups of patients. Limitations: The limitation of this study is its retrospective nature. Conclusions: This study confirms the results of our previous research demonstrating that it is possible to treat inoperable MCC exclusively with radiotherapy to obtain an outcome similar to that which is achievable with conventional treatment. ?? 2010 by the American Academy of Dermatology, Inc.},
  number = {5},
  journal = {Journal of the American Academy of Dermatology},
  author = {Pape, Emeline and Rezvoy, Nicolas and Penel, Nicolas and Salleron, Julia and Martinot, Veronique and Guerreschi, Pierre and Dziwniel, Veronique and Darras, Sophie and Mirabel, Xavier and Mortier, Laurent},
  year = {2011},
  keywords = {MCC,Prognosis,inoperable patient,Merkel cell carcinoma,neuroendocrine tumor,radiation therapy,skin tumor,prognosis},
  pages = {983-990},
  file = {/Users/k/Zotero/storage/J295KZK8/Pape et al. - 2011 - Radiotherapy alone for Merkel cell carcinoma A comparative and retrospective study of 25 patients.pdf;/Users/k/Zotero/storage/JK4XPFF4/Pape et al. - 2011 - Radiotherapy alone for Merkel cell carcinoma A comparative and retrospective study of 25 patients.pdf},
  pmid = {21641081}
}

@article{Allen2005,
  title = {Merkel {{Cell Carcinoma}}: {{Prognosis}} and {{Treatment}} of {{Patients From}} a {{Single Institution}}},
  volume = {23},
  issn = {0732-183X},
  doi = {10.1200/JCO.2005.02.329},
  number = {10},
  journal = {Journal of Clinical Oncology},
  author = {Allen, P. J.},
  year = {2005},
  keywords = {MCC},
  pages = {2300-2309},
  file = {/Users/k/Zotero/storage/XPACPXX4/Allen - 2005 - Merkel Cell Carcinoma Prognosis and Treatment of Patients From a Single Institution.pdf;/Users/k/Zotero/storage/YBRN9PRV/Allen - 2005 - Merkel Cell Carcinoma Prognosis and Treatment of Patients From a Single Institution.pdf}
}

@article{Lewis2006,
  title = {Adjuvant Local Irradiation for {{Merkel}} Cell Carcinoma.},
  volume = {142},
  issn = {00933619},
  doi = {10.1016/S0093-3619(08)70612-9},
  abstract = {OBJECTIVES: To determine the effect of adjuvant local irradiation on (1) disease recurrence and (2) survival rates in Merkel cell carcinoma (MCC). DATA SOURCES: An Ovid MEDLINE search (January 1966-May 26, 2004) was performed using the following criteria: group 1, "Merkel cell OR trabecular OR neuroendocrine skin OR APUDoma skin OR primary small cell skin OR primary undifferentiated skin OR endocrine skin OR neuroepithelial" AND group 2, "carcinoma OR tumor OR cancer" with mapping modifiers "-title, -abstract, -keyword, -subject heading." The search yielded 843 citations. STUDY SELECTION: The Ovid set was then searched using the following criteria: "surgery OR radiation OR radiotherapy," which yielded 242 discrete citations. Reports from all 242 citations were reviewed. For the remaining 601 citations, abstracts (when available) were reviewed to assess the level of relevance for potential inclusion; reports from 63 of these citations were reviewed. An additional 28 secondary references were reviewed, for a total of 333 reports. DATA EXTRACTION: The following criteria for inclusion were applied to each potential patient: (1) a histopathologic diagnosis of MCC; (2) a single, primary tumor arising on the skin, for which (3) the primary treatment was surgical excision (local excision, wide excision, or Mohs surgery) with or without the use of adjuvant irradiation (to the tumor bed); (4) following surgery, negative (clear) surgical margins were obtained; (5) during the postoperative follow-up period, disease recurrence, progression, and survival and/or duration of event-free interval was documented with (6) a minimum follow-up of 1 month. A total of 1254 patients were included in the analysis. RESULTS: Statistically significant reductions in local (hazard ratio [HR], 0.27; P $<$ .001) and regional (HR, 0.34; P $<$ .001) recurrence were observed among patients treated with combination therapy compared with surgery alone. Similar rates of distant metastasis were observed between treatment groups (HR, 0.79; P = .31). Overall survival rates were 87\% (1 year) and 49\% (5 years). Cause-specific survival rates were 90\% (1 year) and 62\% (5 year). In general, differences in overall (HR, 0.78; P = .16) and cause-specific (due to MCC: HR, 0.72; P = .14) survival rates between treatment groups did not reach statistical significance. A subgroup analysis that excluded single-patient case reports and studies of only 1 treatment group revealed a significant overall (HR, 0.63; P = .02) and cause-specific (HR, 0.62; P = .04) survival advantage after treatment with combination therapy. CONCLUSIONS: Surgery plus local adjuvant irradiation was associated with significantly lower rates of local and regional recurrence of MCC than surgery alone. Prospective investigation is needed to clarify the presence of a survival benefit from combination therapy.},
  number = {6},
  journal = {Archives of dermatology},
  author = {Lewis, Kevan G and a Weinstock, Martin and Weaver, Amy L and Otley, Clark C},
  year = {2006},
  keywords = {MCC},
  pages = {693-700},
  file = {/Users/k/Zotero/storage/9DT7I4FQ/Lewis et al. - 2006 - Adjuvant local irradiation for Merkel cell carcinoma.pdf;/Users/k/Zotero/storage/BXBRJU9E/Lewis et al. - 2006 - Adjuvant local irradiation for Merkel cell carcinoma.pdf},
  pmid = {16785371}
}

@article{Paoletti2015,
  title = {Statistical Controversies in Clinical Research: Requiem for the 3 + 3 Design for Phase {{I}} Trials},
  volume = {26},
  issn = {0923-7534},
  doi = {10.1093/annonc/mdv266},
  number = {9},
  journal = {Annals of Oncology},
  author = {Paoletti, X. and Ezzalfani, M. and Le Tourneau, C.},
  year = {2015},
  keywords = {Continual reassessment method,Dose finding,efficiency,targeted agents,continual reassessment method,dose finding,Anti3+3},
  pages = {1808-1812},
  file = {/Users/k/Zotero/storage/FQNN874B/Paoletti, Ezzalfani, Le Tourneau - 2015 - Statistical controversies in clinical research requiem for the 3 3 design for phase I trials.pdf}
}

@article{Taylor2009,
  title = {The Use of Surrogate Outcomes in Model-Based Cost-Effectiveness Analyses: A Survey of {{UK Health Technology Assessment}} Reports},
  volume = {13},
  issn = {1366-5278},
  doi = {10.3310/hta13080},
  number = {8},
  journal = {Health Technology Assessment},
  author = {Taylor, R and Elston, J},
  year = {2009},
  keywords = {SurrogateOutcomes,COST-EFFECTIVENESS-MODEL,FINAL-OUTCOME,HEALTH-TECHNOLOGY-ASSESSMENT,SURROGATE-OUTCOME},
  file = {/Users/k/Zotero/storage/KHZZWERW/Taylor, Elston - 2009 - The use of surrogate outcomes in model-based cost-effectiveness analyses a survey of UK Health Technology Assess.pdf;/Users/k/Zotero/storage/SLTTTETY/Taylor, Elston - 2009 - The use of surrogate outcomes in model-based cost-effectiveness analyses a survey of UK Health Technology Assess.pdf}
}

@article{Ciani2013,
  title = {Comparison of Treatment Effect Sizes Associated with Surrogate and Final Patient Relevant Outcomes in Randomised Controlled Trials: Meta-Epidemiological Study},
  volume = {346},
  issn = {1756-1833},
  doi = {10.1136/bmj.f457},
  number = {jan29 1},
  journal = {Bmj},
  author = {Ciani, O. and Buyse, M. and Garside, R. and Pavey, T. and Stein, K. and Sterne, J. a. C. and Taylor, R. S.},
  year = {2013},
  keywords = {SurrogateOutcomes},
  pages = {f457-f457},
  file = {/Users/k/Zotero/storage/F54T93TI/Ciani et al. - 2013 - Comparison of treatment effect sizes associated with surrogate and final patient relevant outcomes in randomised c.pdf;/Users/k/Zotero/storage/Z42ERFVW/Ciani et al. - 2013 - Comparison of treatment effect sizes associated with surrogate and final patient relevant outcomes in randomised c.pdf}
}

@article{Garrido2009,
  title = {Surrogate Outcomes in Health Technology Assessment: {{An}} International Comparison},
  volume = {25},
  issn = {0266-4623},
  doi = {10.1017/S0266462309990213},
  number = {03},
  journal = {International Journal of Technology Assessment in Health Care},
  author = {Garrido, Marcial Velasco and Mangiapane, Sandra},
  year = {2009},
  keywords = {Biological Markers,Intermedia,intermediate outcomes,outcome,Surrogate outcomes,biological markers,surrogate outcomes,Surrogate outcomes; Biological Markers; Intermedia},
  pages = {315},
  file = {/Users/k/Zotero/storage/MB2FMBIM/Garrido, Mangiapane - 2009 - Surrogate outcomes in health technology assessment An international comparison.pdf;/Users/k/Zotero/storage/Z753AEAA/Garrido, Mangiapane - 2009 - Surrogate outcomes in health technology assessment An international comparison.pdf}
}

@article{Topalian2012,
  title = {Safety, {{Activity}}, and {{Immune Correlates}} of {{Anti}}\textendash{{PD}}-1 {{Antibody}} in {{Cancer}}},
  journal = {The New England journal of medicineNew},
  author = {Suzanne L. Topalian, M.D. and F. Stephen Hodi, M.D. and Julie R. Brahmer, M.D. and Scott N. Gettinger, M.D. and David C. Smith, M.D. and David F. McDermott, M.D. and John D. Powderly, M.D. and Richard D. Carvajal, M.D. and Jeffrey A. Sosman, M.D. and Michael B. Atkins, M.D. and Philip D. Leming, M.D. and David R. Spigel, M.D. and Scott J. Antonia, M.D., Ph.D., Leora Horn, M.D. and Charles G. Drake, M.D., Ph.D., Drew M. Pardoll, M.D., Ph.D., Lieping Chen, M.D., Ph.D., William H. Sharfman, M.D., Robert A. Anders, M.D., Ph.D., Janis M. Taube, M.D. and Tracee L. McMiller, M.S. and Haiying Xu, B.A. and Alan J. Korman, Ph.D. and {Maria Jure-Kunkel}, Ph.D. and Shruti Agrawal, Ph.D. and Daniel McDonald, M.B.A. and Georgia D. Kollia, Ph.D. and Ashok Gupta, M.D., Ph.D. and Jon M. Wigginton, M.D. and Mario Sznol, M.D.},
  year = {2012},
  keywords = {NSCLC,PD1,Nivolumab},
  pages = {2443-2454},
  file = {/Users/k/Zotero/storage/A8PNNH4D/Svensson et al. - 2011 - Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer.pdf;/Users/k/Zotero/storage/US5XT8SK/Suzanne L. Topalian et al. - 2012 - Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer.pdf}
}

@article{Dimairo2015,
  title = {Missing Steps in a Staircase: A Qualitative Study of the Perspectives of Key Stakeholders on the Use of Adaptive Designs in Confirmatory Trials},
  volume = {16},
  issn = {1745-6215},
  doi = {10.1186/s13063-015-0958-9},
  number = {1},
  journal = {Trials},
  author = {Dimairo, Munyaradzi and Boote, Jonathan and a. Julious, Steven and Nicholl, Jonathan P. and Todd, Susan},
  year = {2015},
  keywords = {clinical trials,early stopping,uk,ac,correspondence,Adaptive designs,confirmatory trials,dimairo,Flexible designs,funded trials,interim analyses,m,phase 3,publicly,Qualitative inte,qualitative interviews,sheffield,adaptive designs,Adaptive designs;Flexible designs;Qualitative inte,flexible designs},
  pages = {430},
  file = {/Users/k/Zotero/storage/BLDQGPKZ/Dimairo et al. - 2015 - Missing steps in a staircase a qualitative study of the perspectives of key stakeholders on the use of adaptive.pdf;/Users/k/Zotero/storage/DTDB2VG3/Dimairo et al. - 2015 - Missing steps in a staircase a qualitative study of the perspectives of key stakeholders on the use of adaptive.pdf}
}

@book{Spiegelhalter2004,
  title = {Bayesian {{Approaches}} to {{Clinical Trials}} and {{Helath}}-{{Care Evaluation}}},
  isbn = {0-471-49975-7},
  author = {Spiegelhalter, David J. and Abrams, Keith R. and Myles, Jonathan P.},
  year = {2004},
  keywords = {bayesian,Books,Bayesian},
  file = {/Users/k/Zotero/storage/8ZG99BAX/Spiegelhalter, Abrams, Myles - 2004 - Bayesian Approaches to Clinical Trials and Helath-Care Evaluation.pdf;/Users/k/Zotero/storage/PLTWL29P/Spiegelhalter, Abrams, Myles - 2004 - Bayesian Approaches to Clinical Trials and Helath-Care Evaluation.pdf}
}

@article{Lachin1986,
  title = {Evaluation of {{Sample Size}} and {{Power}} for {{Analyses}} of {{Survival}} with {{Allowance}} for {{Nonuniform Patient Entry}}, {{Losses}} to {{Follow}}-up, {{Noncompliance}}, and {{Stratification}}.Pdf},
  volume = {42},
  number = {3},
  journal = {Biometrics},
  author = {Lachin, John M and Foulkes, Mary A},
  year = {1986},
  keywords = {Phase III},
  pages = {507-519},
  file = {/Users/k/Zotero/storage/5UVJQX9P/Lachin, Foulkes - 1986 - Evaluation of Sample Size and Power for Analyses of Survival with Allowance for Nonuniform Patient Entry, Losse.pdf;/Users/k/Zotero/storage/KRVFXQP6/Lachin, Foulkes - 1986 - Evaluation of Sample Size and Power for Analyses of Survival with Allowance for Nonuniform Patient Entry, Losse.pdf}
}

@article{Thatcher2005,
  title = {Gefitinib plus Best Supportive Care in Previously Treated Patients with Refractory Advanced Non-Small-Cell Lung Cancer: {{Results}} from a Randomised, Placebo-Controlled, Multicentre Study ({{Iressa Survival Evaluation}} in {{Lung Cancer}})},
  volume = {366},
  issn = {01406736},
  doi = {10.1016/S0140-6736(05)67625-8},
  abstract = {Background: This placebo-controlled phase III study investigated the effect on survival of gefitinib as second-line or third-line treatment for patients with locally advanced or metastatic non-small-cell lung cancer. Methods: 1692 patients who were refractory to or intolerant of their latest chemotherapy regimen were randomly assigned in a ratio of two to one either gefitinib (250 mg/day) or placebo, plus best supportive care. The primary endpoint was survival in the overall population of patients and those with adenocarcinoma. The primary analysis of the population for survival was by intention to treat. This study has been submitted for registration with ClinicalTrials.gov, number 1839IL/709. Findings: 1129 patients were assigned gefitinib and 563 placebo. At median follow-up of 7$\cdot$2 months, median survival did not differ significantly between the groups in the overall population (5$\cdot$6 months for gefitinib and 5$\cdot$1 months for placebo; hazard ratio 0$\cdot$89 [95\% CI 0$\cdot$77-1$\cdot$02], p=0$\cdot$087) or among the 812 patients with adenocarcinoma (6$\cdot$3 months vs 5$\cdot$4 months; 0$\cdot$84 [0$\cdot$68-1$\cdot$03], p=0$\cdot$089). Preplanned subgroup analyses showed significantly longer survival in the gefitinib group than the placebo group for never-smokers (n=375; 0$\cdot$67 [0$\cdot$49-0$\cdot$92], p=0$\cdot$012; median survival 8$\cdot$9 vs 6$\cdot$1 months) and patients of Asian origin (n=342; 0$\cdot$66 [0$\cdot$48-0$\cdot$91], p=0$\cdot$01; median survival 9$\cdot$5 vs 5$\cdot$5 months). Gefitinib was well tolerated, as in previous studies. Interpretation: Treatment with gefitinib was not associated with significant improvement in survival in either coprimary population. There was pronounced heterogeneity in survival outcomes between groups of patients, with some evidence of benefit among never-smokers and patients of Asian origin.},
  number = {9496},
  journal = {Lancet},
  author = {Thatcher, Nick and Chang, Alex and Parikh, Purvish and Pereira, Jos\'e Rodrigues and Ciuleanu, Tudor and Von Pawel, Joachim and Thongprasert, Sumitra and Tan, Eng Huat and Pemberton, Kristine and Archer, Venice and Carroll, Kevin},
  year = {2005},
  pages = {1527-1537},
  file = {/Users/k/Zotero/storage/I4GMPV5L/Thatcher et al. - 2005 - Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung.pdf;/Users/k/Zotero/storage/TH2G4XZI/Thatcher et al. - 2005 - Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung.pdf},
  pmid = {16257339}
}

@article{Salter2015a,
  title = {B i o s t a t i s t i c s {{D}} e p a r t m e n t {{T}} e c h n i c a l {{R}} e p o r t {{B S T}} 2 0 1 5 - 0 0 1 {{T}} w o - {{G}} r o u p {{T}} i m e - {{T}} o - {{E}} v e n t {{C}} o n t i n u a l {{R}} e a s s e s s m e n t {{M}} e t h o d {{U}} s i n g {{L}} i k e l i h o o d {{E}} s t i m a t i o n {{A}} m b e R},
  author = {Salter, Amber and O'Quigley, J and Cutter, G and Aban, I},
  keywords = {DoseFinding,CRM},
  file = {/Users/k/Zotero/storage/PZS36KIZ/Salter et al. - Unknown - B i o s t a t i s t i c s D e p a r t m e n t T e c h n i c a l R e p o r t B S T 2 0 1 5 - 0 0 1 T w o - G r.pdf;/Users/k/Zotero/storage/SRRIF3RR/Salter et al. - Unknown - B i o s t a t i s t i c s D e p a r t m e n t T e c h n i c a l R e p o r t B S T 2 0 1 5 - 0 0 1 T w o - G r.pdf}
}

@article{OQuigley1999,
  title = {Two-Sample Continual Reassessment Method.},
  volume = {9},
  issn = {1054-3406},
  doi = {10.1081/BIP-100100998},
  abstract = {We discuss an extension of the continual reassessment method (CRM) for use in phase I dose-finding studies. The extension enables the method to be applied to two groups of patients to determine the appropriate dose levels for each group. The method takes the specification of a simple relationship between the dose-toxicity curves for the two groups and runs the CRM on the bivariate model using maximum likelihood. We prove consistency of the method under fairly weak conditions and provide several simulations to give an idea how the method works in practice. We also undertake an evaluation of its performance by considering three possible situations: The first is the two-sample CRM, which directly uses a working model for the relationship between the two groups, carrying out a single trial using this method; the second situation carries out single trials for each of the two groups separately using the original (one-sample) CRM. The third situation is the case where such heterogeneity is ignored and the two groups are pooled into a single group, again using the original (one-sample) CRM. Simulations are carried out under a large class of model misspecifications, both of the dose-toxicity relationships and of the functional form linking the groups, and are backed up by asymptotic results. Our conclusions match intuition: The first scheme gives the most favorable results when the two groups are different but share some features. When the groups are very different, the second scheme performs similarly to the first for finite sample sizes while having some advantages in terms of asymptotic efficiency. The third, as expected, gives the best results in the absence of patient heterogeneity. The two-sample method appears particularly advantageous when there may not be enough subjects in one of the subgroups for it to be feasible to carry out two trials.},
  number = {1},
  journal = {Journal of biopharmaceutical statistics},
  author = {O'Quigley, J and Shen, L Z and Gamst, A},
  year = {1999},
  keywords = {DoseFinding,CRM},
  pages = {17-44},
  file = {/Users/k/Zotero/storage/8KV5I66V/O'Quigley, Shen, Gamst - 1999 - Two-sample continual reassessment method.pdf;/Users/k/Zotero/storage/Z5WZ5W2V/O'Quigley, Shen, Gamst - 1999 - Two-sample continual reassessment method.pdf},
  pmid = {10091908}
}

@article{Murtaugh1990,
  title = {Bivariate {{Binary Models}} of {{Efficacy}} and {{Toxicity}} in {{Dose}}-{{Ranging Trials}}},
  volume = {19},
  number = {6},
  journal = {Communications in Statistics-Theory and Methods},
  author = {Murtaugh, Paul A. and Fisher, L},
  year = {1990},
  keywords = {EfficacyToxicity},
  pages = {2003-2020},
  file = {/Users/k/Zotero/storage/SIJKMC7Q/Murtaugh, Fisher - 1990 - cis-1990.pdf.pdf;/Users/k/Zotero/storage/YR3T2NEM/Murtaugh, Fisher - 1990 - Bivariate Binary Models of Efficacy and Toxicity in Dose-Ranging Trials.pdf}
}

@article{Salter2013,
  title = {Evaluating {{Approaches}} in {{Dose Finding}} for {{Two Groups Using}} the {{Time}}-to-{{Event Continual Reassessment Method}}},
  author = {Salter, Amber and Al, Et},
  year = {2013},
  keywords = {CRM,MyReviews},
  file = {/Users/k/Zotero/storage/8HQTA33V/Salter, Al - 2013 - Evaluating Approaches in Dose Finding for Two Groups Using the Time-to-Event Continual Reassessment Method.pdf;/Users/k/Zotero/storage/KHW678CJ/Salter, Al - 2013 - Evaluating Approaches in Dose Finding for Two Groups Using the Time-to-Event Continual Reassessment Method.pdf}
}

@article{Ivanova2009,
  title = {An Adaptive Design for Identifying the Dose with the Best Efficacy/Tolerability Profile with Application to a Crossover Dose-Finding Study},
  volume = {28},
  number = {15},
  journal = {Statistics in medicine},
  author = {Ivanova, Anastasia (University of North Carolina) and Liu, Ken and Snyder, Ellen and Snavely, Duane},
  year = {2009},
  keywords = {Dose finding,proof-of-concept trial,utility function,dose finding},
  pages = {1999-2011},
  file = {/Users/k/Zotero/storage/ST8NVI2W/Ivanova et al. - 2009 - An adaptive design for identifying the dose with the best efficacytolerability profile with application to a cro.pdf;/Users/k/Zotero/storage/WVITEMG4/Ivanova et al. - 2009 - An adaptive design for identifying the dose with the best efficacytolerability profile with application to a cro.pdf},
  pmid = {19455509}
}

@article{Wang2010,
  title = {Adaptive {{Bayesian}} Design for Phase {{I}} Dose-Finding Trials Using a Joint Model of Response and Toxicity.},
  volume = {20},
  issn = {1054-3406},
  doi = {10.1080/10543400903280613},
  abstract = {We present a new adaptive Bayesian method for dose-finding in phase I clinical trials based on both response and toxicity. Although clinical responses are usually rare in phase I cancer trials, molecularly targeted therapy may make clinical responses more likely. In addition, biological responses may be common. Thus responses may be frequent enough to help decide how aggressive a phase I escalation should be. The model assumes that response and toxicity events happen depending on respective dose thresholds for the individual, assuming that the thresholds jointly follow a bivariate log-normal distribution or a mixture. The design utilizes prior information about the population threshold distribution as well as accumulated data. The next dose is assigned to maximize a patient-oriented expected utility integrated over the current posterior distribution. The design is evaluated through simulation with population parameters equaling estimates from early Gleevec trials. This exercise provides evidence for the value of the use of the proposed design for future clinical trials.},
  number = {1},
  journal = {Journal of biopharmaceutical statistics},
  author = {Wang, Meihua and Day, Roger},
  year = {2010},
  keywords = {DoseFinding,EfficacyToxicity},
  pages = {125-144},
  file = {/Users/k/Zotero/storage/GZZC5VSB/Wang, Day - 2010 - Adaptive Bayesian design for phase I dose-finding trials using a joint model of response and toxicity.pdf;/Users/k/Zotero/storage/W7K6KKFA/Wang, Day - 2010 - Adaptive Bayesian design for phase I dose-finding trials using a joint model of response and toxicity.pdf},
  pmid = {20077253}
}

@article{Ivanova2003,
  title = {A {{New Dose}}-{{Finding Design}} for {{Bivariate Outcomes}}},
  volume = {59},
  issn = {0006341X},
  doi = {10.1111/j.0006-341X.2003.00115.x},
  abstract = {For some drugs, toxicity events lead to early termination of treatment before a therapeutic response is observed. That is, there are three possible outcomes: toxicity (therapeutic response unknown), therapeutic response without toxicity, and no response with no toxicity. The optimal dose is the dose that maximizes the probability of the joint event, response, and no toxicity. The optimal safe dose is the dose, from among the doses with toxicity rate less than the maximum tolerable level, that maximizes the probability of response and no toxicity. We present a new sequential design to maximize the number of subjects assigned in the neighborhood of the optimal safe dose in a dose-finding trial with two outcomes.},
  number = {4},
  journal = {Biometrics},
  author = {Ivanova, Anastasia},
  year = {2003},
  keywords = {phase i trial,dose-finding studies,Optimal dose,Random walk,Up-and-down design,Dose-finding studies,Phase I trial},
  pages = {1001-1007},
  file = {/Users/k/Zotero/storage/3KFIEEZR/Ivanova - 2003 - A New Dose-Finding Design for Bivariate Outcomes.pdf;/Users/k/Zotero/storage/EY7XG8VA/Ivanova - 2003 - A New Dose-Finding Design for Bivariate Outcomes.pdf},
  pmid = {14969479}
}

@article{Zhang2006,
  title = {An Adaptive Dose-Finding Design Incorporating Both Toxicity and Efficacy},
  volume = {25},
  issn = {02776715},
  doi = {10.1002/sim.2325},
  abstract = {Novel therapies are challenging the standards of drug development. Agents with specific biologic targets and limited toxicity require novel designs to determine doses to be taken forward into larger studies. In this paper, we describe an approach that incorporates both toxicity and efficacy data into the estimation of the biologically optimal dose of an agent in a phase I trial. The approach is based on the flexible continuation-ratio model, and uses straightforward optimal dose selection criteria. Dose selection is based on all patients treated up until that time point, using a continual reassessment method approach. Dose-outcome curves considered include monotonically increasing, monotonically decreasing, and unimodal curves. Our simulation studies demonstrate that the proposed design, which we call TriCRM, has favourable operating characteristics.},
  number = {14},
  journal = {Statistics in Medicine},
  author = {Zhang, Wei and Sargent, Daniel J. and Mandrekar, Sumithra},
  year = {2006},
  keywords = {DoseFinding,Continual reassessment method,CRM,EfficacyToxicity,Bayesian method,Continuation-ratio model,Phase I trail,Proportional odds model,Trinomial},
  pages = {2365-2383},
  file = {/Users/k/Zotero/storage/2EQQDAAC/Zhang, Sargent, Mandrekar - 2006 - An adaptive dose-finding design incorporating both toxicity and efficacy.pdf;/Users/k/Zotero/storage/XUIDSP2T/Zhang, Sargent, Mandrekar - 2006 - An adaptive dose-finding design incorporating both toxicity and efficacy.pdf},
  pmid = {16220478}
}

@article{Brutti2011,
  title = {An Extension of the Single Threshold Design for Monitoring Efficacy and Safety in Phase {{II}} Clinical Trials},
  volume = {30},
  issn = {02776715},
  doi = {10.1002/sim.4229},
  abstract = {Tan and Machin (biStat. Med. 2002; 21:1991-2012) introduce a Bayesian two-stage design for phase II clinical trials where the binary endpoint of interest is treatment efficacy. In this paper we propose an extension of their design to incorporate safety considerations. At each stage we define the treatment successful and deserving of further study if the total number of adverse events is sufficiently small and the number of responders who simultaneously do not experience any toxicity is sufficiently large. Therefore, our criterion is based on the joint posterior probability that the true overall toxicity rate and the true efficacy-and-safety rate are, respectively, smaller and larger than conveniently pre-specified target values. The optimal two-stage sample sizes are determined specifying a minimum threshold for the above-mentioned posterior probability, computed under the assumption that favorable outcomes have occurred. Besides describing the proposed design, we suggest how to construct informative prior scenarios and we also apply the reference algorithm to derive a non-informative prior distribution. Finally, some numerical results are provided and a real data application is illustrated.},
  number = {14},
  journal = {Statistics in Medicine},
  author = {Brutti, P. and Gubbiotti, S. and Sambucini, V.},
  year = {2011},
  keywords = {EfficacyToxicityPhaseII,Two-stage design,bayesian design,Binary outcomes,Multiple endpoints,Phase II clinical trials,Bayesian design},
  pages = {1648-1664},
  file = {/Users/k/Zotero/storage/E8CEF7RM/Brutti, Gubbiotti, Sambucini - 2011 - An extension of the single threshold design for monitoring efficacy and safety in phase II clinica.pdf;/Users/k/Zotero/storage/ICC7ZPFK/Brutti, Gubbiotti, Sambucini - 2011 - An extension of the single threshold design for monitoring efficacy and safety in phase II clinica.pdf},
  pmid = {21520453}
}

@article{Mandrekar2010,
  title = {Model-Based Phase {{I}} Designs Incorporating Toxicity and Efficacy for Single and Dual Agent Drug Combinations: {{Methods}} and Challenges},
  volume = {29},
  issn = {02776715},
  doi = {10.1002/sim.3706},
  abstract = {Novel therapies are challenging the standards of drug development. Agents with specific biologic targets, unknown dose-efficacy curves, and limited toxicity mandate novel designs to identify biologically optimal doses. We review two model-based designs that utilize either a proportional odds model or a continuation ratio model to identify an optimal dose of a single or two-agent combination in a Phase I setting utilizing both toxicity and efficacy data. A continual reassessment method with straightforward dose selection criterion using accumulated data from all patients treated until that time point is employed while allowing for separate toxicity and efficacy curves for each drug in a two-drug setting. The simulation studies demonstrate considerable promise, at least theoretically, in the ability of such model-based designs to identify the optimal dose. Despite such favorable operating characteristics, there are several pragmatic challenges that hinder the routine implementation of such model-based designs in practice. We review and offer practical solutions to potentially overcome some of these challenges. The acceptance and integration of these designs in practice may be quicker and easier if they are developed in concert with a clinical paradigm.},
  number = {10},
  journal = {Statistics in Medicine},
  author = {Mandrekar, Sumithra J. and Qin, Rui and Sargent, Daniel J.},
  year = {2010},
  keywords = {DoseFinding,Continual reassessment method,efficacy,toxicity,EfficacyToxicity,dose-finding,Model-based designs,Trinary outcome,Dose-finding,Efficacy,Toxicity,model-based designs},
  pages = {1077-1083},
  file = {/Users/k/Zotero/storage/333S86ED/Mandrekar, Qin, Sargent - 2010 - Model-based phase I designs incorporating toxicity and efficacy for single and dual agent drug combinat.pdf;/Users/k/Zotero/storage/6ABSI34N/Mandrekar, Qin, Sargent - 2010 - Model-based phase I designs incorporating toxicity and efficacy for single and dual agent drug combinat.pdf},
  pmid = {20419760}
}

@article{Jennison1993,
  title = {Group Sequential Tests for Bivariate Response: Interim Analyses of Clinical Trials with Both Efficacy and Safety Endpoints.},
  volume = {49},
  issn = {0006-341X},
  abstract = {We describe group sequential tests for a bivariate response. The tests are defined in terms of the two response components jointly, rather than through a single summary statistic. Such methods are appropriate when the two responses concern different aspects of a treatment; for example, one might wish to show that a new treatment is both as effective and as safe as the current standard. We present a formulation of the bivariate testing problem, introduce group sequential tests that satisfy Type I error conditions, and show how to find the sample size guaranteeing a specified power. We describe how properties of group sequential tests for bivariate normal observations can be computed by numerical integration.},
  number = {3},
  journal = {Biometrics},
  author = {Jennison, C and Turnbull, B W},
  year = {1993},
  keywords = {EfficacyToxicityPhaseII,bivariate},
  pages = {741-752},
  file = {/Users/k/Zotero/storage/8IK95KGI/Jennison, Turnbull - 1993 - Group sequential tests for bivariate response interim analyses of clinical trials with both efficacy and saf.pdf;/Users/k/Zotero/storage/VESPBQWF/Jennison, Turnbull - 1993 - Group sequential tests for bivariate response interim analyses of clinical trials with both efficacy and saf.pdf},
  pmid = {8241370}
}

@article{Conaway1995,
  title = {Bivariate Sequential Designs for Phase {{II}} Trials.},
  volume = {51},
  issn = {0006341X},
  doi = {10.2307/2532952},
  abstract = {In this paper we propose methods for designing group sequential phase II trials with two dependent binary endpoints. The emphasis is on the derivation of stopping rules for phase II trials which require the enrollment of a small number of patients. The methods are based on enumerating the exact distribution for the binary endpoints. We illustrate the methods with a recent study which required the use of group sequential design to monitor antitumor activity and toxicity.},
  number = {2},
  journal = {Biometrics},
  author = {Conaway, M R and Petroni, G R},
  year = {1995},
  keywords = {EfficacyToxicityPhaseII},
  pages = {656-664},
  file = {/Users/k/Zotero/storage/IU5X6Z2W/Conaway, Petroni - 1995 - Bivariate sequential designs for phase II trials.pdf;/Users/k/Zotero/storage/LWJ5HFFN/Conaway, Petroni - 1995 - Bivariate sequential designs for phase II trials.pdf},
  pmid = {7662852}
}

@article{Conaway1996,
  title = {Designs for Phase {{II}} Trials Allowing for a Trade-off between Response and Toxicity.},
  volume = {52},
  issn = {0006-341X},
  doi = {10.2307/2532851},
  abstract = {In this paper we propose methods for designing phase II trials that allow for a trade-off between treatment safety and antitumor activity, where safety and antitumor activity are measured as binary endpoints. The designs can be carried out either in a single stage or can be conducted in two stages, with an interim analysis to assess whether the treatment appears sufficiently safe and effective to warrant continuing. The emphasis is on the derivation of stopping rules for phase II trials that require the enrollment of a small number of patients and are based on enumerating the exact distribution of the proposed test statistic. We illustrate the methods with a recent study that required the use of a group sequential design to monitor antitumor activity and toxicity.},
  number = {4},
  journal = {Biometrics},
  author = {Conaway, M R and Petroni, G R},
  year = {1996},
  keywords = {EfficacyToxicityPhaseII},
  pages = {1375-1386},
  file = {/Users/k/Zotero/storage/7UH4SQ7Q/Conaway, Petroni - 1996 - Designs for phase II trials allowing for a trade-off between response and toxicity.pdf;/Users/k/Zotero/storage/M9VEI6BH/Conaway, Petroni - 1996 - Designs for phase II trials allowing for a trade-off between response and toxicity.pdf},
  pmid = {8962459}
}

@article{Jin2007,
  title = {Alternative Designs of Phase {{II}} Trials Considering Response and Toxicity},
  volume = {28},
  issn = {15517144},
  doi = {10.1016/j.cct.2007.03.003},
  abstract = {Phase II clinical trials in oncology are used to initially evaluate the therapeutic efficacy of a new treatment regimen. Simon's two-stage design is commonly used for such trials. However, he only focused on the "response rate", the proportion of patients experiencing tumor regression. In clinical practice, it is preferred of a sequential design to monitor antitumor activity as well as toxicity. Conaway and Petroni proposed a method for designing phase II trials on the basis of both treatment efficacy and safety, which imply an equal weighing of response and toxicity. In this paper, we developed an alternative test to cope with the trade-off between safety and efficacy. The main idea is to control for the marginal type I errors of response rate and toxicity rate separately. We provide guides on searching the stopping and rejecting regions and determination of sample size. The proposed method has advantage over other designs, including those of Conaway and Petroni's and Bryant and Day's, that it can definitely control one type I error of the interests such as treatment antitumor activity or safety and is robust against the real association parameter. Furthermore, it is conceptive intuitive, very simple to implement, and also feasible for the requirement of small sample size in a phase II trial. ?? 2007 Elsevier Inc. All rights reserved.},
  number = {4},
  journal = {Contemporary Clinical Trials},
  author = {Jin, Hua},
  year = {2007},
  keywords = {EfficacyToxicityPhaseII,Phase II clinical trial,Robust,Two-stage design,Type I error},
  pages = {525-531},
  file = {/Users/k/Zotero/storage/VHKHVJWH/Jin - 2007 - Alternative designs of phase II trials considering response and toxicity.pdf;/Users/k/Zotero/storage/XTEREM6W/Jin - 2007 - Alternative designs of phase II trials considering response and toxicity.pdf},
  pmid = {17428744}
}

@article{Bouckaert2001,
  title = {Sure Outcomes of Random Events: {{A}} Model for Clinical Trials},
  volume = {20},
  issn = {02776715},
  doi = {10.1002/sim.659},
  abstract = {We consider the outcomes of a clinical trial as determined by one, or several, possibly hidden causes. This paper proposes a statistical model that allows such a distinction of causes not only for the main, or therapeutic, effects but also for the side, or toxic, effects. More specifically, we focus on trials where the effects are naturally dichotomized, that is, where the health of a patient has improved or not, and where a specific adverse effect has occurred or not. A case study provides an example of the way this model can help to solve some problems of suspected drug toxicity. Finally, the model is shown to be a part of a hierarchy of models and the way to select a best model is investigated.},
  number = {4},
  journal = {Statistics in Medicine},
  author = {Bouckaert, A. and Mouchart, M.},
  year = {2001},
  keywords = {EfficacyToxicityPhaseII},
  pages = {521-543},
  file = {/Users/k/Zotero/storage/HAB7DKVR/Bouckaert, Mouchart - 2001 - Sure outcomes of random events A model for clinical trials.pdf;/Users/k/Zotero/storage/VML8ZVWV/Bouckaert, Mouchart - 2001 - Sure outcomes of random events A model for clinical trials.pdf},
  pmid = {11223899}
}

@article{Cook1994,
  title = {Guidelines for Monitoring Efficacy and Toxicity Responses in Clinical Trials.},
  volume = {50},
  issn = {0006-341X},
  doi = {10.2307/2533451},
  abstract = {There is currently a need for clinical trial methodology that allows formal consideration of toxicity responses. Since a complete evaluation of an experimental therapy addresses both relative efficacy and relative toxicity, general methods for handling bivariate response data are of interest. A procedure for sequentially analysing both efficacy and toxicity data is presented. The procedure is designed to allow early termination due to efficacy results, toxicity results, or both. The method is based on modified marginal sequential analyses, accounting for bivariate correlated responses and multiple analyses over time. The theory is presented in the context of normally distributed responses. Extensions to bivariate failure time data are indicated and an example from a kidney transplant study demonstrates the procedure.},
  number = {4},
  journal = {Biometrics},
  author = {Cook, R J and Farewell, V T},
  year = {1994},
  keywords = {EfficacyToxicityPhaseII},
  pages = {1146-1152},
  file = {/Users/k/Zotero/storage/6J2EPSNP/Cook, Farewell - 1994 - Guidelines for monitoring efficacy and toxicity responses in clinical trials.pdf;/Users/k/Zotero/storage/DDN5EX8K/Cook, Farewell - 1994 - Guidelines for monitoring efficacy and toxicity responses in clinical trials.pdf},
  pmid = {7786995}
}

@article{Ghebretinsae2012,
  title = {Joint Modeling of Hierarchically Clustered and Overdispersed Non-Gaussian Continuous Outcomes for Comet Assay Data},
  volume = {11},
  issn = {15391604},
  doi = {10.1002/pst.1533},
  abstract = {Multivariate longitudinal or clustered data are commonly encountered in clinical trials and toxicological studies. Typically, there is no single standard endpoint to assess the toxicity or efficacy of the compound of interest, but co-primary endpoints are available to assess the toxic effects or the working of the compound. Modeling the responses jointly is thus appealing to draw overall inferences using all responses and to capture the association among the responses. Non-Gaussian outcomes are often modeled univariately using exponential family models. To accommodate both the overdispersion and hierarchical structure in the data, Molenberghs et al. A family of generalized linear models for repeated measures with normal and conjugate random effects. Statistical Science 2010; 25:325-347 proposed using two separate sets of random effects. This papers considers a model for multivariate data with hierarchically clustered and overdispersed non-Gaussian data. Gamma random effect for the over-dispersion and normal random effects for the clustering in the data are being used. The two outcomes are jointly analyzed by assuming that the normal random effects for both endpoints are correlated. The association structure between the response is analytically derived. The fit of the joint model to data from a so-called comet assay are compared with the univariate analysis of the two outcomes. Copyright \textcopyright{} 2012 John Wiley \& Sons, Ltd.},
  number = {6},
  journal = {Pharmaceutical Statistics},
  author = {Ghebretinsae, Aklilu Habteab and Faes, Christel and Molenberghs, Geert and Geys, Helena and Van Der Leede, Bas Jan},
  year = {2012},
  keywords = {EfficacyToxicityPhaseII,comet assay,gamma random effect,hierarchical model,joint model,normal random effect},
  pages = {449-455},
  file = {/Users/k/Zotero/storage/FQ3SB2EB/Ghebretinsae et al. - 2012 - Joint modeling of hierarchically clustered and overdispersed non-gaussian continuous outcomes for comet ass.pdf;/Users/k/Zotero/storage/WIHH7T9P/Ghebretinsae et al. - 2012 - Joint modeling of hierarchically clustered and overdispersed non-gaussian continuous outcomes for comet ass.pdf},
  pmid = {22997130}
}

@article{Cheung2000,
  title = {Sequential Designs for Phase {{I}} Clinical Trials with Late-Onset Toxicities.},
  volume = {56},
  issn = {0006-341X},
  abstract = {Traditional designs for phase I clinical trials require each patient (or small group of patients) to be completely followed before the next patient or group is assigned. In situations such as when evaluating late-onset effects of radiation or toxicities from chemopreventive agents, this may result in trials of impractically long duration. We propose a new method, called the time-to-event continual reassessment method (TITE-CRM), that allows patients to be entered in a staggered fashion. It is an extension of the continual reassessment method (CRM; O'Quigley, Pepe, and Fisher, 1990, Biometrics 46, 33-48). We also note that this time-to-toxicity approach can be applied to extend other designs for studies of short-term toxicities. We prove that the recommended dose given by the TITE-CRM converges to the correct level under certain conditions. A simulation study shows our method's accuracy and safety are comparable with CRM's while the former takes a much shorter trial duration: a trial that would take up to 12 years to complete by the CRM could be reduced to 2-4 years by our method.},
  number = {4},
  journal = {Biometrics},
  author = {Cheung, Y K and Chappell, R},
  year = {2000},
  keywords = {DoseFinding,Continual reassessment method,CRM,TITE-CRM,phase i trial,dose limiting,late-onset toxicities,likelihood-based design,time-to-event,continual reassessment method},
  pages = {1177-1182},
  file = {/Users/k/Zotero/storage/5CKU7WF4/Cheung, Chappell - 2000 - Sequential designs for phase I clinical trials with late-onset toxicities.pdf;/Users/k/Zotero/storage/7HTGQ6VU/Cheung, Chappell - 2000 - Sequential designs for phase I clinical trials with late-onset toxicities.pdf},
  pmid = {11129476}
}

@article{Deng2014,
  title = {Bayesian Modeling and Prediction of Accrual in Multi-Regional Clinical Trials},
  issn = {0962-2802},
  doi = {10.1177/0962280214557581},
  journal = {Statistical Methods in Medical Research},
  author = {Deng, Y. and Zhang, X. and Long, Q.},
  year = {2014},
  keywords = {clinical trials,Accrual,bayesian modeling,multi-regional trials,nonhomogeneous poisson process,patient accrual},
  file = {/Users/k/Zotero/storage/YD8BYZR6/Deng, Zhang, Long - 2014 - Bayesian modeling and prediction of accrual in multi-regional clinical trials.pdf}
}

@techreport{Wason,
  title = {Supplementary Material for `` {{Using}} Continuous Data on Tumour Measurements to Improve Inference in Phase {{II}} Cancer Studies ''},
  author = {Wason, James and Seaman, Shaun R.},
  keywords = {Anti-dichotomisation},
  pages = {1-9},
  file = {/Users/k/Zotero/storage/N978A7WS/Wason, Seaman - Unknown - Supplementary material for “ Using continuous data on tumour measurements to improve inference in phase II.pdf}
}

@article{Brown2001,
  title = {Interval {{Estimation}} for a {{Binomial Proportion}}},
  volume = {16},
  issn = {0883-4237},
  doi = {10.1214/ss/1009213286},
  abstract = {We revisit the problem of interval estimation of a binomial proportion. The erratic behavior of the coverage probability of the stan- dard Wald confidence interval has previously been remarked on in the literature (Blyth and Still, Agresti and Coull, Santner and others). We begin by showing that the chaotic coverage properties of the Wald inter- val are far more persistent than is appreciated. Furthermore, common textbook prescriptions regarding its safety are misleading and defective in several respects and cannot be trusted. This leads us to consideration of alternative intervals. A number of natural alternatives are presented, each with its motivation and con- text. Each interval is examined for its coverage probability and its length. Based on this analysis, we recommend the Wilson interval or the equal- tailed Jeffreys prior interval for small n and the interval suggested in Agresti and Coull for larger n. We also provide an additional frequentist justification for use of the Jeffreys interval},
  number = {2},
  journal = {Statistical Science},
  author = {Brown, Lawrence D. and Cai, T. Tony and DasGupta, Anirban},
  year = {2001},
  keywords = {Bayes,and phrases,binomial distribution,BinomialConfidenceInterval,confidence,coverage probability,edgeworth expansion,expected length,intervals,jeffreys prior,normal approximation,posterior,bayes},
  pages = {101-133},
  file = {/Users/k/Zotero/storage/4LCCLVBC/Brown, Cai, DasGupta - 2001 - Interval Estimation for a Binomial Proportion.pdf;/Users/k/Zotero/storage/QMQ7BGH7/Brown, Cai, DasGupta - 2001 - Interval Estimation for a Binomial Proportion.pdf},
  pmid = {17566141}
}

@article{Souers2013,
  title = {{{ABT}}-199, a Potent and Selective {{BCL}}-2 Inhibitor, Achieves Antitumor Activity While Sparing Platelets.},
  volume = {19},
  issn = {1546-170X},
  doi = {10.1038/nm.3048},
  abstract = {Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-X(L) inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers.},
  number = {2},
  journal = {Nature medicine},
  author = {Souers, Andrew J and Leverson, Joel D and Boghaert, Erwin R and Ackler, Scott L and Catron, Nathaniel D and Chen, Jun and Dayton, Brian D and Ding, Hong and Enschede, Sari H and Fairbrother, Wayne J and Huang, David C S and Hymowitz, Sarah G and Jin, Sha and Khaw, Seong Lin and Kovar, Peter J and Lam, Lloyd T and Lee, Jackie and Maecker, Heather L and Marsh, Kennan C and Mason, Kylie D and Mitten, Michael J and Nimmer, Paul M and Oleksijew, Anatol and Park, Chang H and Park, Cheol-Min and Phillips, Darren C and Roberts, Andrew W and Sampath, Deepak and Seymour, John F and Smith, Morey L and Sullivan, Gerard M and Tahir, Stephen K and Tse, Chris and Wendt, Michael D and Xiao, Yu and Xue, John C and Zhang, Haichao and a Humerickhouse, Rod and Rosenberg, Saul H and Elmore, Steven W},
  year = {2013},
  keywords = {Female,Humans,CLL,Antineoplastic Agents,Antineoplastic Agents: therapeutic use,BCL-2,ABT199,Aniline Compounds,Aniline Compounds: pharmacology,Animals,Antineoplastic Agents: pharmacology,Apoptosis,Apoptosis: drug effects,bcl-X Protein,bcl-X Protein: antagonists \& inhibitors,Bicyclo Compounds,Blood Platelets,Blood Platelets: drug effects,Cell Survival,Cell Survival: drug effects,Dogs,HeLa Cells,Hematologic Neoplasms,Hematologic Neoplasms: drug therapy,Heterocyclic,Heterocyclic: pharmacology,Mice,Proto-Oncogene Proteins c-bcl-2,Proto-Oncogene Proteins c-bcl-2: antagonists \& inh,Proto-Oncogene Proteins c-bcl-2: chemistry,SCID,Sulfonamides,Sulfonamides: pharmacology,Tumor Burden,Xenograft Model Antitumor Assays},
  pages = {202-8},
  file = {/Users/k/Zotero/storage/BUSXNDBJ/Souers et al. - 2013 - ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets.pdf;/Users/k/Zotero/storage/X5KSC5M9/Souers et al. - 2013 - ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets.pdf},
  pmid = {23291630}
}

@article{Schnipper2015,
  title = {American {{Society}} of {{Clinical Oncology Statement}}: {{A Conceptual Framework}} to {{Assess}} the {{Value}} of {{Cancer Treatment Options}}},
  issn = {0732-183X},
  doi = {10.1200/JCO.2015.61.6706},
  journal = {Journal of Clinical Oncology},
  author = {Schnipper, L. E. and Davidson, N. E. and Wollins, D. S. and Tyne, C. and Blayney, D. W. and Blum, D. and Dicker, a. P. and a. Ganz, P. and Hoverman, J. R. and Langdon, R. and Lyman, G. H. and Meropol, N. J. and Mulvey, T. and Newcomer, L. and Peppercorn, J. and Polite, B. and Raghavan, D. and Rossi, G. and Saltz, L. and Schrag, D. and Smith, T. J. and Yu, P. P. and a. Hudis, C. and Schilsky, R. L.},
  year = {2015},
  keywords = {ASCO,ValueInCancer},
  file = {/Users/k/Zotero/storage/JSUZ8CJN/Schnipper et al. - 2015 - American Society of Clinical Oncology Statement A Conceptual Framework to Assess the Value of Cancer Treatment.pdf;/Users/k/Zotero/storage/PEPQ48GD/Schnipper et al. - 2015 - American Society of Clinical Oncology Statement A Conceptual Framework to Assess the Value of Cancer Treatment.pdf}
}

@article{Wadhwa2012,
  title = {Factors Affecting Duration of Survival after Onset of Blastic Transformation of Chronic Myeloid Leukemia {{Factors}} Affecting Duration of Survival after Onset of Blastic Transformation of Chronic Myeloid Leukemia},
  volume = {99},
  doi = {10.1182/blood.V99.7.2304},
  number = {7},
  author = {Wadhwa, Jyoti and Szydlo, Richard M and Apperley, Jane F and Chase, Andrew and Bua, Marco and Marin, David and Kanfer, Edward and Goldman, John M and Olavarria, Eduardo},
  year = {2012},
  keywords = {CML},
  pages = {2304-2309},
  file = {/Users/k/Zotero/storage/BUGECS3R/Wadhwa et al. - 2012 - Factors affecting duration of survival after onset of blastic transformation of chronic myeloid leukemia Factors.pdf;/Users/k/Zotero/storage/TC4IHEPH/Wadhwa et al. - 2012 - Factors affecting duration of survival after onset of blastic transformation of chronic myeloid leukemia Factors.pdf}
}

@article{Cortes2012,
  title = {Ponatinib in Refractory {{Philadelphia}} Chromosome-Positive Leukemias.},
  volume = {367},
  issn = {1533-4406},
  doi = {10.1056/NEJMoa1205127},
  abstract = {BACKGROUND: Resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) is frequently caused by mutations in the BCR-ABL kinase domain. Ponatinib (AP24534) is a potent oral tyrosine kinase inhibitor that blocks native and mutated BCR-ABL, including the gatekeeper mutant T315I, which is uniformly resistant to tyrosine kinase inhibitors.$\backslash$n$\backslash$nMETHODS: In this phase 1 dose-escalation study, we enrolled 81 patients with resistant hematologic cancers, including 60 with CML and 5 with Ph-positive ALL. Ponatinib was administered once daily at doses ranging from 2 to 60 mg. Median follow-up was 56 weeks (range, 2 to 140).$\backslash$n$\backslash$nRESULTS: Dose-limiting toxic effects included elevated lipase or amylase levels and pancreatitis. Common adverse events were rash, myelosuppression, and constitutional symptoms. Among Ph-positive patients, 91\% had received two or more approved tyrosine kinase inhibitors, and 51\% had received all three approved tyrosine kinase inhibitors. Of 43 patients with chronic-phase CML, 98\% had a complete hematologic response, 72\% had a major cytogenetic response, and 44\% had a major molecular response. Of 12 patients who had chronic-phase CML with the T315I mutation, 100\% had a complete hematologic response and 92\% had a major cytogenetic response. Of 13 patients with chronic-phase CML without detectable mutations, 100\% had a complete hematologic response and 62\% had a major cytogenetic response. Responses among patients with chronic-phase CML were durable. Of 22 patients with accelerated-phase or blast-phase CML or Ph-positive ALL, 36\% had a major hematologic response and 32\% had a major cytogenetic response.$\backslash$n$\backslash$nCONCLUSIONS: Ponatinib was highly active in heavily pretreated patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I mutation, other mutations, or no mutations. (Funded by Ariad Pharmaceuticals and others; ClinicalTrials.gov number, NCT00660920.).},
  number = {22},
  journal = {The New England journal of medicine},
  author = {Cortes, Jorge E and Kantarjian, Hagop and Shah, Neil P and Bixby, Dale and Mauro, Michael J and Flinn, Ian and O'Hare, Thomas and Hu, Simin and Narasimhan, Narayana I and Rivera, Victor M and Clackson, Tim and Turner, Christopher D and Haluska, Frank G and Druker, Brian J and Deininger, Michael W N and Talpaz, Moshe},
  year = {2012},
  keywords = {Adult,Female,Humans,CML,Follow-Up Studies,Fusion Proteins,Leukemia,Middle Aged,Antineoplastic Agents,bcr-abl,BCR-ABL Positive,BCR-ABL Positive:,Chronic,Myelogenous,Male,Antineoplastic Agents: administration \& dosage,Antineoplastic Agents: adverse effects,Dose-Response Relationship,Drug,80 and over,Aged,Imidazoles,Imidazoles: adverse effects,Ponatinib,Precursor Cell Lymphoblastic Leukemia-Lymphoma,Precursor Cell Lymphoblastic Leukemia-Lymphoma: dr,Pyridazines,Pyridazines: adverse effects,Amylases,Amylases: blood,Antineoplastic Agents: chemistry,bcr-abl: antagonists \& inhibitors,bcr-abl: genetics,Drug Resistance,Imidazoles: administration \& dosage,Imidazoles: chemistry,Lipase,Lipase: blood,Mutation,Neoplasm,Pancreatitis,Pancreatitis: chemically induced,Protein-Tyrosine Kinases,Protein-Tyrosine Kinases: antagonists \& inhibitors,Protein-Tyrosine Kinases: genetics,Pyridazines: administration \& dosage,Pyridazines: chemistry,Structure-Activity Relationship},
  pages = {2075-88},
  file = {/Users/k/Zotero/storage/3QVZ97PP/Cortes et al. - 2012 - Ponatinib in refractory Philadelphia chromosome-positive leukemias.pdf;/Users/k/Zotero/storage/5JNARNCW/Cortes et al. - 2012 - Ponatinib in refractory Philadelphia chromosome-positive leukemias.pdf;/Users/k/Zotero/storage/M9HGXIJI/Cortes et al. - 2012 - Ponatinib in Refractory Philadelphia Chromosome–Positive Leukemias.pdf},
  pmid = {23190221}
}

@article{Cortes2013,
  title = {A Phase 2 Trial of Ponatinib in {{Philadelphia}} Chromosome-Positive Leukemias.},
  volume = {369},
  issn = {1533-4406},
  doi = {10.1056/NEJMoa1306494},
  abstract = {BACKGROUND: Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor-refractory threonine-to-isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). METHODS: We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months. RESULTS: Among 267 patients with chronic-phase CML, 56\% had a major cytogenetic response (51\% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70\% of patients with the T315I mutation), 46\% had a complete cytogenetic response (40\% and 66\% in the two subgroups, respectively), and 34\% had a major molecular response (27\% and 56\% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91\%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55\% had a major hematologic response and 39\% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31\% had a major hematologic response and 23\% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41\% had a major hematologic response and 47\% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37\% of patients), rash (in 34\%), dry skin (in 32\%), and abdominal pain (in 22\%). Serious arterial thrombotic events were observed in 9\% of patients; these events were considered to be treatment-related in 3\%. A total of 12\% of patients discontinued treatment because of an adverse event. CONCLUSIONS: Ponatinib had significant antileukemic activity across categories of disease stage and mutation status. (Funded by Ariad Pharmaceuticals and others; PACE ClinicalTrials.gov number, NCT01207440 .).},
  number = {19},
  journal = {The New England journal of medicine},
  author = {Cortes, J E and Kim, D-W and {Pinilla-Ibarz}, J and {le Coutre}, P and Paquette, R and Chuah, C and Nicolini, F E and Apperley, J F and Khoury, H J and Talpaz, M and DiPersio, J and DeAngelo, D J and Abruzzese, E and Rea, D and Baccarani, M and M\"uller, M C and {Gambacorti-Passerini}, C and Wong, S and Lustgarten, S and Rivera, V M and Clackson, T and Turner, C D and Haluska, F G and Guilhot, F and Deininger, M W and Hochhaus, A and Hughes, T and Goldman, J M and Shah, N P and Kantarjian, H},
  year = {2013},
  keywords = {Adult,Female,Humans,CML,Leukemia,Middle Aged,BCR-ABL Positive,Chronic,Myelogenous,Male,80 and over,Adolescent,Aged,BCR-ABL Positive: drug therapy,Imidazoles,Imidazoles: adverse effects,Imidazoles: therapeutic use,Ponatinib,Precursor Cell Lymphoblastic Leukemia-Lymphoma,Precursor Cell Lymphoblastic Leukemia-Lymphoma: dr,Protein Kinase Inhibitors,Protein Kinase Inhibitors: adverse effects,Protein Kinase Inhibitors: therapeutic use,Pyridazines,Pyridazines: adverse effects,Pyridazines: therapeutic use,Thrombocytopenia,Thrombocytopenia: chemically induced,Thrombosis,Thrombosis: chemically induced,Young Adult},
  pages = {1783-96},
  file = {/Users/k/Zotero/storage/FBZDBEAV/Cortes et al. - 2013 - A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias.pdf;/Users/k/Zotero/storage/SUKNEKDA/Cortes et al. - 2013 - A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias.pdf},
  pmid = {24180494}
}

@book{Cheung2011,
  address = {New York},
  title = {Dose {{Finding}} by the {{Continual Reassessment Method}}},
  publisher = {{Chapman \& Hall / CRC Press}},
  author = {Cheung, Ying Kuen},
  year = {2011},
  keywords = {DoseFinding,CRM},
  file = {/Users/k/Zotero/storage/SEF8W28V/Cheung - 2011 - Dose Finding by the Continual Reassessment Method.pdf}
}

@article{AhnOptimal,
  title = {Optimal {{Biological Dose}} for {{Molecularly}}-{{Targeted Therapies}}},
  journal = {Wiley StatsRef: Statistics Reference Online},
  author = {Ahn, Chul and Kang, Seung-Ho and Xie, Yang}
}

@article{Babb1998,
  title = {Cancer Phase {{I}} Clinical Trials: {{Efficient}} Dose Escalation with Overdose Control},
  volume = {17},
  issn = {02776715},
  doi = {10.1002/(SICI)1097-0258(19980530)17:10<1103::AID-SIM793>3.0.CO;2-9},
  abstract = {We describe an adaptive dose escalation scheme for use in cancer phase I clinical trials. The method is fully adaptive, makes use of all the information available at the time of each dose assignment, and directly addresses the ethical need to control the probability of overdosing. It is designed to approach the maximum tolerated dose as fast as possible subject to the constraint that the predicted proportion of patients who receive an overdose does not exceed a specified value. We conducted simulations to compare the proposed method with four up-and-down designs, two stochastic approximation methods, and with a variant of the continual reassessment method. The results showed the proposed method effective as a means to control the frequency of overdosing. Relative to the continual reassessment method, our scheme overdosed a smaller proportion of patients, exhibited fewer toxicities and estimated the maximum tolerated dose with comparable accuracy. When compared to the non-parametric schemes, our method treated fewer patients at either subtherapeutic or severely toxic dose levels, treated more patients at optimal dose levels and estimated the maximum tolerated dose with smaller average bias and mean squared error. Hence, the proposed method is promising alternative to currently used cancer phase I clinical trial designs.},
  number = {10},
  journal = {Statistics in Medicine},
  author = {Babb, James and Rogatko, Andr\'e and Zacks, Shelemyahu},
  year = {1998},
  keywords = {DoseFinding},
  pages = {1103-1120},
  file = {/Users/k/Zotero/storage/ATN8HW28/Babb, Rogatko, Zacks - 1998 - Cancer phase I clinical trials Efficient dose escalation with overdose control.pdf;/Users/k/Zotero/storage/MD9WA7WM/Babb, Rogatko, Zacks - 1998 - Cancer phase I clinical trials Efficient dose escalation with overdose control.pdf},
  pmid = {9618772}
}

@article{Ji2010,
  title = {A Modified Toxicity Probability Interval Method for Dose-Finding Trials.},
  volume = {7},
  issn = {1740-7745},
  doi = {10.1177/1740774510382799},
  abstract = {Building on earlier work, the toxicity probability interval (TPI) method, we present a modified TPI (mTPI) design that is calibration-free for phase I trials.},
  number = {6},
  journal = {Clinical trials (London, England)},
  author = {Ji, Yuan and Liu, Ping and Li, Yisheng and Bekele, B Nebiyou},
  year = {2010},
  keywords = {DoseFinding},
  pages = {653-663},
  file = {/Users/k/Zotero/storage/SN8PGGPD/Ji et al. - 2010 - A modified toxicity probability interval method for dose-finding trials.pdf},
  pmid = {20935021}
}

@article{OQuigley2001,
  title = {Dose-Finding Designs for {{HIV}} Studies.},
  volume = {57},
  issn = {0006341X},
  doi = {10.1111/j.0006-341X.2001.01018.x},
  abstract = {We present a class of simple designs that can be used in early dose-finding studies in HIV. Such designs, in contrast with Phase I designs in cancer, have a lot of the Phase II flavor about them. Information on efficacy is obtained during the trial and is as important as that relating to toxicity. The designs proposed here sequentially incorporate the information obtained on viral reduction. Initial doses are given from some fixed range of dose regimens. The doses are ordered in terms of their toxic potential. At any dose, a patient can have one of three outcomes: inability to take the treatment (toxicity), ability to take the treatment but insufficient reduction in viral load (viral failure), and ability to take the treatment as well as a sufficient reduction of viral load (success). A clear goal for some class of designs would be the identification of the dose leading to the greatest percentage of successes. Under certain assumptions, which we identify and discuss, we can obtain efficient designs for this task. Under weaker, sometimes more realistic assumptions, we can still obtain designs that have good operating characteristics in identifying a level, if such a level exists, having some given or greater success rate. In the absence of such a level, the designs will come to an early closure, indicating the ineffectiveness of the new treatment.},
  number = {4},
  journal = {Biometrics},
  author = {O'Quigley, J and Hughes, M D and Fenton, T},
  year = {2001},
  keywords = {DoseFinding,clinical trials,Continual reassessment method,toxicity,EfficacyToxicity,phase ii trial,phase i trial,dose-finding studies,dose escalation,efficacy studies,hiv,continual reassessment method},
  pages = {1018-1029},
  file = {/Users/k/Zotero/storage/US5P9SXJ/O'Quigley, Hughes, Fenton - 2001 - Dose-finding designs for HIV studies.pdf},
  pmid = {11764240}
}

@article{Iasonos2008,
  title = {A Comprehensive Comparison of the Continual Reassessment Method to the Standard 3 + 3 Dose Escalation Scheme in {{Phase I}} Dose-Finding Studies.},
  volume = {5},
  issn = {1740-7745},
  doi = {10.1177/1740774508096474},
  abstract = {BACKGROUND: An extensive literature has covered the statistical properties of the Continual Reassessment Method (CRM) and the modifications of this method. While there are some applications of CRM designs in recent Phase I trials, the standard method (SM) of escalating doses after three patients with an option for an additional three patients SM remains very popular, mainly due to its simplicity. From a practical perspective, clinicians are interested in designs that can estimate the MTD using fewer patients for a fixed number of doses, or can test more dose levels for a given sample size. PURPOSE: This article compares CRM-based methods with the SM in terms of the number of patients needed to reach the MTD, total sample size required, and trial duration. METHODS: The comparisons are performed under two alternative schemes: a fixed or a varying sample approach with the implementation of a stopping rule. The stopping rule halts the trial if the confidence interval around the MTD is within a pre-specified bound. Our simulations evaluated several CRM-based methods under different scenarios by varying the number of dose levels from five to eight and the location of the true MTD. RESULTS: CRM and SM are comparable in terms of how fast they reach the MTD and the total sample size required when testing a limited number of dose levels ($<$or=5), but as the number of dose levels increases, CRM reaches the MTD in fewer patients when used with a fixed sample of 20 patients. However, a sample size of 20-25 patients is not sufficient to achieve a narrow precision around the estimated toxicity rate at the MTD. LIMITATIONS: We focused on methods with practical design features that are of interest to clinicians. However, there are several alternative CRM-based designs that are not investigated in this manuscript, and hence our results are not generalizable to other designs. CONCLUSIONS: We show that CRM-based methods are an improvement over the SM in terms of accuracy and optimal dose allocation in almost all cases, except when the true dose is among the lower levels.},
  number = {5},
  journal = {Clinical trials (London, England)},
  author = {Iasonos, Alexia and Wilton, Andrew S and Riedel, Elyn R and Seshan, Venkatraman E and Spriggs, David R},
  year = {2008},
  keywords = {README},
  pages = {465-477},
  file = {/Users/k/Zotero/storage/9GD65VQK/Iasonos et al. - 2008 - A comprehensive comparison of the continual reassessment method to the standard 3 3 dose escalation scheme in P.pdf},
  pmid = {18827039}
}

@article{Garrett-Mayer2006,
  title = {The Continual Reassessment Method for Dose-Finding Studies: A Tutorial.},
  volume = {3},
  issn = {17407745},
  doi = {10.1191/1740774506cn134oa},
  abstract = {The Continual Reassessment Method (CRM), along with other adaptive dose-finding study designs, has gained popularity since its proposal by O'Quigley. Several of the reasons it has been embraced by clinical trialists is that it tends to incur fewer toxic events, and more accurately estimate the maximum tolerated dose as compared to the standard Phase I dose escalation designs. Many variations have been published and discussed in the statistical literature, but there has not been as much practical advice for choosing design parameters and implementing the CRM. As a result, the CRM has not been as widely utilized as it could be for dose-finding studies. The goal of this paper is to provide a tutorial for those unfamiliar with the CRM who are either statisticians considering using the CRM for the first time, or investigators with some statistical background. This paper presents the original CRM, and then some of its modified versions. It also explains the specifications that define a CRM design, along with simulated examples of CRMs and standard designs, for illustration.},
  number = {1},
  journal = {Clinical trials (London, England)},
  author = {{Garrett-Mayer}, Elizabeth},
  year = {2006},
  keywords = {DoseFinding,CRM},
  pages = {57-71},
  file = {/Users/k/Zotero/storage/FANYZIHP/Garrett-Mayer - 2006 - The continual reassessment method for dose-finding studies a tutorial.pdf},
  pmid = {16539090}
}

@article{Altman2006,
  title = {Statistics {{Notes}} 52: {{The}} Cost of Dichotomising Continuous Variables},
  volume = {332},
  issn = {1468-5833},
  doi = {10.1136/bmj.332.7549.1080},
  abstract = {\#statistics},
  number = {7549},
  journal = {British Medical Journal},
  author = {Altman, Douglas G and Royston, Patrick},
  year = {2006},
  keywords = {Anti-dichotomisation,Data Interpretation,Statistical,Regression Analysis},
  pages = {1080},
  file = {/Users/k/Zotero/storage/CKUEHX7B/Altman, Royston - 2006 - Statistics Notes 52 The cost of dichotomising continuous variables.pdf},
  pmid = {16675816}
}

@article{Gajewsji2008,
  title = {Predicting Accrual in Clinical Trials with {{Bayesian}} Posterior Predictive Distributions},
  volume = {27},
  abstract = {Although sample size calculations have become an important element in the design of research projects, such methods for studies involving current status data are scarce. Here, we propose a method for calculating power and sample size for studies using current status data. This method is based on a Weibull survival model for a two-group comparison. The Weibull model allows the investigator to specify a group difference in terms of a hazards ratio or a failure time ratio. We consider exponential, Weibull and uniformly distributed censoring distributions. We base our power calculations on a parametric approach with the Wald test because it is easy for medical investigators to conceptualize and specify the required input variables. As expected, studies with current status data have substantially less power than studies with the usual right-censored failure time data. Our simulation results demonstrate the merits of these proposed power calculations.},
  journal = {Statistics in medicine},
  author = {Gajewski, Byron J. and Simon, Stephen D. and Carlson, Susan E.},
  year = {2008},
  keywords = {Accrual,bayesian,sample size,exponential,inverse gamma,prior elicitation},
  pages = {2328-2340},
  file = {/Users/k/Zotero/storage/MDNEHZMW/Gajewski, Simon, Carlson - 2008 - Predicting accrual in clinical trials with Bayesian posterior predictive distributions.pdf},
  pmid = {19455509}
}

@article{Lai2001,
  title = {Brownian Motion and Long-Term Clinical Trial Recruitment},
  volume = {93},
  doi = {10.1016/s0378-3758(00)00203-2},
  abstract = {Accurate prediction of recruitment in a clinical trial may help investigator to better allocate resources and to quickly make decision to intervene in the case of slow recruitment. In this paper, the theory of Brownian motion was used to model recruitment in a long-term clinical trial. The proposed model is illustrated using the recruitment experience of the Cholesterol and Recurrent Event (CARE) Trial. (C) 2001 Elsevier Science B.V. All rights reserved. MSG: 60G35; 60J65; 62F25; 62J05.},
  number = {1-2},
  journal = {Journal of Statistical Planning and Inference},
  author = {Lai, D J and a Moye, L and Davis, B R and Brown, L E and Sacks, F M},
  year = {2001},
  keywords = {Prediction,brownian motion,clinical trial recruitment,decision making,prediction},
  pages = {239-246},
  file = {/Users/k/Zotero/storage/XE5JVN2Q/Lai et al. - 2001 - Brownian motion and long-term clinical trial recruitment.pdf}
}

@article{OQuigley1990,
  title = {Continual Reassessment Method: A Practical Design for Phase 1 Clinical Trials in Cancer.},
  volume = {46},
  issn = {0006-341X},
  doi = {10.2307/2531628},
  abstract = {This paper looks at a new approach to the design and analysis of Phase 1 clinical trials in cancer. The basic idea and motivation behind the approach stem from an attempt to reconcile the needs of dose-finding experimentation with the ethical demands of established medical practice. It is argued that for these trials the particular shape of the dose toxicity curve is of little interest. Attention focuses rather on identifying a dose with a given targeted toxicity level and on concentrating experimentation at that which all current available evidence indicates to be the best estimate of this level. Such an approach not only makes an explicit attempt to meet ethical requirements but also enables the use of models whose only requirements are that locally (i.e., around the dose corresponding to the targeted toxicity level) they reasonably well approximate the true probability of toxic response. Although a large number of models could be contemplated, we look at a particularly simple one. Extensive simulations show the model to have real promise.},
  number = {1},
  journal = {Biometrics},
  author = {O'Quigley, J and Pepe, M and Fisher, L},
  year = {1990},
  keywords = {DoseFinding,CRM,Anti3+3},
  pages = {33-48},
  file = {/Users/k/Zotero/storage/GPTXLC3P/O'Quigley, Pepe, Fisher - 1990 - Continual reassessment method a practical design for phase 1 clinical trials in cancer.pdf},
  pmid = {2350571}
}

@article{Eisenhauer2009,
  title = {New Response Evaluation Criteria in Solid Tumours: {{Revised RECIST}} Guideline (Version 1.1)},
  volume = {45},
  issn = {09598049},
  doi = {10.1016/j.ejca.2008.10.026},
  abstract = {Background: Assessment of the change in tumour burden is an important feature of the clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response) and disease progression are useful endpoints in clinical trials. Since RECIST was published in 2000, many investigators, cooperative groups, industry and government authorities have adopted these criteria in the assessment of treatment outcomes. However, a number of questions and issues have arisen which have led to the development of a revised RECIST guideline (version 1.1). Evidence for changes, summarised in separate papers in this special issue, has come from assessment of a large data warehouse ($>$6500 patients), simulation studies and literature reviews. Highlights of revised RECIST 1.1: Major changes include: Number of lesions to be assessed: based on evidence from numerous trial databases merged into a data warehouse for analysis purposes, the number of lesions required to assess tumour burden for response determination has been reduced from a maximum of 10 to a maximum of five total (and from five to two per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes with a short axis of $\geq$15 mm are considered measurable and assessable as target lesions. The short axis measurement should be included in the sum of lesions in calculation of tumour response. Nodes that shrink to $<$10 mm short axis are considered normal. Confirmation of response is required for trials with response primary endpoint but is no longer required in randomised studies since the control arm serves as appropriate means of interpretation of data. Disease progression is clarified in several aspects: in addition to the previous definition of progression in target disease of 20\% increase in sum, a 5 mm absolute increase is now required as well to guard against over calling PD when the total sum is very small. Furthermore, there is guidance offered on what constitutes 'unequivocal progression' of non-measurable/non-target disease, a source of confusion in the original RECIST guideline. Finally, a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included. Imaging guidance: the revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions. Future work: A key question considered by the RECIST Working Group in developing RECIST 1.1 was whether it was appropriate to move from anatomic unidimensional assessment of tumour burden to either volumetric anatomical assessment or to functional assessment with PET or MRI. It was concluded that, at present, there is not sufficient standardisation or evidence to abandon anatomical assessment of tumour burden. The only exception to this is in the use of FDG-PET imaging as an adjunct to determination of progression. As is detailed in the final paper in this special issue, the use of these promising newer approaches requires appropriate clinical validation studies. \textcopyright{} 2008 Elsevier Ltd.},
  number = {2},
  journal = {European Journal of Cancer},
  author = {a. Eisenhauer, E. and Therasse, P. and Bogaerts, J. and Schwartz, L. H. and Sargent, D. and Ford, R. and Dancey, J. and Arbuck, S. and Gwyther, S. and Mooney, M. and Rubinstein, L. and Shankar, L. and Dodd, L. and Kaplan, R. and Lacombe, D. and Verweij, J.},
  year = {2009},
  keywords = {Guidelines,Response criteria,Solid tumours},
  pages = {228-247},
  file = {/Users/k/Zotero/storage/8JJSDEKA/Eisenhauer et al. - 2009 - New response evaluation criteria in solid tumours Revised RECIST guideline (version 1.1).pdf},
  pmid = {19097774}
}

@article{Yin2006,
  title = {Bayesian Dose-Finding in Phase {{I}}/{{II}} Clinical Trials Using Toxicity and Efficacy Odds Ratios},
  volume = {62},
  issn = {0006341X},
  doi = {10.1111/j.1541-0420.2006.00534.x},
  abstract = {A Bayesian adaptive design is proposed for dose-finding in phase I/II clinical trials to incorporate the bivariate outcomes, toxicity and efficacy, of a new treatment. Without specifying any parametric functional form for the drug dose-response curve, we jointly model the bivariate binary data to account for the correlation between toxicity and efficacy. After observing all the responses of each cohort of patients, the dosage for the next cohort is escalated, deescalated, or unchanged according to the proposed odds ratio criteria constructed from the posterior toxicity and efficacy probabilities. A novel class of prior distributions is proposed through logit transformations which implicitly imposes a monotonic constraint on dose toxicity probabilities and correlates the probabilities of the bivariate outcomes. We conduct simulation studies to evaluate the operating characteristics of the proposed method. Under various scenarios, the new Bayesian design based on the toxicity-efficacy odds ratio trade-offs exhibits good properties and treats most patients at the desirable dose levels. The method is illustrated with a real trial design for a breast medical oncology study.},
  number = {3},
  journal = {Biometrics},
  author = {Yin, Guosheng and Li, Yisheng and Ji, Yuan},
  year = {2006},
  keywords = {DoseFinding,bayesian adaptive design,EfficacyToxicity,Bivariate binary model,Equivalence contour,Gibbs sampling,Trade-offs,Bayesian adaptive design},
  pages = {777-787},
  file = {/Users/k/Zotero/storage/PN6WYMVV/Yin, Li, Ji - 2006 - Bayesian dose-finding in phase III clinical trials using toxicity and efficacy odds ratios.pdf},
  pmid = {16984320}
}

@article{Braun2002,
  title = {The Bivariate Continual Reassessment Method: {{Extending}} the {{CRM}} to Phase {{I}} Trials of Two Competing Outcomes},
  volume = {23},
  issn = {01972456},
  doi = {10.1016/S0197-2456(01)00205-7},
  abstract = {Traditional phase I studies find the therapeutic dose of an investigational drug based solely on toxicity and without regard to the drug's efficacy. We propose extending the continual reassessment method (CRM) to a bivariate trial design in which the maximum tolerated dose is based jointly on both toxicity and disease progression. We call our study design bCRM, for bivariate CRM, which we apply to a study of bone marrow patients seeking to find the optimal time after bone marrow transplant at which to taper immune suppression and eventually begin donor leukocyte infusions. We demonstrate through simulation that bCRM has excellent operating characteristics and compare the performance of bCRM in a bone marrow transplantation study to designs proposed by previous investigators. We also attempt to provide some direction to future investigators with regard to plausible models and distributions to use with a bivariate study design. \textcopyright{} 2002 Elsevier Science Inc. All rights reserved.},
  number = {3},
  journal = {Controlled Clinical Trials},
  author = {Braun, Thomas M.},
  year = {2002},
  keywords = {DoseFinding,Bayesian inference,Bone marrow transplant,clinical trial,Correlated binary data,CRM,EfficacyToxicity,Clinical trial},
  pages = {240-256},
  file = {/Users/k/Zotero/storage/K8UQY97E/Braun - 2002 - The bivariate continual reassessment method Extending the CRM to phase I trials of two competing outcomes.pdf},
  pmid = {12057877}
}

@article{Thall2006,
  title = {Adaptive Dose Selection Using Efficacy-Toxicity Trade-Offs: Illustrations and Practical Considerations.},
  volume = {16},
  issn = {1054-3406},
  doi = {10.1080/10543400600860394},
  abstract = {The purpose of this paper is to describe and illustrate an outcome-adaptive Bayesian procedure, proposed by Thall and Cook (2004), for assigning doses of an experimental treatment to successive cohorts of patients. The method uses elicited (efficacy, toxicity) probability pairs to construct a family of trade-off contours that are used to quantify the desirability of each dose. This provides a basis for determining a best dose for each cohort. The method combines the goals of conventional Phase I and Phase II trials, and thus may be called a "Phase I-II" design. We first give a general review of the probability model and dose-finding algorithm. We next describe an application to a trial of a biologic agent for treatment of acute myelogenous leukemia, including a computer simulation study to assess the design's average behavior. To illustrate how the method may work in practice, we present a cohort-by-cohort example of a particular trial. We close with a discussion of some practical issues that may arise during implementation.},
  number = {5},
  journal = {Journal of biopharmaceutical statistics},
  author = {Thall, PF and Cook, JD and Estey, EH},
  year = {2006},
  keywords = {DoseFinding,EfficacyToxicity},
  pages = {623-638},
  file = {/Users/k/Zotero/storage/87EU859C/Thall, Cook, Estey - 2006 - Adaptive dose selection using efficacy-toxicity trade-offs illustrations and practical considerations.pdf;/Users/k/Zotero/storage/ZVS5GCP5/Thall, Cook, Estey - 2006 - Adaptive dose selection using efficacy-toxicity trade-offs illustrations and practical considerations.pdf},
  pmid = {17037262}
}

@article{Anisimov2011,
  title = {Predictive Event Modelling in Multicenter Clinical Trials with Waiting Time to Response},
  volume = {10},
  issn = {15391604},
  doi = {10.1002/pst.525},
  abstract = {A new analytic statistical technique for predictive event modeling in ongoing multicenter clinical trials with waiting time to response is developed. It allows for the predictive mean and predictive bounds for the number of events to be constructed over time, accounting for the newly recruited patients and patients already at risk in the trial, and for different recruitment scenarios. For modeling patient recruitment, an advanced Poisson-gamma model is used, which accounts for the variation in recruitment over time, the variation in recruitment rates between different centers and the opening or closing of some centers in the future. A few models for event appearance allowing for 'recurrence', 'death' and 'lost-to-follow-up' events and using finite Markov chains in continuous time are considered. To predict the number of future events over time for an ongoing trial at some interim time, the parameters of the recruitment and event models are estimated using current data and then the predictive recruitment rates in each center are adjusted using individual data and Bayesian re-estimation. For a typical scenario (continue to recruit during some time interval, then stop recruitment and wait until a particular number of events happens), the closed-form expressions for the predictive mean and predictive bounds of the number of events at any future time point are derived under the assumptions of Markovian behavior of the event progression. The technique is efficiently applied to modeling different scenarios for some ongoing oncology trials. Case studies are considered.},
  number = {6},
  journal = {Pharmaceutical Statistics},
  author = {Anisimov, Vladimir V.},
  year = {2011},
  keywords = {Prediction,Accrual,estimation,Poisson-gamma recruitment model,Event modeling,Markov model,multicenter clinical trial,prediction},
  pages = {517-522},
  file = {/Users/k/Zotero/storage/S79WJ4ZS/Anisimov - 2011 - Predictive event modelling in multicenter clinical trials with waiting time to response.pdf},
  pmid = {22140055}
}

@article{Ying2013,
  title = {Prediction of Event Times in the {{REMATCH Trial}}.},
  volume = {10},
  issn = {1740-7753},
  doi = {10.1177/1740774512470314},
  abstract = {In clinical trials with time-to-event outcomes, it is common to design the interim analysis plan around the occurrence of designated target numbers of events. As the trial progresses, one may wish to use the accumulating data to predict the calendar times of these events as an aid to logistical planning.},
  number = {2},
  journal = {Clinical trials (London, England)},
  author = {Ying, Gui-Shuang and Heitjan, Daniel F},
  year = {2013},
  keywords = {Accrual},
  pages = {197-206},
  file = {/Users/k/Zotero/storage/QPJYJVQB/Ying, Heitjan - 2013 - Prediction of event times in the REMATCH Trial.pdf},
  pmid = {23321264}
}

@article{Zhang2012,
  title = {Modeling and Prediction of Subject Accrual and Event Times in Clinical Trials : A Systematic Review},
  issn = {1740-7745},
  doi = {10.1177/1740774512447996},
  abstract = {BACKGROUND: Modeling and prediction of subject accrual and event times in clinical trials has been a topic of considerable interest for important practical reasons. It has implications not only at the initial planning stage of a trial but also on its ongoing monitoring.$\backslash$n$\backslash$nPURPOSE: To provide a systematic view of the recent research in the field of modeling and prediction of subject accrual and event times in clinical trials.$\backslash$n$\backslash$nMETHODS: Two classes of methods for modeling and prediction of subject accrual are reviewed, namely, one that uses the Brownian motion and the other uses the Poisson process. Extensions of the accrual models in multicenter clinical trials are also discussed. Trials with survival endpoints require proper joint modeling of subject accrual and event/lost-to-follow-up (LTFU) times, the latter of which can be modeled either parametrically (e.g., exponential and Weibull) or nonparametrically.$\backslash$n$\backslash$nRESULTS: Flexible stochastic models are better suited when modeling real trials that does not follow constant underlying enrollment rate. The accrual model generally improves as center-specific information is accounted for in multicenter trials. The choice between parametric and nonparametric event models can depend on confidence on the underlying event rates.$\backslash$n$\backslash$nLIMITATIONS: All methods reviewed in event modeling assume noninformative censoring, which cannot be tested.$\backslash$n$\backslash$nCONCLUSIONS: We recommend using proper stochastic accrual models, in combination with flexible event time models when applicable, for modeling and prediction of subject enrollment and event times in clinical trials.},
  journal = {Clinical Trials},
  author = {Zhang, X. and Long, Q.},
  year = {2012},
  keywords = {Accrual},
  file = {/Users/k/Zotero/storage/A6M4682D/Zhang, Long - 2012 - Modeling and prediction of subject accrual and event times in clinical trials a systematic review.pdf},
  pmid = {22674642}
}

@article{Anisimov2011a,
  title = {Statistical {{Modeling}} of {{Clinical Trials}} ({{Recruitment}} and {{Randomization}})},
  volume = {40},
  issn = {0361-0926},
  doi = {10.1080/03610926.2011.581189},
  abstract = {This article is devoted to developing further a statistical technique for modeling patient recruitment together with randomization process in multicentre clinical trials. The analytic technique for predicting the number of patients recruited in different centers/regions for ongoing trials accounting for possible delays and closure of some centers is developed. The asymptotic properties of the recruitment in particular regions are investigated and the analysis of recruitment performance in centers/regions is provided. The approximations and predictive confidence bounds for the number of randomized patients in some region using center-stratified randomization are derived. These results are used for creating software tools for predictive patient recruitment and drug supply modeling in GlaxoSmithKline.},
  number = {19-20},
  journal = {Communications in Statistics-Theory and Methods},
  author = {Anisimov, Vladimir V},
  year = {2011},
  keywords = {Accrual},
  pages = {3684-3699},
  file = {/Users/k/Zotero/storage/5NGZYREW/Anisimov - 2011 - Statistical Modeling of Clinical Trials (Recruitment and Randomization).pdf}
}

@article{Anisimov2011b,
  title = {Effects of Unstratified and Centre-Stratified Randomization in Multi-Centre Clinical Trials},
  volume = {10},
  issn = {15391604},
  doi = {10.1002/pst.412},
  abstract = {This paper deals with the analysis of randomization effects in multi-centre clinical trials. The two randomization schemes most often used in clinical trials are considered: unstratified and centre-stratified block-permuted randomization. The prediction of the number of patients randomized to different treatment arms in different regions during the recruitment period accounting for the stochastic nature of the recruitment and effects of multiple centres is investigated. A new analytic approach using a Poisson-gamma patient recruitment model (patients arrive at different centres according to Poisson processes with rates sampled from a gamma distributed population) and its further extensions is proposed. Closed-form expressions for corresponding distributions of the predicted number of the patients randomized in different regions are derived. In the case of two treatments, the properties of the total imbalance in the number of patients on treatment arms caused by using centre-stratified randomization are investigated and for a large number of centres a normal approximation of imbalance is proved. The impact of imbalance on the power of the study is considered. It is shown that the loss of statistical power is practically negligible and can be compensated by a minor increase in sample size. The influence of patient dropout is also investigated. The impact of randomization on predicted drug supply overage is discussed.},
  number = {1},
  journal = {Pharmaceutical Statistics},
  author = {Anisimov, Vladimir V.},
  year = {2011},
  keywords = {Accrual,sample size,centre-stratified randomization,imbalance,multicentre trials,Poisson-gamma recruitment model,unstratified randomization},
  pages = {50-59},
  file = {/Users/k/Zotero/storage/TRBIWGBP/Anisimov - 2011 - Effects of unstratified and centre-stratified randomization in multi-centre clinical trials.pdf},
  pmid = {20112277}
}

@article{Anisimov2007,
  title = {Modelling, Prediction and Adaptive Adjustment of Recruitment in Multicentre Trials},
  volume = {26},
  abstract = {This paper is focused on statistical modelling, prediction and adaptive adjustment of patient recruitment in multicentre clinical trials. We consider a recruitment model, where patients arrive at different centres according to Poisson processes, with recruitment rates viewed as a sample from a gamma distribution. A statistical analysis of completed studies is provided and properties of a few types of parameter estimators are investigated analytically and using simulation. Themodel has been validated usingmany real completed trials. A statistical technique for predictive recruitment modelling for ongoing trials is developed. It allows the prediction of the remaining recruitment time together with confidence intervals using current enrolment information, and also provision of an adaptive adjustment of recruitment by calculating the number of additional centres required to accomplish a study up to a certain deadline with a pre-specified probability. Results are illustrated for different recruitment scenarios.},
  journal = {Statistics in medicine},
  author = {Anisimov, Vladimir V. and Fedorov, Valerii V.},
  year = {2007},
  keywords = {Prediction,Accrual,estimation,multicentre trial,poisson-gamma model,random recruitment,prediction},
  pages = {4958-4975},
  file = {/Users/k/Zotero/storage/952ZUPBZ/Anisimov, Fedorov - 2007 - Modelling, prediction and adaptive adjustment of recruitment in multicentre trials.pdf},
  pmid = {19455509}
}

@article{Bakhshi2011,
  title = {Modelling and Predicting Patient Recruitment in Multi-Centre Clinical Trials},
  abstract = {One of the main concerns in multi-centre clinical trials is how to enrol an adequate number of patients during a specific period of time. Accordingly, the sponsors are keen to minimise the recruitment time for cost effectiveness purposes. This research tended to concentrate on forecasting the patients' accrual time for the pre-arranged number of sample size by simulating an on-going trial. The method was to model the data from the recruitment frequency domain and apply the estimations derived from the frequency domain to predict the time domain. Whereas previous papers did not concentrate on variations of recruiting over centres, this research assumed that patient arrivals followed the Poisson process and let the parameter of the process vary as a Gamma distribution. Consequently, the Poisson-gamma mixed distribution was confirmed as the promising model of the frequency domain. Then with the help of the relationship between the Poisson process and the exponential distribution, accrual time was predicted assuming that the waiting time between patients followed the Gamma-exponential distribution. As the result of the project, a trial was simulated based on the estimated values derived from completed trials. The first part of the prediction estimated the expected average number of patients per centre per month in an on-going trial. The second part, predicted the length of time (in months) to enrol specific number of patients in the simulated trial.},
  author = {Bakhshi, Andisheh},
  year = {2011},
  keywords = {Accrual,QA Mathematics},
  file = {/Users/k/Zotero/storage/PY9P8NTI/Bakhshi - 2011 - Modelling and predicting patient recruitment in multi-centre clinical trials.pdf}
}

@article{Thall1999,
  title = {Treatment Comparisons Based on Two-Dimensional Safety and Efficacy Alternatives in Oncology Trials.},
  volume = {55},
  issn = {0006341X},
  abstract = {In addition to their desired anticancer effects, most cancer treatments may also cause transient toxicity, permanent organ damage, or death. A critical question in comparing an experimental treatment to a standard is how much increase in an adverse event rate is an acceptable trade-off for achieving a targeted improvement in efficacy, or vice versa. We consider settings where one may characterize patient outcome as a bivariate (efficacy, safety) variable and quantify treatment effect as a corresponding two-dimensional parameter. A set of target parameters, each representing a clinically meaningful improvement over the standard, are elicited from the physician. Each target is a two-dimensional generalization of the usual one-dimensional shift parameter. We define the alternative hypothesis in the two-dimensional effect space as the convex hull of the sets of parameters that are at least as desirable as each target point. The rejection region is obtained by shifting the alternative toward (0,0) to achieve a given type I error, with sample size computed to achieve a given power at the targets. The method is illustrated by application to two cancer chemotherapy trials.},
  number = {3},
  journal = {Biometrics},
  author = {Thall, P F and Cheng, S C},
  year = {1999},
  keywords = {bivariate data,cancer chemotherapy,clinical trials,hypothesis testing,safety monitoring},
  pages = {746-753},
  file = {/Users/k/Zotero/storage/47J2WU5X/Thall, Cheng - 1999 - Treatment comparisons based on two-dimensional safety and efficacy alternatives in oncology trials.pdf;/Users/k/Zotero/storage/7HDUYEFB/Thall, Cheng - 1999 - Treatment comparisons based on two-dimensional safety and efficacy alternatives in oncology trials.pdf},
  pmid = {11315002}
}

@article{Larkin2015,
  title = {Combined {{Nivolumab}} and {{Ipilimumab}} or {{Monotherapy}} in {{Untreated Melanoma}}},
  doi = {10.1056/NEJMoa1504030},
  journal = {New England Journal of Medicine},
  author = {Larkin, J and {Chiaron-Sileni}, V and Gonzalez, R and Grob, JJ and Cowey, CL and Lao, CD and Schadendorf, D and Dummer, R and Smylie, M and Rutkowski, P and Ferrucci, P F and Hill, A and Wagstaff, J and Carlino, M S and Haanen, J B and Maio, M and Rodas, I Marquez and Hodi, F S and Wolchok, J D},
  year = {2015},
  keywords = {Immunotherapy,Melanoma},
  file = {/Users/k/Zotero/storage/AZXPUQ8N/Larkin et al. - 2015 - Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.pdf;/Users/k/Zotero/storage/S9KHFSUB/Larkin et al. - 2015 - Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.pdf}
}

@article{Yap2011,
  title = {Screened Selection Design for Randomised Phase {{II}} Oncology Trials: An Example in Chronic Lymphocytic Leukaemia},
  volume = {12},
  issn = {1745-6215},
  doi = {10.1186/1745-6215-12-S1-A91},
  abstract = {BACKGROUND: As there are limited patients for chronic lymphocytic leukaemia trials, it is important that statistical methodologies in Phase II efficiently select regimens for subsequent evaluation in larger-scale Phase III trials.$\backslash$n$\backslash$nMETHODS: We propose the screened selection design (SSD), which is a practical multi-stage, randomised Phase II design for two experimental arms. Activity is first evaluated by applying Simon's two-stage design (1989) on each arm. If both are active, the play-the-winner selection strategy proposed by Simon, Wittes and Ellenberg (SWE) (1985) is applied to select the superior arm. A variant of the design, Modified SSD, also allows the arm with the higher response rates to be recommended only if its activity rate is greater by a clinically-relevant value. The operating characteristics are explored via a simulation study and compared to a Bayesian Selection approach.$\backslash$n$\backslash$nRESULTS: Simulations showed that with the proposed SSD, it is possible to retain the sample size as required in SWE and obtain similar probabilities of selecting the correct superior arm of at least 90\%; with the additional attractive benefit of reducing the probability of selecting ineffective arms. This approach is comparable to a Bayesian Selection Strategy. The Modified SSD performs substantially better than the other designs in selecting neither arm if the underlying rates for both arms are desirable but equivalent, allowing for other factors to be considered in the decision making process. Though its probability of correctly selecting a superior arm might be reduced, it still performs reasonably well. It also reduces the probability of selecting an inferior arm.$\backslash$n$\backslash$nCONCLUSIONS: SSD provides an easy to implement randomised Phase II design that selects the most promising treatment that has shown sufficient evidence of activity, with available R codes to evaluate its operating characteristics.},
  number = {Suppl 1},
  journal = {Trials},
  author = {Yap, Christina and Billingham, Lucinda and Pettitt, Andrew},
  year = {2011},
  keywords = {oncology,moderate sample,Moderate Sample Sizes,Play-the-Winner,Randomised Phase II,Screening Design,Selection Design,Oncology,play-the-winner,randomised phase ii,screening design,selection design},
  pages = {A91},
  file = {/Users/k/Zotero/storage/DXL2LYRY/Yap, Billingham, Pettitt - 2011 - Screened selection design for randomised phase II oncology trials an example in chronic lymphocytic le.pdf;/Users/k/Zotero/storage/TCSMNTSM/Yap, Billingham, Pettitt - 2011 - Screened selection design for randomised phase II oncology trials an example in chronic lymphocytic le.pdf},
  pmid = {23819695}
}

@article{Bryant1995,
  title = {Incorporating Toxicity Considerations into the Design of Two-Stage Phase {{II}} Clinical Trials.},
  volume = {51},
  issn = {0006-341X},
  doi = {10.2307/2533268},
  abstract = {Phase II study designs are proposed that evaluate both clinical response and toxicity, and that are similar in structure to Simon's two-stage designs. Sample sizes and decision criteria are chosen to minimize the maximum expected accrual, given that the treatment is unacceptable either in terms of clinical response or toxicity. This is achieved subject to control of error rates, either uniformly over all possible correlation structures linking response and toxicity, or alternatively, under an assumption of independence between response and toxicity. In the latter case, bounds on the error rates show that effective control is still uniformly achieved even if the independence assumption is relaxed.},
  number = {4},
  journal = {Biometrics},
  author = {Bryant, J and Day, R},
  year = {1995},
  keywords = {EfficacyToxicity,early stopping,ii trials,toxicity considerations in phase,two-stage clinical trials},
  pages = {1372-1383},
  file = {/Users/k/Zotero/storage/JIWEGPKN/Bryant, Day - 1995 - Incorporating toxicity considerations into the design of two-stage phase II clinical trials.pdf;/Users/k/Zotero/storage/UDN8QF6T/Bryant, Day - 1995 - Incorporating toxicity considerations into the design of two-stage phase II clinical trials.pdf},
  pmid = {8589229}
}

@techreport{Cook2006,
  title = {Efficacy-{{Toxicity}} Trade-Offs Based on {{L}}-p Norms: {{Technical Report UTMDABTR}}-003-06},
  author = {Cook, John D},
  year = {2006},
  keywords = {DoseFinding,EfficacyToxicity},
  pages = {1-9},
  file = {/Users/k/Zotero/storage/6DT78CZD/Cook - 2006 - Efficacy-Toxicity trade-offs based on L p norms Technical Report UTMDABTR-003-06 Bivariate binary model.pdf;/Users/k/Zotero/storage/CN8RK9GN/Cook - 2006 - Efficacy-Toxicity trade-offs based on L-p norms Technical Report UTMDABTR-003-06.pdf}
}

@article{Thall2014,
  title = {Effective Sample Size for Computing Prior Hyperparameters in {{Bayesian}} Phase {{I}}-{{II}} Dose-Finding},
  volume = {11},
  issn = {1740-7745},
  doi = {10.1177/1740774514547397},
  number = {6},
  journal = {Clinical Trials},
  author = {Thall, PF and Herrick, RC and Nguyen, HQ and Venier, JJ and Norris, JC},
  year = {2014},
  keywords = {adaptive design,DoseFinding,clinical trial,EfficacyToxicity,dose-finding,bayesian design,ii trial,phase i},
  pages = {657-666},
  file = {/Users/k/Zotero/storage/GQAB5HPD/Thall et al. - 2014 - Effective sample size for computing prior hyperparameters in Bayesian phase I-II dose-finding.pdf;/Users/k/Zotero/storage/PHB238TN/Thall et al. - 2014 - Effective sample size for computing prior hyperparameters in Bayesian phase I-II dose-finding.pdf}
}

@article{LeTourneau2009,
  title = {Dose Escalation Methods in Phase i Cancer Clinical Trials},
  volume = {101},
  issn = {00278874},
  doi = {10.1093/jnci/djp079},
  abstract = {Phase I clinical trials are an essential step in the development of anticancer drugs. The main goal of these studies is to establish the recommended dose and/or schedule of new drugs or drug combinations for phase II trials. The guiding principle for dose escalation in phase I trials is to avoid exposing too many patients to subtherapeutic doses while preserving safety and maintaining rapid accrual. Here we review dose escalation methods for phase I trials, including the rule-based and model-based dose escalation methods that have been developed to evaluate new anticancer agents. Toxicity has traditionally been the primary endpoint for phase I trials involving cytotoxic agents. However, with the emergence of molecularly targeted anticancer agents, potential alternative endpoints to delineate optimal biological activity, such as plasma drug concentration and target inhibition in tumor or surrogate tissues, have been proposed along with new trial designs. We also describe specific methods for drug combinations as well as methods that use a time-to-event endpoint or both toxicity and efficacy as endpoints. Finally, we present the advantages and drawbacks of the various dose escalation methods and discuss specific applications of the methods in developmental oncotherapeutics.},
  number = {10},
  journal = {Journal of the National Cancer Institute},
  author = {Le Tourneau, Christophe and Lee, J. Jack and Siu, Lillian L.},
  year = {2009},
  keywords = {DoseFinding},
  pages = {708-720},
  file = {/Users/k/Zotero/storage/LBBXUJF8/Le Tourneau, Lee, Siu - 2009 - Dose escalation methods in phase i cancer clinical trials.pdf;/Users/k/Zotero/storage/US4GRSMJ/Le Tourneau, Lee, Siu - 2009 - Dose escalation methods in phase i cancer clinical trials.pdf},
  pmid = {19436029}
}

@article{Thall2003,
  title = {Hierarchical {{Bayesian}} Approaches to Phase {{II}} Trials in Diseases with Multiple Subtypes},
  volume = {22},
  issn = {02776715},
  doi = {10.1002/sim.1399},
  abstract = {We propose a methodology for conducting phase II clinical trials in settings where the disease is categorized into multiple subtypes. A hierarchical Bayesian model is assumed for treatment effects within the subtypes. The hierarchical model, which is tailored to each particular application, allows treatment effects to differ across subtypes while assuming a priori that the effects are exchangeable and correlated. Two applications are described. The first is a trial of imatinib for sarcoma in which treatment activity is characterized by a binary indicator of tumour response. The second is a phase II trial of a new preparative regimen for allogeneic bone marrow transplantation in patients with haematologic malignancies, with treatment effect characterized by the mean time from transplant to disease progression or death. The applications illustrate how the hierarchical Bayesian model borrows strength across subtypes.},
  number = {5},
  journal = {Statistics in Medicine},
  author = {Thall, Peter F. and Wathen, J. Kyle and Bekele, B. Nebiyou and Champlin, Richard E. and Baker, Laurence H. and Benjamin, Robert S.},
  year = {2003},
  keywords = {Phase II clinical trial,Heterogeneity,Activity trial,Bone marrow transplantation,Sarcoma},
  pages = {763-780},
  file = {/Users/k/Zotero/storage/6QG7SIGK/Thall et al. - 2003 - Hierarchical Bayesian approaches to phase II trials in diseases with multiple subtypes.pdf;/Users/k/Zotero/storage/9MSJG9R3/Thall et al. - 2003 - Hierarchical Bayesian approaches to phase II trials in diseases with multiple subtypes.pdf},
  pmid = {12587104}
}

@article{Thall2005,
  title = {Monitoring Event Times in Early Phase Clinical Trials: Some Practical Issues.},
  volume = {2},
  issn = {17407745},
  doi = {10.1191/1740774505cn121oa},
  abstract = {BACKGROUND: In many early phase clinical trials it is scientifically inappropriate or logistically infeasible to characterize patient outcome as a binary variable. In such settings, it often is more natural to construct early stopping rules based on time-to-event variables. This type of design may involve a variety of complications, however. PURPOSE: The purpose of this paper is to illustrate by example how one may deal with various complications that may arise when monitoring time-to-event outcomes in an early phase clinical trial. METHODS: We present a series of Bayesian designs for a phase II clinical trial in kidney cancer. Each design includes a procedure for monitoring the times to a severe adverse event, disease progression and death. The first design, which is the simplest, is based on the time to failure, defined as any of the three events, assuming exponentially distributed failure times with an inverse gamma prior on the mean. This design is compared by simulation to the CMAP design (Cheung and Thall, Biometrics, 2002; 58: 89-97). The model and monitoring procedure are then extended successively to accommodate several common practical complications, and we also study the method's robustness. RESULTS: Our simulations show that 1) one may apply the monitoring rule periodically, rather than continuously, without a substantive degradation of the design's reliability; 2) it is very important to account for interval censoring due to periodic evaluation of disease status; 3) it is important to account for the effect of disease progression on the subsequent death rate; 4) conducting a randomized trial presents little additional difficulty and provides unbiased comparisons; and 5) the exponential-inverse gamma model is surprisingly robust in most cases. LIMITATIONS: The methods discussed here do not account for patient heterogeneity. This is an important but complex issue that may be dealt with by extending the models and methods given here to accommodate patient covariates and treatment-covariate interaction. CONCLUSIONS: Bayesian procedures for monitoring time-to-event outcomes offer a practical way to conduct a variety of early phase trials. Considerable care must be given, however, to modeling the important aspects of the trial at hand, and to calibrating the prior and the design parameters to ensure that the design will have good operating characteristics.},
  number = {6},
  journal = {Clinical trials (London, England)},
  author = {Thall, Peter F and Wooten, Leiko H and Tannir, Nizar M},
  year = {2005},
  keywords = {TTE},
  pages = {467-478},
  file = {/Users/k/Zotero/storage/HNFMJJSC/Thall, Wooten, Tannir - 2005 - Monitoring event times in early phase clinical trials some practical issues.pdf;/Users/k/Zotero/storage/PPRIPTV9/Thall, Wooten, Tannir - 2005 - Monitoring event times in early phase clinical trials some practical issues.pdf},
  pmid = {16422307}
}

@article{Abel2012,
  title = {Sample Sizes for Time-to-Event Endpoints: {{Should}} You Insure against Chance Variations in Accrual?},
  volume = {33},
  issn = {15517144},
  doi = {10.1016/j.cct.2011.10.009},
  abstract = {This note addresses the questions of whether one should safeguard against a potential loss of power due to random variations of the accrual time, how this "insurance" can be formulated, and how much the sample size needs to be increased to obtain it. \textcopyright{} 2011 Elsevier Inc.},
  number = {2},
  journal = {Contemporary Clinical Trials},
  author = {Abel, Ulrich R. and Jensen, Katrin and {Karapanagiotou-Schenkel}, Irini},
  year = {2012},
  keywords = {Accrual,TTE,sample size,Controlled clinical trials,Survival,Sample size},
  pages = {456-458},
  file = {/Users/k/Zotero/storage/9SS9MWC9/Abel, Jensen, Karapanagiotou-Schenkel - 2012 - Sample sizes for time-to-event endpoints Should you insure against chance variations in a.pdf;/Users/k/Zotero/storage/QX5TQVXE/Abel, Jensen, Karapanagiotou-Schenkel - 2012 - Sample sizes for time-to-event endpoints Should you insure against chance variations in a.pdf},
  pmid = {22094431}
}

@article{Wason2011,
  title = {The Choice of Test in Phase {{II}} Cancer Trials Assessing Continuous Tumour Shrinkage When Complete Responses Are Expected},
  issn = {0962-2802},
  doi = {10.1177/0962280211432192},
  abstract = {Traditionally, phase II cancer trials test a binary endpoint formed from a dichotomisation of the continuous change in tumour size. Directly testing the continuous endpoint provides considerable gains in power, although also results in several statistical issues. One such issue is when complete responses, i.e. complete tumour removal, are observed in multiple patients; this is a problem when normality is assumed. Using simulated data and a recently published phase II trial, we investigate how the choice of test affects the operating characteristics of the trial. We propose using parametric tests based on the censored normal distribution, comparing them to the t-test and Wilcoxon non-parametric test. The censored normal distribution fits the real dataset well, but simulations indicate its type-I error rate is inflated, and its power is only slightly higher than the t-test. The Wilcoxon test has deflated type I error. For two-arm designs, the differences are much smaller. We conclude that the t-test is suitable for use when complete responses are present, although positively skewed data can result in the non-parametric test having higher power.},
  journal = {Statistical Methods in Medical Research},
  author = {Wason, J. M. and Mander, a. P.},
  year = {2011},
  keywords = {Anti-dichotomisation},
  file = {/Users/k/Zotero/storage/IY4ZI5ZU/Wason, Mander - 2011 - The choice of test in phase II cancer trials assessing continuous tumour shrinkage when complete responses are ex.pdf;/Users/k/Zotero/storage/Z3QJDP7M/Wason, Mander - 2011 - The choice of test in phase II cancer trials assessing continuous tumour shrinkage when complete responses are ex.pdf},
  pmid = {22179821}
}

@article{Wason2013,
  title = {Using Continuous Data on Tumour Measurements to Improve Inference in Phase {{II}} Cancer Studies},
  volume = {32},
  issn = {02776715},
  doi = {10.1002/sim.5867},
  abstract = {In phase II cancer trials, tumour response is either the primary or an important secondary endpoint. Tumour response is a binary composite endpoint determined, according to the Response Evaluation Criteria in Solid Tumors, by (1) whether the percentage change in tumour size is greater than a prescribed threshold and (2) (binary) criteria such as whether a patient develops new lesions. Further binary criteria, such as death or serious toxicity, may be added to these criteria. The probability of tumour response (i.e. 'success' on the composite endpoint) would usually be estimated simply as the proportion of successes among patients. This approach uses the tumour size variable only through a discretised form, namely whether or not it is above the threshold. In this article, we propose a method that also estimates the probability of success but that gains precision by using the information on the undiscretised (i.e. continuous) tumour size variable. This approach can also be used to increase the power to detect a difference between the probabilities of success under two different treatments in a comparative trial. We demonstrate these increases in precision and power using simulated data. We also apply the method to real data from a phase II cancer trial and show that it results in a considerably narrower confidence interval for the probability of tumour response.},
  number = {26},
  journal = {Statistics in Medicine},
  author = {Wason, James M S and Seaman, Shaun R.},
  year = {2013},
  keywords = {Anti-dichotomisation,Continuous tumour shrinkage endpoints,Informative dropout,Longitudinal model,Phase II cancer trial},
  pages = {4639-4650},
  file = {/Users/k/Zotero/storage/AHU3AHHR/Wason, Seaman - 2013 - Using continuous data on tumour measurements to improve inference in phase II cancer studies.pdf;/Users/k/Zotero/storage/XIUNTFGV/Wason, Seaman - 2013 - Using continuous data on tumour measurements to improve inference in phase II cancer studies.pdf},
  pmid = {23776143}
}

@article{Wason2011a,
  title = {Reducing Sample Sizes in Two-Stage Phase {{II}} Cancer Trials by Using Continuous Tumour Shrinkage End-Points},
  volume = {47},
  issn = {09598049},
  doi = {10.1016/j.ejca.2010.12.007},
  abstract = {Reducing the number of patients required for a clinical trial is important for shortening development time. Phase II cancer trials assess the tumour-shrinking effect of a novel compound through a binary end-point formed from the percentage change in total lesion diameter. We compare single-arm two-stage designs which use the binary end-point to those which directly use the continuous end-point. Using the continuous end-point results in lower expected and maximum sample sizes. For larger trials the reduction is around 37\%. This assumes that the dichotomisation point of the continuous end-point is chosen to give the best sample size, with the trial design using the binary end-point performing even worse otherwise. We consider a previous trial designed using a Simon two-stage design and show that if the continuous end-point had been used, the expected and maximum sample sizes of the trial would be reduced by around 50\%. Using the continuous end-point in a two-stage cancer trial results in large sample size reductions. The methods discussed in this paper work best when the number of complete responses is low, as is true in several types of cancer. We discuss what could be done if this is not the case. \textcopyright{} 2010 Elsevier Ltd. All rights reserved.},
  number = {7},
  journal = {European Journal of Cancer},
  author = {Wason, James M S and Mander, Adrian P. and Eisen, Tim G.},
  year = {2011},
  keywords = {Anti-dichotomisation,Phase II cancer clinical trials,RECIST,Sample sizes,Trial design},
  pages = {983-989},
  file = {/Users/k/Zotero/storage/4MQWGGS9/Wason, Mander, Eisen - 2011 - Reducing sample sizes in two-stage phase II cancer trials by using continuous tumour shrinkage end-points.pdf;/Users/k/Zotero/storage/X9U2I5FM/Wason, Mander, Eisen - 2011 - Reducing sample sizes in two-stage phase II cancer trials by using continuous tumour shrinkage end-points.pdf},
  pmid = {21239164}
}

@article{Andtbacka2015,
  title = {Talimogene {{Laherparepvec Improves Durable Response Rate}} in {{Patients With Advanced Melanoma}}},
  issn = {0732-183X},
  doi = {10.1200/JCO.2014.58.3377},
  journal = {Journal of Clinical Oncology},
  author = {Andtbacka, R. H. I. and Kaufman, H. L. and Collichio, F. and Amatruda, T. and Senzer, N. and Chesney, J. and a. Delman, K. and Spitler, L. E. and Puzanov, I. and Agarwala, S. S. and Milhem, M. and Cranmer, L. and Curti, B. and Lewis, K. and Ross, M. and Guthrie, T. and Linette, G. P. and a. Daniels, G. and Harrington, K. and Middleton, M. R. and Miller, W. H. and Zager, J. S. and Ye, Y. and Yao, B. and Li, A. and Doleman, S. and VanderWalde, A. and Gansert, J. and Coffin, R.},
  year = {2015},
  keywords = {Immunotherapy,Melanoma},
  file = {/Users/k/Zotero/storage/4Z7R3QXB/Andtbacka et al. - 2015 - Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma.pdf;/Users/k/Zotero/storage/6GEEVL4I/Andtbacka et al. - 2015 - Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma.pdf}
}

@article{Wages2014,
  title = {Seamless {{Phase I}}/{{II Adaptive Design For Oncology Trials}} of {{Molecularly Targeted Agents}}.},
  issn = {1520-5711},
  doi = {10.1080/10543406.2014.920873},
  abstract = {Abstract In dose-finding trials of chemotherapeutic agents, the goal of identifying the maximum tolerated dose is usually determined by considering information on toxicity only, with the assumption that the highest safe dose also provides the most promising outlook for efficacy. Trials of molecularly targeted agents challenge accepted dose-finding methods because minimal toxicity may arise over all doses under consideration and higher doses may not result in greater response. In this article, we propose a new early-phase method for trials investigating targeted agents. We provide simulation results illustrating the operating characteristics of our design.},
  journal = {Journal of biopharmaceutical statistics},
  author = {a Wages, Nolan and Tait, Christopher},
  year = {2014},
  keywords = {DoseFinding,Continual reassessment method,Dose finding,Molecularly targeted agent,Optimal biological dose,EfficacyToxicity,larly targeted agent,molecu-,continual reassessment method,dose finding,optimal biological dose},
  pages = {1-30},
  file = {/Users/k/Zotero/storage/I5ISRGFD/Wages, Tait - 2015 - Seamless Phase III Adaptive Design for Oncology Trials of Molecularly Targeted Agents.pdf;/Users/k/Zotero/storage/IRXXM6XK/Wages, Tait - 2014 - Seamless Phase III Adaptive Design For Oncology Trials of Molecularly Targeted Agents.pdf;/Users/k/Zotero/storage/PKSBCHXU/Wages, Tait - 2014 - Seamless Phase III Adaptive Design For Oncology Trials of Molecularly Targeted Agents.pdf;/Users/k/Zotero/storage/Z7AED2BT/Wages, Tait - 2015 - Seamless Phase III Adaptive Design for Oncology Trials of Molecularly Targeted Agents.pdf},
  pmid = {24904956}
}

@article{Thall2004,
  title = {Dose-{{Finding Based}} on {{Efficacy}}-{{Toxicity Trade}}-{{Offs}}},
  volume = {60},
  number = {3},
  journal = {Biometrics},
  author = {Thall, PF and Cook, JD},
  year = {2004},
  keywords = {adaptive design,phase ii,DoseFinding,EfficacyToxicity,dose-finding,bayesian design,biologic agents,phase i clinical trial},
  pages = {684-693},
  file = {/Users/k/Zotero/storage/EUBUF8QW/Thall, Cook - 2004 - Dose-Finding Based on Efficacy-Toxicity Trade-Offs.pdf;/Users/k/Zotero/storage/S84SNZVB/Thall, Cook - 2004 - Dose-Finding Based on Efficacy-Toxicity Trade-Offs.pdf}
}

@article{Shewchuk1994,
  title = {An {{Introduction}} to the {{Conjugate Gradient Method Without}} the {{Agonizing Pain}}},
  volume = {49},
  abstract = {The Conjugate Gradient Method is the most prominent iterative method for solving sparse systems of linear equations. Unfortunately, many textbook treatments of the topic are written with neither illustrations nor intuition, and their victims can be found to this day babbling senselessly in the corners of dusty libraries. For this reason, a deep, geometric understanding of the method has been reserved for the elite brilliant few who have painstakingly decoded the mumblings of their forebears. Nevertheless, the Conjugate Gradient Method is a composite of simple, elegant ideas that almost anyone can understand. Of course, a reader as intelligent as yourself will learn them almost effortlessly. The idea of quadratic forms is introduced and used to derive the methods of Steepest Descent, Conjugate Directions, and Conjugate Gradients. Eigenvectors are explained and used to examine the convergence of the Jacobi Method, Steepest Descent, and Conjugate Gradients. Other topics include preconditioning and the nonlinear Conjugate Gradient Method. I have taken pains to make this article easy to read. Sixty-six illustrations are provided. Dense prose is avoided. Concepts are explained in several differentways. Most equations are coupled with an intuitive interpretation.},
  number = {CS-94-125},
  journal = {Science},
  author = {Shewchuk, Jonathan Richard},
  year = {1994},
  keywords = {1,2,5,agonizing pain,conjugate gradient method,convergence analysis,eigen do,eigenvalues,i try,jacobi iterations,preconditioning,thinking with eigenvectors},
  pages = {64}
}

@book{Nocedal1999,
  title = {Numerical {{Optimization}}},
  volume = {43},
  isbn = {0-387-98793-2},
  abstract = {Despite application of cryogen spray (CS) precooling, customary treatment of port wine stain (PWS) birthmarks with a single laser pulse does not result in complete lesion blanching for a majority of patients. One obvious reason is nonselective absorption by epidermal melanin, which limits the maximal safe radiant exposure. Another possible reason for treatment failure is screening of laser light within large PWS vessels, which prevents uniform heating of the entire vessel lumen. Our aim is to identify the parameters of sequential CS cooling and laser irradiation that will allow optimal photocoagulation of various PWS blood vessels with minimal risk of epidermal thermal damage.},
  publisher = {{Springer}},
  author = {Nocedal, J and Wright, S J},
  editor = {Glynn, Peter and Robinson, Stephen M},
  year = {1999},
  doi = {10.1002/lsm.21040},
  issn = {10969101},
  pmid = {21384397},
  note = {Series Title: Springer Series in Operations Research
Publication Title: Analysis}
}

@article{Tibshirani2011,
  title = {Regression Shrinkage and Selection via the Lasso: {{A}} Retrospective},
  volume = {73},
  abstract = {We propose a new method for estimation in linear models. The "lasso" minimizes the residual sum of squares subject to the sum of the absolute value of the coefficients being less than a constant. Because of the nature of this constraint it tends to produce some coefficients that are exactly zero and hence gives interpretable models. Our simulation studies suggest that the lasso enjoys some of the favourable properties of both subset selection and ridge regression. It produces interpretable models like subset selection and exhibits the stability of ridge regression. There is also an interesting relationship with recent work in adaptive function estimation by Donoho and Johnstone. The lasso idea is quite general and can be applied in a variety of statistical models: extensions to generalized regression models and tree-based models are briefly described. Keywords: regression, subset selection, shrinkage, quadratic programming.},
  number = {3},
  journal = {Journal of the Royal Statistical Society. Series B: Statistical Methodology},
  author = {Tibshirani, Robert},
  year = {2011},
  keywords = {l 1-penalty,Penalization,Regularization,l
                        1-penalty},
  pages = {273-282},
  pmid = {16272381}
}

@article{Kantarjian2014,
  title = {Dasatinib or Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia : 2-Year Follow-up from a Randomized Phase 3 Trial ( {{DASISION}} )},
  volume = {119},
  doi = {10.1182/blood-2011-08-376087.The},
  number = {5},
  author = {Kantarjian, Hagop M and Shah, Neil P and Cortes, Jorge E and Baccarani, Michele and Agarwal, Mohan B and Undurraga, Mar\'ia Soledad and Wang, Jianxiang and Julio, Juan and Ipin, Kassack and Kim, Dong-wook and Ogura, Michinori and Pavlovsky, Carolina},
  year = {2014},
  keywords = {CML},
  pages = {1123-1129},
  file = {/Users/k/Zotero/storage/HP8I8X25/Kantarjian et al. - 2014 - Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia 2-year follow-up from a rand.pdf}
}

@article{Chen2010,
  title = {Nilotinib versus {{Imatinib}} for {{Newly Diagnosed Chronic Myeloid Leukemia}}},
  volume = {362},
  doi = {10.1056/NEJMoa1514204},
  number = {24},
  journal = {New England Journal of Medicine},
  author = {Chen, Dalei and Ph, D and Ramirez, Luz Margarita and Investigators, Advance-},
  year = {2010},
  keywords = {CML},
  pages = {2487-2498},
  file = {/Users/k/Zotero/storage/DM42Y8AJ/Chen et al. - 2010 - Nilotinib versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia.pdf},
  pmid = {19038878}
}

@article{Kantarjian2011,
  title = {Nilotinib versus Imatinib for the Treatment of Patients with Newly Diagnosed Chronic Phase, {{Philadelphia}} Chromosome-Positive, Chronic Myeloid Leukaemia: 24-Month Minimum Follow-up of the Phase 3 Randomised {{ENESTnd}} Trial},
  volume = {12},
  issn = {14702045},
  doi = {10.1016/S1470-2045(11)70201-7},
  abstract = {Background: Nilotinib has shown greater efficacy than imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukaemia (CML) in chronic phase after a minimum follow-up of 12 months. We present data from the Evaluating Nilotinib Efficacy and Safety in clinical Trials-newly diagnosed patients (ENESTnd) study after a minimum follow-up of 24 months. Methods: ENESTnd was a phase 3, multicentre, open-label, randomised study. Adult patients were eligible if they had been diagnosed with chronic phase, Philadelphia chromosome-positive CML within the previous 6 months. Patients were randomly assigned (1:1:1) to receive nilotinib 300 mg twice a day, nilotinib 400 mg twice a day, or imatinib 400 mg once a day, all administered orally, by use of a computer-generated randomisation schedule, using permuted blocks, and stratified according to Sokal score. Efficacy results are reported for the intention-to-treat population. The primary endpoint was major molecular response at 12 months, defined as BCR-ABL transcript levels on the International Scale (BCR-ABLIS) of 0??1\% or less by real-time quantitative PCR in peripheral blood. This study is registered with ClinicalTrials.gov, number NCT00471497. Findings: 282 patients were randomly assigned to receive nilotinib 300 mg twice daily, 281 to receive nilotinib 400 mg twice daily, and 283 to receive imatinib. By 24 months, significantly more patients had a major molecular response with nilotinib than with imatinib (201 [71\%] with nilotinib 300 mg twice daily, 187 [67\%] with nilotinib 400 mg twice daily, and 124 [44\%] with imatinib; p$<$0??0001 for both comparisons). Significantly more patients in the nilotinib groups achieved a complete molecular response (defined as a reduction of BCR-ABLIS levels to ???0??0032\%) at any time than did those in the imatinib group (74 [26\%] with nilotinib 300 mg twice daily, 59 [21\%] with nilotinib 400 mg twice daily, and 29 [10\%] with imatinib; p$<$0??0001 for nilotinib 300 mg twice daily vs imatinib, p=0??0004 for nilotinib 400 mg twice daily vs imatinib). There were fewer progressions to accelerated or blast phase on treatment, including clonal evolution, in the nilotinib groups than in the imatinib group (two with nilotinib 300 mg twice daily, five with nilotinib 400 mg twice daily, and 17 with imatinib; p=0??0003 for nilotinib 300 mg twice daily vs imatinib, p=0??0089 for nilotinib 400 mg twice daily vs imatinib). At 24 months, survival was comparable in all treatment groups, but fewer CML-related deaths had occurred in both the nilotinib groups than in the imatinib group (five with nilotinib 300 mg twice daily, three with nilotinib 400 mg twice daily, and ten with imatinib). Overall, the only grade 3 or 4 non-haematological adverse events that occurred in at least 2??5\% of patients were headache (eight [3\%] with nilotinib 300 mg twice daily, four [1\%] with nilotinib 400 mg twice daily, and two [$<$1\%] with imatinib) and rash (two [$<$1\%], seven [3\%], and five [2\%], respectively). Grade 3 or 4 neutropenia was more common with imatinib than with either dose of nilotinib (33 [12\%] with nilotinib 300 mg twice daily, 30 [11\%] with nilotinib 400 mg twice daily, and 59 [21\%] with imatinib). Serious adverse events were reported in eight additional patients in the second year of the study (four with nilotinib 300 mg twice daily, three with nilotinib 400 mg twice daily, and one with imatinib). Interpretation: Nilotinib continues to show better efficacy than imatinib for the treatment of patients with newly diagnosed CML in chronic phase. These results support nilotinib as a first-line treatment option for patients with newly diagnosed disease. Funding: Novartis. ?? 2011 Elsevier Ltd.},
  number = {9},
  journal = {The Lancet Oncology},
  author = {Kantarjian, Hagop M. and Hochhaus, Andreas and Saglio, Giuseppe and Souza, Carmino De and Flinn, Ian W. and Stenke, Leif and Goh, Yeow Tee and Rosti, Gianantonio and Nakamae, Hirohisa and Gallagher, Neil J. and Hoenekopp, Albert and Blakesley, Rick E. and Larson, Richard A. and Hughes, Timothy P.},
  year = {2011},
  keywords = {CML},
  pages = {841-851},
  file = {/Users/k/Zotero/storage/6MFFIX5Z/Kantarjian et al. - 2011 - Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chro.pdf},
  pmid = {21856226}
}

@article{Herbst2016,
  title = {Pembrolizumab versus Docetaxel for Previously Treated, {{PD}}-{{L1}}-Positive, Advanced Non-Small-Cell Lung Cancer ({{KEYNOTE}}-010): {{A}} Randomised Controlled Trial},
  volume = {387},
  issn = {1474547X},
  doi = {10.1016/S0140-6736(15)01281-7},
  abstract = {Background Despite recent advances in the treatment of advanced non-small-cell lung cancer, there remains a need for effective treatments for progressive disease. We assessed the efficacy of pembrolizumab for patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer. Methods We did this randomised, open-label, phase 2/3 study at 202 academic medical centres in 24 countries. Patients with previously treated non-small-cell lung cancer with PD-L1 expression on at least 1\% of tumour cells were randomly assigned (1:1:1) in blocks of six per stratum with an interactive voice-response system to receive pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m2 every 3 weeks. The primary endpoints were overall survival and progression-free survival both in the total population and in patients with PD-L1 expression on at least 50\% of tumour cells. We used a threshold for significance of p$<$0$\cdot$00825 (one-sided) for the analysis of overall survival and a threshold of p$<$0$\cdot$001 for progression-free survival. This trial is registered at ClinicalTrials.gov, number NCT01905657. Findings Between Aug 28, 2013, and Feb 27, 2015, we enrolled 1034 patients: 345 allocated to pembrolizumab 2 mg/kg, 346 allocated to pembrolizumab 10 mg/kg, and 343 allocated to docetaxel. By Sept 30, 2015, 521 patients had died. In the total population, median overall survival was 10$\cdot$4 months with pembrolizumab 2 mg/kg, 12$\cdot$7 months with pembrolizumab 10 mg/kg, and 8$\cdot$5 months with docetaxel. Overall survival was significantly longer for pembrolizumab 2 mg/kg versus docetaxel (hazard ratio [HR] 0$\cdot$71, 95\% CI 0$\cdot$58-0$\cdot$88; p=0$\cdot$0008) and for pembrolizumab 10 mg/kg versus docetaxel (0$\cdot$61, 0$\cdot$49-0$\cdot$75; p$<$0$\cdot$0001). Median progression-free survival was 3$\cdot$9 months with pembrolizumab 2 mg/kg, 4$\cdot$0 months with pembrolizumab 10 mg/kg, and 4$\cdot$0 months with docetaxel, with no significant difference for pembrolizumab 2 mg/kg versus docetaxel (0$\cdot$88, 0$\cdot$74-1$\cdot$05; p=0$\cdot$07) or for pembrolizumab 10 mg/kg versus docetaxel (HR 0$\cdot$79, 95\% CI 0$\cdot$66-0$\cdot$94; p=0$\cdot$004). Among patients with at least 50\% of tumour cells expressing PD-L1, overall survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 14$\cdot$9 months vs 8$\cdot$2 months; HR 0$\cdot$54, 95\% CI 0$\cdot$38-0$\cdot$77; p=0$\cdot$0002) and with pembrolizumab 10 mg/kg than with docetaxel (17$\cdot$3 months vs 8$\cdot$2 months; 0$\cdot$50, 0$\cdot$36-0$\cdot$70; p$<$0$\cdot$0001). Likewise, for this patient population, progression-free survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 5$\cdot$0 months vs 4$\cdot$1 months; HR 0$\cdot$59, 95\% CI 0$\cdot$44-0$\cdot$78; p=0$\cdot$0001) and with pembrolizumab 10 mg/kg than with docetaxel (5$\cdot$2 months vs 4$\cdot$1 months; 0$\cdot$59, 0$\cdot$45-0$\cdot$78; p$<$0$\cdot$0001). Grade 3-5 treatment-related adverse events were less common with pembrolizumab than with docetaxel (43 [13\%] of 339 patients given 2 mg/kg, 55 [16\%] of 343 given 10 mg/kg, and 109 [35\%] of 309 given docetaxel). Interpretation Pembrolizumab prolongs overall survival and has a favourable benefit-to-risk profile in patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer. These data establish pembrolizumab as a new treatment option for this population and validate the use of PD-L1 selection.},
  number = {10027},
  journal = {The Lancet},
  author = {Herbst, Roy S. and Baas, Paul and Kim, Dong Wan and Felip, Enriqueta and {P\'erez-Gracia}, Jos\'e L. and Han, Ji Youn and Molina, Julian and Kim, Joo Hang and Arvis, Catherine Dubos and Ahn, Myung Ju and Majem, Margarita and Fidler, Mary J. and De Castro, Gilberto and Garrido, Marcelo and Lubiniecki, Gregory M. and Shentu, Yue and Im, Ellie and {Dolled-Filhart}, Marisa and Garon, Edward B.},
  year = {2016},
  keywords = {NSCLC,PD1,Pembrolizumab,pembrolizumab},
  pages = {1540-1550},
  file = {/Users/k/Zotero/storage/6EPEJCNG/Herbst et al. - 2016 - Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNO.pdf;/Users/k/Zotero/storage/CET3G2JE/Gillespie et al. - 2014 - Estimating minimally important differences for two vision-specific quality of life measures(3).pdf},
  pmid = {26712084}
}

@article{Fayers2015,
  title = {Estimates of {{Minimally Important Differences}}},
  volume = {23},
  doi = {10.1007/s11136-013-0443-4.Don},
  number = {1},
  author = {Fayers, Peter M and Hays, Ron D},
  year = {2015},
  keywords = {Quality of Life,MicrobialKeratitis,clinical significance,minimally important difference,patient-reported outcomes,regression to the mean,quality of life},
  pages = {1-4},
  file = {/Users/k/Zotero/storage/8SXDZTGX/Gillespie et al. - 2014 - Estimating minimally important differences for two vision-specific quality of life measures(2).pdf;/Users/k/Zotero/storage/BDEBCZWR/Fayers, Hays - 2015 - Estimates of Minimally Important Differences.pdf}
}

@article{Li2014,
  title = {Vision-{{Related Quality}} of {{Life}} in {{Patients}} with {{Infectious Keratitis}}},
  volume = {91},
  number = {3},
  journal = {Optometry and Vision Science},
  author = {Li, Yimin and Hong, Jiaxu and Wei, Anji and Wang, Xin and Chen, Yan and Cui, Xinhan and Sun, Xinghuai and Liu, Zuguo and Xu, Jianjiang},
  year = {2014},
  keywords = {Quality of Life,MicrobialKeratitis,best corrected visual acuity,infectious keratitis,nei vfq-25,vision-related quality of life,quality of life},
  pages = {278-283},
  file = {/Users/k/Zotero/storage/HEGSPS7J/Gillespie et al. - 2014 - Estimating minimally important differences for two vision-specific quality of life measures(8).pdf;/Users/k/Zotero/storage/II98BMXL/Li et al. - 2014 - Vision-Related Quality of Life in Patients with Infectious Keratitis.pdf}
}

@article{Basch2014,
  title = {Development of the {{National Cancer Institute}}'s Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events ({{PRO}}-{{CTCAE}}).},
  volume = {106},
  issn = {1460-2105},
  doi = {10.1093/jnci/dju244},
  abstract = {The standard approach for documenting symptomatic adverse events (AEs) in cancer clinical trials involves investigator reporting using the National Cancer Institute's (NCI's) Common Terminology Criteria for Adverse Events (CTCAE). Because this approach underdetects symptomatic AEs, the NCI issued two contracts to create a patient-reported outcome (PRO) measurement system as a companion to the CTCAE, called the PRO-CTCAE. This Commentary describes development of the PRO-CTCAE by a group of multidisciplinary investigators and patient representatives and provides an overview of qualitative and quantitative studies of its measurement properties. A systematic evaluation of all 790 AEs listed in the CTCAE identified 78 appropriate for patient self-reporting. For each of these, a PRO-CTCAE plain language term in English and one to three items characterizing the frequency, severity, and/or activity interference of the AE were created, rendering a library of 124 PRO-CTCAE items. These items were refined in a cognitive interviewing study among patients on active cancer treatment with diverse educational, racial, and geographic backgrounds. Favorable measurement properties of the items, including construct validity, reliability, responsiveness, and between-mode equivalence, were determined prospectively in a demographically diverse population of patients receiving treatments for many different tumor types. A software platform was built to administer PRO-CTCAE items to clinical trial participants via the internet or telephone interactive voice response and was refined through usability testing. Work is ongoing to translate the PRO-CTCAE into multiple languages and to determine the optimal approach for integrating the PRO-CTCAE into clinical trial workflow and AE analyses. It is envisioned that the PRO-CTCAE will enhance the precision and patient-centeredness of adverse event reporting in cancer clinical research.},
  number = {9},
  journal = {Journal of the National Cancer Institute},
  author = {Basch, Ethan and Reeve, Bryce B and Mitchell, Sandra A and Clauser, Steven B and Minasian, Lori M and Dueck, Amylou C and Mendoza, Tito R and Hay, Jennifer and Atkinson, Thomas M and Abernethy, Amy P and Bruner, Deborah W and Cleeland, Charles S and Sloan, Jeff A and Chilukuri, Ram and Baumgartner, Paul and Denicoff, Andrea and St Germain, Diane and O'Mara, Ann M and Chen, Alice and Kelaghan, Joseph and Bennett, Antonia V and Sit, Laura and Rogak, Lauren and Barz, Allison and Paul, Diane B and Schrag, Deborah},
  year = {2014},
  keywords = {AdverseEvents},
  file = {/Users/k/Zotero/storage/E9DXSX5C/Gillespie et al. - 2014 - Estimating minimally important differences for two vision-specific quality of life measures(7).pdf;/Users/k/Zotero/storage/K9JEXLIH/Basch et al. - 2014 - Development of the National Cancer Institute's patient-reported outcomes version of the common terminology criteri.pdf},
  pmid = {25265940}
}

@article{Glimelius2011,
  title = {Window-of-Opportunity Trials to Evaluate Clinical Activity of New Molecular Entities in Oncology},
  volume = {22},
  issn = {09237534},
  doi = {10.1093/annonc/mdq622},
  abstract = {The introduction of molecular targeted agents (e.g., monoclonal antibodies or kinase inhibitors) and cancer vaccines has raised the question whether alternate clinical trial designs, including window trials, are better suited to evaluate such new molecular entities (NMEs) and improve their approval rates. In window trials, patients receive an NME for a window of time before starting standard treatment allowing the evaluation of an NME in tumors unperturbed by previous therapies.},
  number = {8},
  journal = {Annals of Oncology},
  author = {Glimelius, B. and Lahn, M.},
  year = {2011},
  keywords = {safety monitoring,MTA,New molecular entities,Systematic review,Window trial,Safety monitoring},
  pages = {1717-1725},
  file = {/Users/k/Zotero/storage/AA2CKG4H/Glimelius, Lahn - 2011 - Window-of-opportunity trials to evaluate clinical activity of new molecular entities in oncology.pdf;/Users/k/Zotero/storage/V3WVEIRA/Gillespie et al. - 2014 - Estimating minimally important differences for two vision-specific quality of life measures(6).pdf},
  pmid = {21239400}
}

@techreport{Agency2012,
  title = {Guideline on the Evaluation of Anticancer Medicinal Products in Man},
  abstract = {Guideline on Evaluation of Anticancer Medicinal Products in Man},
  author = {Agency, European Medicines},
  year = {2012},
  keywords = {Phase III,biomarker,cancer,20 7418 8400 facsimile,20 7418 8416,44,7 westferry circus,canary wharf,london e14 4hb,malignancy,pharmacogenomics,targeted drugs,telephone,united kingdom,Phase I,Phase II},
  pages = {33},
  file = {/Users/k/Zotero/storage/AEAYHBDC/Agency - 2012 - Guideline on the evaluation of anticancer medicinal products in man.pdf},
  note = {Publication Title: European Medicines Agency}
}

@article{Sharma2016,
  title = {Clinical Development of New Drug\textendash{}Radiotherapy Combinations},
  issn = {1759-4774},
  doi = {10.1038/nrclinonc.2016.79},
  journal = {Nature Reviews Clinical Oncology},
  author = {Sharma, Ricky A. and Plummer, Ruth and Stock, Julie K. and Greenhalgh, Tessa A. and Ataman, Ozlem and Kelly, Stephen and Clay, Robert and Adams, Richard A. and Baird, Richard D. and Billingham, Lucinda and Brown, Sarah R. and Buckland, Sean and Bulbeck, Helen and Chalmers, Anthony J. and Clack, Glen and Cranston, Aaron N. and Damstrup, Lars and Ferraldeschi, Roberta and Forster, Martin D. and Golec, Julian and Hagan, Russell M. and Hall, Emma and Hanauske, Axel-R. and Harrington, Kevin J. and Haswell, Tom and Hawkins, Maria A. and Illidge, Tim and Jones, Hazel and Kennedy, Andrew S. and McDonald, Fiona and Melcher, Thorsten and O'Connor, James P. B. and Pollard, John R. and Saunders, Mark P. and {Sebag-Montefiore}, David and Smitt, Melanie and Staffurth, John and Stratford, Ian J. and Wedge, Stephen R. and Group, NCRI CTRad Academia-Pharma Joint Working},
  year = {2016},
  file = {/Users/k/Zotero/storage/3DM83BA5/Gillespie et al. - 2014 - Estimating minimally important differences for two vision-specific quality of life measures(5).pdf;/Users/k/Zotero/storage/K7XQIP9I/Sharma et al. - 2016 - Clinical development of new drug–radiotherapy combinations.pdf},
  pmid = {27245279}
}

@article{Lilford2001,
  title = {Issues in Methodological Research: {{Perspectives}} from Researchers and Commissioners},
  volume = {5},
  issn = {13665278},
  doi = {10.3310/hta5080},
  abstract = {OBJECTIVES: (1) Methodological research has few well-defined tools and processes analogous to those available for reviews and data collection in substantive health technology assessment. (2) This project was set up to obtain researchers' and others' views on the innovative projects on research methodology under the NHS Health Technology Assessment Programme and the usefulness of the research. (3) The study was intended to span both epistemological and management issues. (4) The following issues were explored: (a) the degree to which researchers would feel constrained by the "Cochrane" approach to systematic reviews when undertaking reviews of a methodological nature; (b) whether methodological projects may require exceptional design and management arrangements, in view of their novelty, subjectivity and complexity; (c) whether researchers would seek out other methods, in addition to undertaking reviews of argument, as a means of extending their understanding of methodological issues (there may be three categories of research methods in methodology: reviews of methodological argument, studies that use the literature as a source of data, and research that collects new primary data); (d) whether the Methodology Programme overall can be considered a "success". METHODS: (1) Telephone interviews were carried out on researchers (one senior and one junior per project), resulting in 35 interviews from 19 of the 20 target projects. (2) A qualitative postal survey was sent to 12 people who had played a key role in the development of the Methodology Programme; replies were received from six of them. (3) Analysis was undertaken of the hit rates for 29 projects on the NCCHTA website by the end of February and the end of May 1999, comparing those concerned with methodology (n = 10) and those concerned with other issues (n = 19). RESULTS--UNDERTAKING METHODOLOGICAL RESEARCH: VIEWS OF RESEARCHERS: This section summarises the views of 35 researchers who were interviewed by telephone. RESULTS--UNDERTAKING METHODOLOGICAL RESEARCH: VIEWS OF RESEARCHERS: (THE NATURE OF METHODOLOGICAL REVIEWS): (1) There was a reluctance among researchers to use the term "systematic review" in the methodological context. (2) Practical problems in undertaking methodological reviews were found at every stage of the research process. (a) In the initial search stage, preplanned strategies were difficult to maintain, owing to the need to respond to the problems of too few or too many references. (b) At the analysis stage, most studies were not formally weighted, but there was implicit weighting in researchers' views of their merits or relevance. (c) It was often only at the synthesis stage that researchers could see clearly what their study was able to do; iteration was frequently necessary at this point. (d) It was difficult to form simple conclusions and recommendations beyond summaries of what was known in the field. (e) Dissemination activities were most often directed to other health service researchers, with some attention to NHS policy makers and research commissioners. RESULTS--UNDERTAKING METHODOLOGICAL RESEARCH: VIEWS OF RESEARCHERS (THE NEED FOR FLEXIBILITY): (1) Few researchers had amended their topic or methods once their research was under way, although some had made minor changes to their original plan, generally to refine the topic to fit the time or data available. (2) Changing a topic was seen as inappropriate unless checked with funders, but changes in research methods were viewed as reasonable because questions might be refined in the light of information gained or early thinking. RESULTS--UNDERTAKING METHODOLOGICAL RESEARCH: VIEWS OF RESEARCHERS (THE QUESTION OF BIAS): (1) Few researchers considered that this kind of research could be undertaken or presented in a wholly unbiased way because of the need to assess the research studied. (2) Objectivity was nonetheless seen as something that researchers should strive towards. Efforts to do so included presenting data clearly, separating findings from discussion, covering all points of view, setting out their own assumptions and values, and testing their ideas on others known to have differing views. (3) The formal peer-review process was not seen to have made a difference here, primarily because of the stage at which referees become involved. RESULTS--UNDERTAKING METHODOLOGICAL RESEARCH: VIEWS OF RESEARCHERS (PROJECT MANAGEMENT--TIMING AND TIME MANAGEMENT): (1) A majority of projects were completed within 3 months of their due date. Those studies completed roughly on time were considered to have efficient junior researchers and good project management, including clear deadlines for different stages of the research. (2) Some studies had severe problems of time management. Too much time tended to be spent on collecting and reading the literature and the writing stage was not always well planned. Referees' comments were also slow in coming. (ABSTRACT TRUNCATED)},
  number = {8},
  journal = {Health Technology Assessment},
  author = {Lilford, R. J. and Richardson, a. and Stevens, a. and Fitzpatrick, R. and Edwards, S. and Rock, F. and Hutton, J. L.},
  year = {2001},
  file = {/Users/k/Zotero/storage/7TW7UPQI/Lilford et al. - 2001 - Issues in methodological research Perspectives from researchers and commissioners.pdf;/Users/k/Zotero/storage/HJ7R47YR/Lilford et al. - 2001 - Issues in methodological research Perspectives from researchers and commissioners.pdf},
  pmid = {11368832}
}

@book{Diggle2000,
  title = {Analysis of {{Longitudinal Data}}},
  isbn = {0-19-852284-3},
  publisher = {{Oxford University Press}},
  author = {Diggle, Peter J. and Liang, Kung-Yee and Zeger, Scott L.},
  year = {2000}
}

@article{Lindsey2001,
  title = {Adapting Sample Size Calculations to Repeated Measurements in Clinical Trials},
  volume = {28},
  issn = {0266-4763, 1360-0532},
  doi = {10.1080/02664760120011617},
  number = {1},
  journal = {Journal of Applied Statistics},
  author = {Lindsey, P. J.},
  year = {2001},
  keywords = {RepeatedMeasurements},
  pages = {81-89},
  file = {/Users/k/Zotero/storage/4M9PB7S5/Lindsey - 2001 - Adapting sample size calculations to repeated measurements in clinical trials.pdf;/Users/k/Zotero/storage/SR9EYJZQ/Lindsey - 2001 - Adapting sample size calculations to repeated measurements in clinical trials.pdf}
}

@article{Bogaerts2015,
  title = {Clinical Trial Designs for Rare Diseases: {{Studies}} Developed and Discussed by the {{International Rare Cancers Initiative}}},
  volume = {51},
  issn = {18790852},
  doi = {10.1016/j.ejca.2014.10.027},
  abstract = {Background The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research. Settings The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional - usually randomised - clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed. Results The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design. Interpretation Trials can be designed using a wide array of possibilities. There is no 'one size fits all' solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases.},
  number = {3},
  journal = {European Journal of Cancer},
  author = {Bogaerts, Jan and Sydes, Matthew R. and Keat, Nicola and McConnell, Andrea and Benson, Al and Ho, Alan and Roth, Arnaud and Fortpied, Catherine and Eng, Cathy and Peckitt, Clare and Coens, Corneel and Pettaway, Curtis and Arnold, Dirk and Hall, Emma and Marshall, Ernie and Sclafani, Francesco and Hatcher, Helen and Earl, Helena and {Ray-Coquard}, Isabelle and Paul, James and Blay, Jean Yves and Whelan, Jeremy and Panageas, Kathy and Wheatley, Keith and Harrington, Kevin and Licitra, Lisa and Billingham, Lucinda and Hensley, Martee and McCabe, Martin and Patel, Poulam M. and Carvajal, Richard and Wilson, Richard and {Glynne-Jones}, Rob and McWilliams, Rob and Leyvraz, Serge and Rao, Sheela and Nicholson, Steve and Filiaci, Virginia and Negrouk, Anastassia and Lacombe, Denis and Dupont, Elisabeth and Pauport\'e, Iris and Welch, John J. and Law, Kate and Trimble, Ted and Seymour, Matthew},
  year = {2015},
  keywords = {clinical trials,bayesian,Frequentist,Methodology,Multi-arm,Randomised controlled trials,Rare cancers,RareDiseases,Bayesian,Clinical trials},
  pages = {271-281},
  file = {/Users/k/Zotero/storage/D3Y6NUZ6/Bogaerts et al. - 2015 - Clinical trial designs for rare diseases Studies developed and discussed by the International Rare Cancers Init.pdf;/Users/k/Zotero/storage/NC2RID4M/Bogaerts et al. - 2015 - Clinical trial designs for rare diseases Studies developed and discussed by the International Rare Cancers Init.pdf},
  pmid = {25542058}
}

@article{Freidlin2010,
  title = {Randomized Clinical Trials with Biomarkers: {{Design}} Issues},
  volume = {102},
  issn = {00278874},
  doi = {10.1093/jnci/djp477},
  abstract = {Clinical biomarker tests that aid in making treatment decisions will play an important role in achieving personalized medicine for cancer patients. Definitive evaluation of the clinical utility of these biomarkers requires conducting large randomized clinical trials (RCTs). Efficient RCT design is therefore crucial for timely introduction of these medical advances into clinical practice, and a variety of designs have been proposed for this purpose. To guide design and interpretation of RCTs evaluating biomarkers, we present an in-depth comparison of advantages and disadvantages of the commonly used designs. Key aspects of the discussion include efficiency comparisons and special interim monitoring issues that arise because of the complexity of these RCTs. Important ongoing and completed trials are used as examples. We conclude that, in most settings, randomized biomarker-stratified designs (ie, designs that use the biomarker to guide analysis but not treatment assignment) should be used to obtain a rigorous assessment of biomarker clinical utility.},
  number = {3},
  journal = {Journal of the National Cancer Institute},
  author = {Freidlin, Boris and McShane, Lisa M. and Korn, Edward L.},
  year = {2010},
  keywords = {Biomarkers,biomarkers},
  pages = {152-160},
  file = {/Users/k/Zotero/storage/A33YQEIQ/Freidlin, McShane, Korn - 2010 - Randomized clinical trials with biomarkers Design issues.pdf},
  pmid = {20075367}
}

@article{Chen2014,
  title = {Biomarker Adaptive Designs in Clinical Trials},
  volume = {3},
  issn = {2218-676X},
  doi = {10.3978/j.issn.2218-676X.2014.05.04},
  abstract = {Predictive biomarkers are used to develop (binary) classifiers to identify patients as either good or poor candidates for clinical decision to optimize treatment selection. Ideally, these candidate biomarkers have been well studied in the phase II developmental stage, the performance characteristics of the classifier are well established in one or more retrospective validation, and the assay and predictive performance are reproducible and robust experimentally and analytically. However, completely phase II validated biomarkers for uses in phase III trial are often unavailable. Adaptive signature design (ASD) combines the biomarker identification and classifier development to the selection of candidate patients and a statistical test for treatment effect on the selected patient subgroup for phase III clinical trials. Biomarker-adaptive designs identify the most suitable target subpopulations, based on clinical observations or known biomarkers, and evaluate the effectiveness of the treatment on that subpopulation in a statistically valid manner. This review is concerned with statistical aspects in the biomarker adaptive design for randomized clinical trials. Statistical issues include the interaction test to identify predictive biomarkers, subgroup analysis, multiple testing and false discovery rate (FDR), classification of imbalanced class size data, sample size and power, and validation of the classification model.},
  number = {3},
  journal = {Translational Cancer Research},
  author = {Chen, James J. and Lu, Tzu-Pin and Chen, Dung-Tsa and Wang, Sue-Jane},
  year = {2014},
  keywords = {04,10,3978,Biomarkers,doi,issn,j,classification,2014,personalized medicine,05,08,2218-676x,accepted for publication may,adaptive signature design,analysis,asd,predictive classifier,subgroup,subgroup identification,submitted mar 17,biomarkers},
  pages = {279-292},
  file = {/Users/k/Zotero/storage/2S4UHF8D/Chen et al. - 2014 - Biomarker adaptive designs in clinical trials.pdf}
}

@article{Simon2014,
  title = {Biomarker Based Clinical Trial Design.},
  volume = {3},
  issn = {2304-3873},
  doi = {10.3978/j.issn.2304-3865.2014.02.03},
  abstract = {The established molecular heterogeneity of human cancers and the subsequent stratification of conventional diagnostic categories require the development of new paradigms for the development of a reliable basis for predictive medicine. We review clinical trial designs for the development of new therapeutics and predictive biomarkers to inform their use. We cover designs for a wide range of settings. At one extreme is the development of a new drug with a single biomarker and strong biological evidence that marker negative patients are unlikely to benefit from the new drug. At the other extreme are phase III clinical trials involving both genome-wide discovery and internal validation of a predictive classifier that identifies the patients most likely and unlikely to benefit from the new drug.},
  number = {3},
  journal = {Chinese clinical oncology},
  author = {Simon, Richard},
  year = {2014},
  keywords = {10,2304-3865,27,3978,adaptive design,Biomarkers,doi,issn,j,predictive biomarker,clinical trial design,2014,dx,http,org,view this article at,02,03,accepted for publication feb,companion diagnostic,enrichment trial,submitted jan 07,biomarkers,★},
  pages = {39},
  file = {/Users/k/Zotero/storage/F8TQPRCV/Simon - 2014 - Biomarker based clinical trial design.pdf;/Users/k/Zotero/storage/ST6QE89T/Simon - 2014 - Biomarker based clinical trial design.pdf},
  pmid = {25841465}
}

@article{Renfro2014,
  title = {Adaptive Randomized Phase {{II}} Design for Biomarker Threshold Selection and Independent Evaluation.},
  volume = {3},
  issn = {2304-3873},
  doi = {10.3978/j.issn.2304-3865.2013.12.04},
  abstract = {BACKGROUND: Frequently a biomarker capable of defining a patient population with enhanced response to an experimental agent is not fully validated with a known threshold at the start of a phase II trial. When such candidate predictive markers are evaluated and/or validated retrospectively, over-accrual of patients less likely to benefit from the regimen may result, leading to underpowered analyses or sub-optimal patient care.$\backslash$n$\backslash$nPURPOSE: We propose an adaptive randomized phase II study design incorporating prospective biomarker threshold identification (or non-identification), possible early futility stopping, potential mid-trial accrual restriction to marker-positive subjects, and final marker and treatment evaluation in the patient population identified as most likely to benefit.$\backslash$n$\backslash$nMETHODS: An interim analysis is used to determine whether an initially unselected trial should stop early for futility, continue without a promising marker, or adapt accrual and resize (up to a pre-determined maximum) according to a promising biomarker. Final efficacy analyses are performed in the target population identified at the interim as most likely to benefit from the experimental regimen. Simulation studies demonstrate control of false-positive error rates, power, reduced average sample size, and other favorable aspects.$\backslash$n$\backslash$nRESULTS: The design performs well at identifying a truly predictive biomarker at interim analysis, and subsequently restricting accrual to patients most likely to benefit from the experimental treatment. Type I and type II error rates are adequately controlled by restricting the range of marker prevalence via the candidate thresholds, and by careful consideration of the timing of interim analysis.$\backslash$n$\backslash$nCONCLUSIONS: In situations where identification and validation of a naturally continuous biomarker are desired within a randomized phase II trial, the design presented herein offers a potential solution.},
  number = {1},
  journal = {Chinese clinical oncology},
  author = {Renfro, Lindsay A and Coughlin, Christina M and Grothey, Axel M and Sargent, Daniel J},
  year = {2014},
  keywords = {04,10,12,2013,2304-3865,27,3978,accepted for publication dec,adaptive design,Biomarkers,doi,interim futility analysis,issn,j,phase ii,predictive biomarker,randomized clinical trial,submitted oct 09,threshold identification,trial,biomarkers,★},
  pages = {3},
  file = {/Users/k/Zotero/storage/ERV744R2/Renfro et al. - 2014 - Adaptive randomized phase II design for biomarker threshold selection and independent evaluation.pdf},
  pmid = {25842081}
}

@article{Rubinstein2014,
  title = {Phase {{II}} Design : History and Evolution},
  volume = {3},
  issn = {23043873},
  doi = {10.3978/j.issn.2304-3865.2014.02.02},
  number = {4},
  journal = {Chinese Clinical Oncology},
  author = {Rubinstein, Larry},
  year = {2014},
  keywords = {10,2013,2304-3865,3978,doi,issn,j,phase ii,07,2014,02,accepted for publication jan,iii trial,phase ii trial,randomized,randomized phase II trial,randomized screening trial,selection design trial,submitted dec 10,Phase II,randomized phase ii trial},
  pages = {48},
  file = {/Users/k/Zotero/storage/UIRGZE6I/Rubinstein - 2014 - Phase II design history and evolution.pdf}
}

@article{Buyse2016,
  title = {Phase {{III}} Design: Principles},
  volume = {5},
  doi = {10.3978/j.issn.2304-3865.2014.08.05},
  number = {1},
  journal = {Chinese clinical oncology},
  author = {Buyse, Marc},
  year = {2016},
  keywords = {10,2304-3865,3978,doi,issn,j,2014,dx,http,org,view this article at,hypothesis testing,05,08,Phase III,sample size,31,accepted for publication jul,phase iii trials,randomization,stratification,submitted apr 09,★},
  pages = {1-13},
  file = {/Users/k/Zotero/storage/ABBFY792/Buyse - 2016 - Phase III design principles.pdf}
}

@article{Braun2014,
  title = {The Current Design of Oncology Phase {{I}} Clinical Trials},
  volume = {3},
  doi = {10.3978/j.issn.2304-3865.2014.02.01},
  number = {1},
  journal = {Chinese clinical oncology},
  author = {Braun, Thomas M},
  year = {2014},
  keywords = {DoseFinding,phase i,e 1 of 11,Phase I,★},
  file = {/Users/k/Zotero/storage/FS9RJJCN/Braun - 2014 - The current design of oncology phase I clinical trials.pdf}
}

@article{Pang2016,
  title = {Statistical Aspect of Translational and Correlative Studies in Clinical Trials.},
  volume = {5},
  issn = {2304-3873},
  doi = {10.3978/j.issn.2304-3865.2014.07.04},
  abstract = {In this article, we describe statistical issues related to the conduct of translational and correlative studies in cancer clinical trials. In the era of personalized medicine, proper biomarker discovery and validation is crucial for producing groundbreaking research. In order to carry out the framework outlined in this article, a team effort between oncologists and statisticians is the key for success.},
  number = {1},
  journal = {Chinese clinical oncology},
  author = {Pang, Herbert and Wang, Xiaofei},
  year = {2016},
  keywords = {04,10,2304-3865,3978,Biomarkers,doi,issn,j,07,18,2014,accepted for publication jun,big data,bioinformatics,dx,http,oncology,org,personalized medicine,submitted may 05,translational science,view this article at,biomarkers,★},
  pages = {11},
  file = {/Users/k/Zotero/storage/THDGFE2H/Pang, Wang - 2016 - Statistical aspect of translational and correlative studies in clinical trials.pdf},
  pmid = {26932435}
}

@article{Kim2011,
  archivePrefix = {arXiv},
  eprinttype = {arxiv},
  eprint = {1112.3563},
  title = {The {{BATTLE}} Trial: {{Personalizing Therapy}} for {{Lung Cancer}}},
  volume = {1},
  issn = {21598274},
  doi = {10.1158/2159-8274.CD-10-0010},
  abstract = {UNLABELLED: The Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial represents the first completed prospective, biopsy-mandated, biomarker-based, adaptively randomized study in 255 pretreated lung cancer patients. Following an initial equal randomization period, chemorefractory non-small cell lung cancer (NSCLC) patients were adaptively randomized to erlotinib, vandetanib, erlotinib plus bexarotene, or sorafenib, based on relevant molecular biomarkers analyzed in fresh core needle biopsy specimens. Overall results include a 46\% 8-week disease control rate (primary end point), confirm prespecified hypotheses, and show an impressive benefit from sorafenib among mutant-KRAS patients. BATTLE establishes the feasibility of a new paradigm for a personalized approach to lung cancer clinical trials. SIGNIFICANCE: The BATTLE study is the first completed prospective, adaptively randomized study in heavily pretreated NSCLC patients that mandated tumor profiling with "real-time" biopsies, taking a substantial step toward realizing personalized lung cancer therapy by integrating real-time molecular laboratory findings in delineating specific patient populations for individualized treatment.},
  number = {1},
  journal = {Cancer Discovery},
  author = {Kim, Edward S. and Herbst, Roy S. and Wistuba, Ignacio I. and Jack Lee, J. and Blumenschein, George R. and Tsao, Anne and Stewart, David J. and Hicks, Marshall E. and Erasmus, Jeremy and Gupta, Sanjay and Alden, Christine M. and Liu, Suyu and Tang, Ximing and Khuri, Fadlo R. and Tran, Hai T. and Johnson, Bruce E. and Heymach, John V. and Mao, Li and Fossella, Frank and Kies, Merrill S. and Papadimitrakopoulou, Vassiliki and Davis, Suzanne E. and Lippman, Scott M. and Hong, Waun K.},
  year = {2011},
  keywords = {Biomarkers,NSCLC,biomarkers,★},
  pages = {44-53},
  file = {/Users/k/Zotero/storage/4A6JFYUA/Kim et al. - 2011 - The BATTLE trial Personalizing Therapy for Lung Cancer.pdf;/Users/k/Zotero/storage/5NKG4N4B/Kim et al. - 2011 - The BATTLE trial Personalizing Therapy for Lung Cancer.pdf},
  pmid = {22586319}
}

@article{Simon,
  title = {Using {{Predictive Biomarkers}} in the {{Design}} of {{Pivotal Trials}}},
  journal = {Technical Report},
  author = {Simon, Richard},
  keywords = {Biomarkers,predictive biomarker,biometric research branch,classification,clinical trial design,d,gene expression,richard simon,sc,supervised,targeted clinical trial,biomarkers},
  file = {/Users/k/Zotero/storage/A5NE6BEW/Simon - Unknown - Using Predictive Biomarkers in the Design of Pivotal Trials.pdf;/Users/k/Zotero/storage/N39WLAY7/Simon - Unknown - Using Predictive Biomarkers in the Design of Pivotal Trials.pdf}
}

@article{Bang2010,
  title = {Trastuzumab in Combination with Chemotherapy versus Chemotherapy Alone for Treatment of {{HER2}}-Positive Advanced Gastric or Gastro-Oesophageal Junction Cancer ({{ToGA}}): {{A}} Phase 3, Open-Label, Randomised Controlled Trial},
  volume = {376},
  issn = {01406736},
  doi = {10.1016/S0140-6736(10)61121-X},
  abstract = {Background Trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2; also known as ERBB2), was investigated in combination with chemotherapy for first-line treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer. Methods ToGA (Trastuzumab for Gastric Cancer) was an open-label, international, phase 3, randomised controlled trial undertaken in 122 centres in 24 countries. Patients with gastric or gastro-oesophageal junction cancer were eligible for inclusion if their tumours showed overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation. Participants were randomly assigned in a 1:1 ratio to receive a chemotherapy regimen consisting of capecitabine plus cisplatin or fluorouracil plus cisplatin given every 3 weeks for six cycles or chemotherapy in combination with intravenous trastuzumab. Allocation was by block randomisation stratified by Eastern Cooperative Oncology Group performance status, chemotherapy regimen, extent of disease, primary cancer site, and measurability of disease, implemented with a central interactive voice recognition system. The primary endpoint was overall survival in all randomised patients who received study medication at least once. This trial is registered with ClinicalTrials.gov, number NCT01041404. Findings 594 patients were randomly assigned to study treatment (trastuzumab plus chemotherapy, n=298; chemotherapy alone, n=296), of whom 584 were included in the primary analysis (n=294; n=290). Median follow-up was 18??6 months (IQR 11-25) in the trastuzumab plus chemotherapy group and 17??1 months (9-25) in the chemotherapy alone group. Median overall survival was 13??8 months (95 CI 12-16) in those assigned to trastuzumab plus chemotherapy compared with 11??1 months (10-13) in those assigned to chemotherapy alone (hazard ratio 0??74; 95 CI 0??60-0??91; p=0??0046). The most common adverse events in both groups were nausea (trastuzumab plus chemotherapy, 197 [67] vs chemotherapy alone, 184 [63]), vomiting (147 [50] vs 134 [46]), and neutropenia (157 [53] vs 165 [57]). Rates of overall grade 3 or 4 adverse events (201 [68] vs 198 [68]) and cardiac adverse events (17 [6] vs 18 [6]) did not differ between groups. Interpretaion Trastuzumab in combination with chemotherapy can be considered as a new standard option for patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer. Funding F Hoffmann-La Roche. ?? 2010 Elsevier Ltd.},
  number = {9742},
  journal = {The Lancet},
  author = {Bang, Yung Jue and Van Cutsem, Eric and Feyereislova, Andrea and Chung, Hyun C. and Shen, Lin and Sawaki, Akira and Lordick, Florian and Ohtsu, Atsushi and Omuro, Yasushi and Satoh, Taroh and Aprile, Giuseppe and Kulikov, Evgeny and Hill, Julie and Lehle, Michaela and R??schoff, Josef and Kang, Yoon Koo},
  year = {2010},
  keywords = {★,DigestiveCancer,Subgroups},
  pages = {687-697},
  file = {/Users/k/Zotero/storage/2V7EB9M9/Bang et al. - 2010 - Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gast.pdf;/Users/k/Zotero/storage/WS7RCS89/Bang et al. - 2010 - Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gast.pdf},
  pmid = {20728210}
}

@article{Freidlin2010,
  title = {Biomarker-Adaptive Clinical Trial Designs.},
  volume = {11},
  issn = {1744-8042},
  doi = {10.2217/pgs.10.153},
  number = {12},
  journal = {Pharmacogenomics},
  author = {Freidlin, Boris and Korn, Edward L},
  year = {2010},
  keywords = {Humans,Biomarkers,Randomized Controlled Trials as Topic,Research Design,Pharmacological,Pharmacological: analysis,Randomized Controlled Trials as Topic: methods,biomarkers},
  pages = {1679-82},
  file = {/Users/k/Zotero/storage/Q657XMTZ/Freidlin, Korn - 2010 - Biomarker-adaptive clinical trial designs.pdf;/Users/k/Zotero/storage/V49K86UC/Freidlin, Korn - 2010 - Biomarker-adaptive clinical trial designs.pdf},
  pmid = {21142910}
}

@article{Kaplan2013,
  title = {Evaluating Many Treatments and Biomarkers in Oncology: {{A}} New Design},
  volume = {31},
  issn = {15277755},
  doi = {10.1200/JCO.2013.50.7905},
  abstract = {There is a pressing need for more-efficient trial designs for biomarker-stratified clinical trials. We suggest a new approach to trial design that links novel treatment evaluation with the concurrent evaluation of a biomarker within a confirmatory phase II/III trial setting. We describe a new protocol using this approach in advanced colorectal cancer called FOCUS4. The protocol will ultimately answer three research questions for a number of treatments and biomarkers: (1) After a period of first-line chemotherapy, do targeted novel therapies provide signals of activity in different biomarker-defined populations? (2) If so, do these definitively improve outcomes? (3) Is evidence of activity restricted to the biomarker-defined groups? The protocol randomizes novel agents against placebo concurrently across a number of different biomarker-defined population-enriched cohorts: BRAF mutation; activated AKT pathway: PI3K mutation/absolute PTEN loss tumors; KRAS and NRAS mutations; and wild type at all the mentioned genes. Within each biomarker-defined population, the trial uses a multistaged approach with flexibility to adapt in response to planned interim analyses for lack of activity. FOCUS4 is the first test of a protocol that assigns all patients with metastatic colorectal cancer to one of a number of parallel population-enriched, biomarker-stratified randomized trials. Using this approach allows questions regarding efficacy and safety of multiple novel therapies to be answered in a relatively quick and efficient manner, while also allowing for the assessment of biomarkers to help target treatment.},
  number = {36},
  journal = {Journal of Clinical Oncology},
  author = {Kaplan, Richard and Maughan, Timothy and Crook, Angela and Fisher, David and Wilson, Richard and Brown, Louise and Parmar, Mahesh},
  year = {2013},
  keywords = {Biomarkers,biomarkers,★},
  pages = {4562-4568},
  file = {/Users/k/Zotero/storage/FRL5VLZR/Kaplan et al. - 2013 - Evaluating many treatments and biomarkers in oncology A new design.pdf;/Users/k/Zotero/storage/K84TGWPX/Kaplan et al. - 2013 - Evaluating many treatments and biomarkers in oncology A new design.pdf},
  pmid = {24248692}
}

@article{Maughan2014,
  title = {A Feasibility Study Testing Four Hypotheses with Phase {{II}} Outcomes in Advanced Colorectal Cancer ({{MRC FOCUS3}}): A Model for Randomised Controlled Trials in the Era of Personalised Medicine?},
  volume = {110},
  issn = {1532-1827},
  doi = {10.1038/bjc.2014.182},
  abstract = {BACKGROUND Molecular characteristics of cancer vary between individuals. In future, most trials will require assessment of biomarkers to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The MRC FOCUS3 trial is a feasibility study to assess key elements in the planning of such studies. PATIENTS AND METHODS Patients with advanced colorectal cancer were registered from 24 centres between February 2010 and April 2011. With their consent, patients' tumour samples were analysed for KRAS/BRAF oncogene mutation status and topoisomerase 1 (topo-1) immunohistochemistry. Patients were then classified into one of four molecular strata; within each strata patients were randomised to one of two hypothesis-driven experimental therapies or a common control arm (FOLFIRI chemotherapy). A 4-stage suite of patient information sheets (PISs) was developed to avoid patient overload. RESULTS A total of 332 patients were registered, 244 randomised. Among randomised patients, biomarker results were provided within 10 working days (w.d.) in 71\%, 15 w.d. in 91\% and 20 w.d. in 99\%. DNA mutation analysis was 100\% concordant between two laboratories. Over 90\% of participants reported excellent understanding of all aspects of the trial. In this randomised phase II setting, omission of irinotecan in the low topo-1 group was associated with increased response rate and addition of cetuximab in the KRAS, BRAF wild-type cohort was associated with longer progression-free survival. CONCLUSIONS Patient samples can be collected and analysed within workable time frames and with reproducible mutation results. Complex multi-arm designs are acceptable to patients with good PIS. Randomisation within each cohort provides outcome data that can inform clinical practice.},
  number = {9},
  journal = {British journal of cancer},
  author = {Maughan, T S and Meade, a M and a Adams, R and Richman, S D and Butler, R and Fisher, D and Wilson, R H and Jasani, B and Taylor, G R and Williams, G T and Sampson, J R and Seymour, M T and Nichols, L L and Kenny, S L and Nelson, A and Sampson, C M and Hodgkinson, E and a Bridgewater, J and Furniss, D L and Roy, R and Pope, M J and Pope, J K and Parmar, M and Quirke, P and Kaplan, R},
  year = {2014},
  keywords = {Biomarkers,a feasibility study testing,a model for,cancer,colorectal cancer,four hypotheses,in advanced colorectal,mrc focus3,multi-arm trials,personalised medicine,with phase ii outcomes,biomarkers,★},
  pages = {2178-86},
  file = {/Users/k/Zotero/storage/U6LUAVK9/Maughan et al. - 2014 - A feasibility study testing four hypotheses with phase II outcomes in advanced colorectal cancer (MRC FOCUS3) a.pdf;/Users/k/Zotero/storage/WH3E5H2C/Maughan et al. - 2014 - A feasibility study testing four hypotheses with phase II outcomes in advanced colorectal cancer (MRC FOCUS3) a.pdf},
  pmid = {24743706}
}

@article{Norman2016,
  title = {Vaginal Progesterone Prophylaxis for Preterm Birth (the {{OPPTIMUM}} Study): A Multicentre, Randomised, Double-Blind Trial},
  volume = {387},
  issn = {01406736},
  doi = {10.1016/S0140-6736(16)00350-0},
  number = {10033},
  journal = {The Lancet},
  author = {Norman, Jane Elizabeth and Marlow, Neil and Messow, Claudia-Martina and Shennan, Andrew and Bennett, Phillip R and Thornton, Steven and Robson, Stephen C and McConnachie, Alex and Petrou, Stavros and Sebire, Neil J and Lavender, Tina and Whyte, Sonia and Norrie, John},
  year = {2016},
  pages = {2106-2116},
  file = {/Users/k/Zotero/storage/K5CE8NS8/Norman et al. - 2016 - Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study) a multicentre, randomised, double-blind t.pdf;/Users/k/Zotero/storage/SBI6G6F6/Norman et al. - 2016 - Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study) a multicentre, randomised, double-blind t.pdf},
  pmid = {26921136}
}

@article{VanVliet2016,
  title = {Nifedipine versus Atosiban for Threatened Preterm Birth ({{APOSTEL III}}): A Multicentre, Randomised Controlled Trial},
  volume = {387},
  issn = {01406736},
  doi = {10.1016/S0140-6736(16)00548-1},
  number = {10033},
  journal = {The Lancet},
  author = {{van Vliet}, Elvira O G and Nijman, Tobias a J and Schuit, Ewoud and Heida, Karst Y and Opmeer, Brent C and Kok, Marjolein and Gyselaers, Wilfried and Porath, Martina M and Woiski, Mallory and Bax, Caroline J and Bloemenkamp, Kitty W M and Scheepers, Hubertina C J and Jacquemyn, Yves and Beek, Erik Van and Duvekot, Johannes J and Franssen, Maureen T M and Papatsonis, Dimitri N and Kok, Joke H and {van der Post}, Joris a M and Franx, Arie and Mol, Ben W and a Oudijk, Martijn},
  year = {2016},
  keywords = {★},
  pages = {2117-2124},
  file = {/Users/k/Zotero/storage/ANA88GA9/van Vliet et al. - 2016 - Nifedipine versus atosiban for threatened preterm birth (APOSTEL III) a multicentre, randomised controlled tri.pdf;/Users/k/Zotero/storage/D33FP8VX/van Vliet et al. - 2016 - Nifedipine versus atosiban for threatened preterm birth (APOSTEL III) a multicentre, randomised controlled tri.pdf},
  pmid = {26944026}
}

@article{Weber2014,
  title = {American {{Society}} of {{Clinical Oncology Policy Statement Update}}: {{The Critical Role}} of {{Phase I Trials}} in {{Cancer Research}} and {{Treatment}}},
  volume = {33},
  issn = {0732183X},
  doi = {10.1200/JCO.2008.16.3691},
  abstract = {Oncologists have a critical opportunity to utilize risk assessment and cancer prevention strategies to interrupt the initiation or progression of cancer in cancer survivors and individuals at high risk of developing cancer. Expanding knowledge about the natural history and prognosis of cancers positions oncologists to advise patients regarding the risk of second malignancies and treatment-related cancers. In addition, as recognized experts in the full spectrum of cancer care, oncologists are afforded opportunities for involvement in community-based cancer prevention activities. Although oncologists are currently providing many cancer prevention and risk assessment services to their patients, economic barriers exist, including inadequate or lack of insurance, that may compromise uniform patient access to these services. Additionally, insufficient reimbursement for existing and developing interventions may discourage patient access to these services. The American Society of Clinical Oncology (ASCO), the medical society representing cancer specialists involved in patient care and clinical research, is committed to supporting oncologists in their wide-ranging involvement in cancer prevention. This statement on risk assessment and prevention counseling, although not intended to be a comprehensive overview of cancer prevention describes the current role of oncologists in risk assessment and prevention; provides examples of risk assessment and prevention activities that should be offered by oncologists; identifies potential opportunities for coordination between oncologists and primary care physicians in prevention education and coordination of care for cancer survivors; describes ASCO's involvement in education and training of oncologists regarding prevention; and proposes improvement in the payment environment to encourage patient access to these services.},
  number = {3},
  journal = {Journal of Clinical Oncology},
  author = {Weber, Jeffrey and Al, Et},
  year = {2014},
  keywords = {DoseFinding,phase i,Phase I},
  pages = {278-285},
  file = {/Users/k/Zotero/storage/3F5RH63P/Weber, Al - 2014 - American Society of Clinical Oncology Policy Statement Update The Critical Role of Phase I Trials in Cancer Research.pdf;/Users/k/Zotero/storage/Z4TT6BRM/Weber, Al - 2014 - American Society of Clinical Oncology Policy Statement Update The Critical Role of Phase I Trials in Cancer Research.pdf},
  pmid = {25512456}
}

@book{Senn2002,
  edition = {2nd},
  title = {Cross-over {{Trials}} in {{Clinical Research}}},
  isbn = {0-471-49653-7},
  publisher = {{Wiley}},
  author = {Senn, Stephen},
  year = {2002}
}

@article{Meacock2016,
  title = {Higher Mortality Rates amongst Emergency Patients Admitted to Hospital at Weekends Reflect a Lower Probability of Admission},
  doi = {10.1177/1355819616649630},
  journal = {Journal of Health Services Research \& Policy},
  author = {Meacock, Rachel and Anselmi, Laura and Kristensen, Soren Rud and Doran, Tim. and Sutton, Matt},
  year = {2016},
  file = {/Users/k/Zotero/storage/4PWGXIYX/Meacock et al. - 2016 - Higher mortality rates amongst emergency patients admitted to hospital at weekends reflect a lower probability o.pdf}
}

@article{Wall2014,
  title = {Effect of Acetazolamide on Visual Function in Patients with Idiopathic Intracranial Hypertension and Mild Visual Loss: The Idiopathic Intracranial Hypertension Treatment Trial.},
  volume = {311},
  issn = {1538-3598},
  doi = {10.1001/jama.2014.3312},
  abstract = {IMPORTANCE: Acetazolamide is commonly used to treat idiopathic intracranial hypertension (IIH), but there is insufficient information to establish an evidence base for its use.$\backslash$n$\backslash$nOBJECTIVE: To determine whether acetazolamide is beneficial in improving vision when added to a low-sodium weight reduction diet in patients with IIH and mild visual loss.$\backslash$n$\backslash$nDESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized, double-masked, placebo-controlled study of acetazolamide in 165 participants with IIH and mild visual loss who received a low-sodium weight-reduction diet. Participants were enrolled at 38 academic and private practice sites in North America from March 2010 to November 2012 and followed up for 6 months (last visit in June 2013). All participants met the modified Dandy criteria for IIH and had a perimetric mean deviation (PMD) between -2 dB and -7 dB. The mean age was 29 years and all but 4 participants were women.$\backslash$n$\backslash$nINTERVENTIONS: Low-sodium weight-reduction diet plus the maximally tolerated dosage of acetazolamide (up to 4 g/d) or matching placebo for 6 months.$\backslash$n$\backslash$nMAIN OUTCOMES AND MEASURES: The planned primary outcome variable was the change in PMD from baseline to month 6 in the most affected eye, as measured by Humphrey Field Analyzer. Perimetric mean deviation is a measure of global visual field loss (mean deviation from age-corrected normal values), with a range of 2 to -32 dB; larger negative values indicate greater vision loss. Secondary outcome variables included changes in papilledema grade, quality of life (Visual Function Questionnaire 25 [VFQ-25] and 36-Item Short Form Health Survey), headache disability, and weight at month 6.$\backslash$n$\backslash$nRESULTS: The mean improvement in PMD was greater with acetazolamide (1.43 dB, from -3.53 dB at baseline to -2.10 dB at month 6; n = 86) than with placebo (0.71 dB, from -3.53 dB to -2.82 dB; n = 79); the difference was 0.71 dB (95\% CI, 0 to 1.43 dB; P = .050). Mean improvements in papilledema grade (acetazolamide: -1.31, from 2.76 to 1.45; placebo: -0.61, from 2.76 to 2.15; treatment effect, -0.70; 95\% CI, -0.99 to -0.41; P $<$ .001) and vision-related quality of life as measured by the National Eye Institute VFQ-25 (acetazolamide: 8.33, from 82.97 to 91.30; placebo: 1.98, from 82.97 to 84.95; treatment effect, 6.35; 95\% CI, 2.22 to 10.47; P = .003) and its 10-item neuro-ophthalmic supplement (acetazolamide: 9.82, from 75.45 to 85.27; placebo: 1.59, from 75.45 to 77.04; treatment effect, 8.23; 95\% CI, 3.89 to 12.56; P $<$ .001) were also observed with acetazolamide. Participants assigned to acetazolamide also experienced a reduction in weight (acetazolamide: -7.50 kg, from 107.72 kg to 100.22 kg; placebo: -3.45 kg, from 107.72 kg to 104.27 kg; treatment effect, -4.05 kg, 95\% CI, -6.27 to -1.83 kg; P $<$ .001).$\backslash$n$\backslash$nCONCLUSIONS AND RELEVANCE: In patients with IIH and mild visual loss, the use of acetazolamide with a low-sodium weight-reduction diet compared with diet alone resulted in modest improvement in visual field function. The clinical importance of this improvement remains to be determined.$\backslash$n$\backslash$nTRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01003639.},
  number = {16},
  journal = {Jama},
  author = {Wall, Michael and McDermott, Michael P and Kieburtz, Karl D and Corbett, James J and Feldon, Steven E and Friedman, Deborah I and Katz, David M and Keltner, John L and Schron, Eleanor B and Kupersmith, Mark J},
  year = {2014},
  keywords = {Adult,Diet,Female,Humans,IdiopathicIntracranialHypertension,Pseudotumor Cerebri,Pseudotumor Cerebri: diet therapy,Treatment Outcome,Weight Loss,Acetazolamide,Acetazolamide: therapeutic use,Carbonic Anhydrase Inhibitors,Carbonic Anhydrase Inhibitors: therapeutic use,Combined Modality Therapy,Male,Pseudotumor Cerebri: complications,Pseudotumor Cerebri: drug therapy,Quality of Life,Sodium-Restricted,Vision Disorders,Vision Disorders: drug therapy,Vision Disorders: etiology,IIH},
  pages = {1641-51},
  file = {/Users/k/Zotero/storage/56KD56SL/Wall et al. - 2014 - Effect of Acetazolamide on Visual Function in Patients With Idiopathic Intracranial Hypertension and Mild Visual(2).pdf;/Users/k/Zotero/storage/94JYK9YS/Wall et al. - 2014 - Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual lo.pdf;/Users/k/Zotero/storage/RFDRX864/Wall et al. - 2014 - Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual lo.pdf},
  pmid = {24756514}
}

@article{Clarke2007,
  title = {Standardising Outcomes for Clinical Trials and Systematic Reviews.},
  volume = {8},
  issn = {1745-6215},
  doi = {10.1186/1745-6215-8-39},
  abstract = {Commentary article concerning problems associated with the standardisation of clinical trials and systematic reviews.},
  journal = {Trials},
  author = {Clarke, Mike},
  year = {2007},
  pages = {39},
  file = {/Users/k/Zotero/storage/NDISLF79/Clarke - 2007 - Standardising outcomes for clinical trials and systematic reviews.pdf;/Users/k/Zotero/storage/W5V3R3CA/Clarke - 2007 - Standardising outcomes for clinical trials and systematic reviews.pdf},
  pmid = {18039365}
}

@article{Sinclair2010,
  title = {Low Energy Diet and Intracranial Pressure in Women with Idiopathic Intracranial Hypertension: Prospective Cohort Study.},
  volume = {341},
  issn = {1756-1833},
  doi = {10.1136/bmj.c2701},
  abstract = {OBJECTIVE: To observe intracranial pressure in women with idiopathic intracranial hypertension who follow a low energy diet.$\backslash$n$\backslash$nDESIGN: Prospective cohort study.$\backslash$n$\backslash$nSETTING: Outpatient department and the clinical research facility based at two separate hospitals within the United Kingdom.$\backslash$n$\backslash$nPARTICIPANTS: 25 women with body mass index (BMI) $>$25, with active (papilloedema and intracranial pressure $>$25 cm H(2)O), chronic (over three months) idiopathic intracranial hypertension. Women who had undergone surgery to treat idiopathic intracranial hypertension were excluded.$\backslash$n$\backslash$nINTERVENTION: Stage 1: no new intervention; stage 2: nutritionally complete low energy (calorie) diet (1777 kJ/day (425 kcal/day)); stage 3: follow-up period after the diet. Each stage lasted three months.$\backslash$n$\backslash$nMAIN OUTCOME MEASURE: The primary outcome was reduction in intracranial pressure after the diet. Secondary measures included score on headache impact test-6, papilloedema (as measured by ultrasonography of the elevation of the optic disc and diameter of the nerve sheath, together with thickness of the peripapillary retina measured by optical coherence tomography), mean deviation of Humphrey visual field, LogMAR visual acuity, and symptoms. Outcome measures were assessed at baseline and three, six, and nine months. Lumbar puncture, to quantify intracranial pressure, was measured at baseline and three and six months.$\backslash$n$\backslash$nRESULTS: All variables remained stable over stage 1. During stage 2, there were significant reductions in weight (mean 15.7 (SD 8.0) kg, P$<$0.001), intracranial pressure (mean 8.0 (SD 4.2) cm H(2)O, P$<$0.001), score on headache impact test (7.6 (SD 10.1), P=0.004), and papilloedema (optic disc elevation (mean 0.15 (SD 0.23) mm, P=0.002), diameter of the nerve sheath (mean 0.7 (SD 0.8) mm, P=0.004), and thickness of the peripapillary retina (mean 25.7 (SD 36.1) micro, P=0.001)). Mean deviation of the Humphrey visual field remained stable, and in only five patients, the LogMAR visual acuity improved by one line. Fewer women reported symptoms including tinnitus, diplopia, and obscurations (10 v 4, P=0.004; 7 v 0, P=0.008; and 4 v 0, P=0.025, respectively). Re-evaluation at three months after the diet showed no significant change in weight (0.21 (SD 6.8) kg), and all outcome measures were maintained.$\backslash$n$\backslash$nCONCLUSION: Women with idiopathic intracranial hypertension who followed a low energy diet for three months had significantly reduced intracranial pressure compared with pressure measured in the three months before the diet, as well as improved symptoms and reduced papilloedema. These reductions persisted for three months after they stopped the diet.},
  number = {jul07\_2},
  journal = {BMJ (Clinical research ed.)},
  author = {Sinclair, Alexandra J and a Burdon, Michael and Nightingale, Peter G and Ball, Alexandra K and Good, Peter and Matthews, Timothy D and Jacks, Andrew and Lawden, Mark and Clarke, Carl E and Stewart, Paul M and a Walker, Elizabeth and Tomlinson, Jeremy W and Rauz, Saaeha},
  year = {2010},
  keywords = {Adult,Diet,Female,Headache Disorders,Headache Disorders: diet therapy,Humans,IdiopathicIntracranialHypertension,Intracranial Pressure,Intracranial Pressure: physiology,Papilledema,Papilledema: diet therapy,Prospective Studies,Pseudotumor Cerebri,Pseudotumor Cerebri: diet therapy,Reducing,Reducing: methods,Treatment Outcome,Weight Loss},
  pages = {c2701},
  file = {/Users/k/Zotero/storage/35WH2AC6/Sinclair et al. - 2010 - Low energy diet and intracranial pressure in women with idiopathic intracranial hypertension prospective cohort.pdf;/Users/k/Zotero/storage/AW744EW9/Sinclair et al. - 2010 - Low energy diet and intracranial pressure in women with idiopathic intracranial hypertension prospective cohort.pdf},
  pmid = {20610512}
}

@article{Tomlinson2010,
  title = {Composite {{End Points}} in {{Randomized Trials}}},
  volume = {303},
  issn = {0098-7484},
  doi = {10.1001/jama.2009.2017},
  number = {3},
  journal = {Jama},
  author = {Tomlinson, George and Detsky, Allan S.},
  year = {2010},
  keywords = {CompositeOutcomes},
  pages = {267},
  file = {/Users/k/Zotero/storage/B9ADMKEP/Tomlinson, Detsky - 2010 - Composite End Points in Randomized Trials.pdf;/Users/k/Zotero/storage/MFIW9P3F/Tomlinson, Detsky - 2010 - Composite End Points in Randomized Trials.pdf}
}

@article{Potter2015,
  title = {Development of a Core Outcome Set for Research and Audit Studies in Reconstructive Breast Surgery},
  volume = {102},
  issn = {13652168},
  doi = {10.1002/bjs.9883},
  abstract = {Background: Appropriate outcome selection is essential if research is to guide decision-making and inform policy. Systematic reviews of the clinical, cosmetic and patient-reported outcomes of reconstruc-tive breast surgery, however, have demonstrated marked heterogeneity, and results from individual studies cannot be compared or combined. Use of a core outcome set may improve the situation. The BRAVO study developed a core outcome set for reconstructive breast surgery. Methods: A long list of outcomes identified from systematic reviews and stakeholder interviews was used to inform a questionnaire survey. Key stakeholders defined as individuals involved in decision-making for reconstructive breast surgery, including patients, breast and plastic surgeons, specialist nurses and psychologists, were sampled purposively and sent the questionnaire (round 1). This asked them to rate the importance of each outcome on a 9-point Likert scale from 1 (not important) to 9 (extremely important). The proportion of respondents rating each item as very important (score 7\textendash{}9) was calculated. This was fed back to participants in a second questionnaire (round 2). Respondents were asked to reprioritize outcomes based on the feedback received. Items considered very important after round 2 were discussed at consensus meetings, where the core outcome set was agreed. Results: A total of 148 items were combined into 34 domains within six categories. Some 303 participants (51$\cdot$4 per cent) (215 (49$\cdot$5 per cent) of 434 patients; 88 (56$\cdot$4 per cent) of 156 professionals) completed and returned the round 1 questionnaire, and 259 (85$\cdot$5 per cent) reprioritized outcomes in round 2. Fifteen items were excluded based on questionnaire scores and 19 were carried forward to the consensus meetings, where a core outcome set containing 11 key outcomes was agreed. Conclusion: The BRAVO study has used robust consensus methodology to develop a core outcome set for reconstructive breast surgery. Widespread adoption by the reconstructive community will improve the quality of outcome assessment in effectiveness studies. Future work will evaluate how these key outcomes should best be measured.},
  number = {11},
  journal = {British Journal of Surgery},
  author = {Potter, S. and Holcombe, C. and a. Ward, J. and Blazeby, J. M.},
  year = {2015},
  keywords = {Surgery,CoreOutcomeSets},
  pages = {1360-1371},
  file = {/Users/k/Zotero/storage/9NFZPAMW/Potter et al. - 2015 - Development of a core outcome set for research and audit studies in reconstructive breast surgery.pdf;/Users/k/Zotero/storage/QEDCYD2K/Potter et al. - 2015 - Development of a core outcome set for research and audit studies in reconstructive breast surgery.pdf},
  pmid = {26179938}
}

@article{Cordoba2010,
  title = {Definition, Reporting, and Interpretation of Composite Outcomes in Clinical Trials: Systematic Review.},
  volume = {341},
  issn = {1756-1833},
  doi = {10.1136/bmj.c3920},
  abstract = {OBJECTIVE: To study how composite outcomes, which have combined several components into a single measure, are defined, reported, and interpreted.$\backslash$n$\backslash$nDESIGN: Systematic review of parallel group randomised clinical trials published in 2008 reporting a binary composite outcome. Two independent observers extracted the data using a standardised data sheet, and two other observers, blinded to the results, selected the most important component.$\backslash$n$\backslash$nRESULTS: Of 40 included trials, 29 (73\%) were about cardiovascular topics and 24 (60\%) were entirely or partly industry funded. Composite outcomes had a median of three components (range 2-9). Death or cardiovascular death was the most important component in 33 trials (83\%). Only one trial provided a good rationale for the choice of components. We judged that the components were not of similar importance in 28 trials (70\%); in 20 of these, death was combined with hospital admission. Other major problems were change in the definition of the composite outcome between the abstract, methods, and results sections (13 trials); missing, ambiguous, or uninterpretable data (9 trials); and post hoc construction of composite outcomes (4 trials). Only 24 trials (60\%) provided reliable estimates for both the composite and its components, and only six trials (15\%) had components of similar, or possibly similar, clinical importance and provided reliable estimates. In 11 of 16 trials with a statistically significant composite, the abstract conclusion falsely implied that the effect applied also to the most important component.$\backslash$n$\backslash$nCONCLUSIONS: The use of composite outcomes in trials is problematic. Components are often unreasonably combined, inconsistently defined, and inadequately reported. These problems will leave many readers confused, often with an exaggerated perception of how well interventions work.},
  journal = {BMJ (Clinical research ed.)},
  author = {Cordoba, Gloria and Schwartz, Lisa and Woloshin, Steven and Bae, Harold and G\o{}tzsche, Peter C},
  year = {2010},
  keywords = {Treatment Outcome,CompositeOutcomes,Randomized Controlled Trials as Topic,Data Interpretation,Randomized Controlled Trials as Topic: standards,Research Design,Research Design: standards,Statistical},
  pages = {c3920},
  file = {/Users/k/Zotero/storage/RNM23845/Cordoba et al. - 2010 - Definition, reporting, and interpretation of composite outcomes in clinical trials systematic review.pdf;/Users/k/Zotero/storage/WBC3DURW/Cordoba et al. - 2010 - Definition, reporting, and interpretation of composite outcomes in clinical trials systematic review.pdf},
  pmid = {20719825}
}

@article{Macefield2014,
  title = {Selecting and Measuring Optimal Outcomes for Randomised Controlled Trials in Surgery},
  volume = {399},
  issn = {14352451},
  doi = {10.1007/s00423-013-1136-8},
  abstract = {BACKGROUND: Randomised controlled trials (RCTs) in surgery are complex to design and conduct and face unique challenges compared to trials in other specialties. The appropriate selection, measurement and reporting of outcomes are one aspect that requires attention. Outcomes in surgical RCTs are often ill-defined, inconsistent and at high risk of bias in their assessment and historically, there has been an undue focus on short-term outcomes and adverse events meaning the value of trial results for clinical practice and decision-making is limited.$\backslash$n$\backslash$nPURPOSE: This review addresses three key problems with surgical trial outcomes-choosing the right outcomes for the trial design and purpose, selecting relevant outcomes to measure from the range of possible outcomes, and measuring outcomes with minimal risk of bias. Each obstacle is discussed in turn, highlighting some suggested solutions and current initiatives working towards improvements in these areas. Some examples of good practice in this field are also discussed.$\backslash$n$\backslash$nCONCLUSIONS: Many of the historical problems with surgical trial outcomes may be overcome with an increased understanding of the trial design and purpose and recognition that pragmatic trials require assessments of outcomes that are patient-centred in addition to measurement of short-term outcomes. The use of core outcome sets developed for specific surgical interventions and the application of novel methods to blind outcome assessors will also improve outcome measurement and reporting. It is recommended that surgeons work together with trial methodologists to integrate these approaches into RCTs in surgery. This will facilitate the appropriate evaluation of surgical interventions with informative outcomes so that results from trials can be useful for clinical practice.},
  number = {3},
  journal = {Langenbeck's Archives of Surgery},
  author = {Macefield, Rhiannon C. and Boulind, Caroline E. and Blazeby, Jane M.},
  year = {2014},
  keywords = {SurrogateOutcomes,Trial design,Surgery,CompositeOutcomes,Outcomes,Randomised controlled trial,Blinding},
  pages = {263-272},
  file = {/Users/k/Zotero/storage/P4JVENIF/Macefield, Boulind, Blazeby - 2014 - Selecting and measuring optimal outcomes for randomised controlled trials in surgery.pdf;/Users/k/Zotero/storage/Z6QBMBDC/Macefield, Boulind, Blazeby - 2014 - Selecting and measuring optimal outcomes for randomised controlled trials in surgery.pdf},
  pmid = {24233344}
}

@article{Jacobe2007,
  title = {Understanding Clinical Trial Outcomes : Design , Analysis ,},
  volume = {20},
  abstract = {Outcomes (a variable intended for comparison between groups) are integral to the design, conduct, and data analysis of a clinical trial. They are broadly divided into four categories: physician based, patient reported, economic based, and technology based. Each is used in dermato- logy to some degree, but no consensus exists as to what type of outcome or degree of validation should be employed. This is problematical because poor quality outcomes or their incorrect use may invalidate the results of a clinical trial. Despite their importance, outcome measures in dermatology receive little attention. The present authors aim to provide an overview of important considerations for outcome measures and a practical approach to their analysis.},
  journal = {Dermatology Therapy},
  author = {Jacobe, Heidi and Leitenberger, Justin and Bergstresser, Paul},
  year = {2007},
  keywords = {SurrogateOutcomes,clinical trial design,outcome measure,statistical analysis},
  pages = {77-85},
  file = {/Users/k/Zotero/storage/T44PP2FZ/Jacobe, Leitenberger, Bergstresser - 2007 - Understanding clinical trial outcomes design , analysis ,.pdf;/Users/k/Zotero/storage/X7WQ5MXJ/Jacobe, Leitenberger, Bergstresser - 2007 - Understanding clinical trial outcomes design , analysis ,.pdf}
}

@article{Calvert2015,
  title = {Composite {{Outcomes}} in {{Randomized Trials Greater Precision But With Greater Uncertainty}} ? {{COMPOSITE OUTCOMES}}},
  volume = {289},
  doi = {10.1001/jama.289.19.2554},
  number = {19},
  journal = {Jama},
  author = {Freemantle, Nick and Calvert, Melanie and Wood, John and Eastaugh, Joanne and Griffin, Carl},
  year = {2003},
  keywords = {CompositeOutcomes},
  pages = {2554-2559},
  file = {/Users/k/Zotero/storage/YLJC498A/Freemantle et al. - 2003 - Composite Outcomes in Randomized Trials Greater Precision But With Greater Uncertainty COMPOSITE OUTCOMES.pdf}
}

@article{Mrc1998,
  title = {Good {{Clinical Practice}} in {{Clinical Trials}}},
  abstract = {This document provides guidelines for good clinical practice (GCP) in MRC trials. During 1998 it will be sent to all the Principal Investigators of MRC trials. The guidelines will be re-issued during 1999 incorporat- ing necessary modifications from feedback received.},
  journal = {MRC Clinical Trials Series},
  author = {{Mrc}},
  year = {1998},
  pages = {47},
  file = {/Users/k/Zotero/storage/F2XU2E5F/Mrc - 1998 - Good Clinical Practice in Clinical Trials.pdf;/Users/k/Zotero/storage/YL2QU4Z6/Mrc - 1998 - Good Clinical Practice in Clinical Trials.pdf}
}

@article{Heinze2011,
  title = {An Overview of the Objectives of and the Approaches to Propensity Score Analyses},
  volume = {32},
  issn = {0195668X},
  doi = {10.1093/eurheartj/ehr031},
  abstract = {The assessment of treatment effects from observational studies may be biased with patients not randomly allocated to the experimental or control group. One way to overcome this conceptual shortcoming in the design of such studies is the use of propensity scores to adjust for differences of the characteristics between patients treated with experimental and control interventions. The propensity score is defined as the probability that a patient received the experimental intervention conditional on pre-treatment characteristics at baseline. Here, we review how propensity scores are estimated and how they can help in adjusting the treatment effect for baseline imbalances. We further discuss how to evaluate adequate overlap of baseline characteristics between patient groups, provide guidelines for variable selection and model building in modelling the propensity score, and review different methods of propensity score adjustments. We conclude that propensity analyses may help in evaluating the comparability of patients in observational studies, and may account for more potential confounding factors than conventional covariate adjustment approaches. However, bias due to unmeasured confounding cannot be corrected for.},
  number = {14},
  journal = {European Heart Journal},
  author = {Heinze, Georg and J\"uni, Peter},
  year = {2011},
  keywords = {Surgery,Bias,Causality,Confounding by indication,Non-randomized studies,Observational studies},
  pages = {1704-1708},
  file = {/Users/k/Zotero/storage/US4FQEZ3/Heinze, Jüni - 2011 - An overview of the objectives of and the approaches to propensity score analyses.pdf},
  pmid = {21362706}
}

@article{Adamina2006,
  title = {Propensity Scores and the Surgeon},
  volume = {93},
  issn = {00071323},
  doi = {10.1002/bjs.5265},
  abstract = {BACKGROUND: Evidence-based surgery has been established as a cornerstone of good clinical practice, promising to improve the treatment of patients and the quality of surgical education. However, evidence-based surgery requires dedicated clinicians trained to perform methodologically sound clinical investigations. Statistical knowledge is therefore invaluable. Surgical studies often cannot be randomized. Propensity scores offer a powerful alternative to multivariable analysis in the assessment of observational, non-randomized surgical studies. Unfortunately, many surgeons are unaware of this important analytical approach that has gained increasing stature in medical research. Thus, propensity score analyses are not used often in surgical studies. OBJECTIVE: The purpose of this paper is to provide a comprehensive overview of propensity score analysis, allowing the surgeon to understand the role, advantages and limitations of propensity scores, boosting their development in surgical investigations.},
  number = {4},
  journal = {British Journal of Surgery},
  author = {Adamina, M. and Guller, U. and Weber, W. P. and Oertli, D.},
  year = {2006},
  keywords = {Surgery},
  pages = {389-394},
  file = {/Users/k/Zotero/storage/HVDHXRPG/Adamina et al. - 2006 - Propensity scores and the surgeon.pdf;/Users/k/Zotero/storage/Z6JE7AQ6/Adamina et al. - 2006 - Propensity scores and the surgeon.pdf},
  pmid = {16400708}
}

@article{Cook2004,
  title = {Statistical Evaluation of Learning Curve Effects in Surgical Trials.},
  volume = {1},
  issn = {1740-7745},
  doi = {10.1191/1740774504cn042oa},
  abstract = {Randomized controlled trials (RCTs) in surgery have been impeded by concerns that improvements in the technical performance of a new technique over time (a "learning curve") may distort comparisons. The statistical assessment of learning curves in trials has received little attention. In this paper, we discuss what a learning curve effect is, the factors which effect it, how to display it, and how to incorporate the learning effect into the trial analysis. Bayesian hierarchical models are proposed to adjust the trial results for the existence of a learning curve effect. The implications for trial evaluation and data collection are considered.},
  number = {5},
  journal = {Clinical trials (London, England)},
  author = {a Cook, Jonathan and Ramsay, Craig R and Fayers, Peter},
  year = {2004},
  keywords = {Surgery},
  pages = {421-427},
  file = {/Users/k/Zotero/storage/6XGGBJX8/Cook, Ramsay, Fayers - 2004 - Statistical evaluation of learning curve effects in surgical trials.pdf;/Users/k/Zotero/storage/JDXUU4SP/Cook, Ramsay, Fayers - 2004 - Statistical evaluation of learning curve effects in surgical trials.pdf},
  pmid = {16279280}
}

@article{Brock2015a,
  title = {186: {{Forecasting}} Patient Recruitment for Time-to-Event Analysis in {{National Lung Matrix Trial}}},
  volume = {87},
  issn = {01695002},
  doi = {10.1016/S0169-5002(15)50180-3},
  number = {2010},
  journal = {Lung Cancer},
  author = {Brock, K. and Billingham, L. and Crack, L. and Popat, S. and Middleton, G.},
  year = {2015},
  keywords = {MyPubs},
  pages = {S69},
  file = {/Users/k/Zotero/storage/93C9YDQI/Brock et al. - 2015 - 186 Forecasting patient recruitment for time-to-event analysis in National Lung Matrix Trial.pdf;/Users/k/Zotero/storage/P7ICUGZG/Brock et al. - 2015 - 186 Forecasting patient recruitment for time-to-event analysis in National Lung Matrix Trial.pdf}
}

@article{Xu2016,
  title = {Bayesian Two-Stage Dose Finding for Cytostatic Agents via Model Adaptation},
  issn = {14679876},
  doi = {10.1111/rssc.12129},
  journal = {Journal of the Royal Statistical Society (Series C)},
  author = {Xu, Jiajing and Yin, Guosheng and Ohlssen, David and Bretz, Frank},
  year = {2016},
  keywords = {bayesian adaptive design,cytostatic agent,deviance information criterion,dose,efficacy,finding,model selection,probit model,toxicity,★},
  pages = {465-482},
  file = {/Users/k/Zotero/storage/BVNTQMJD/Xu et al. - 2016 - Bayesian two-stage dose finding for cytostatic agents via model adaptation.pdf;/Users/k/Zotero/storage/V4IHBKJV/Xu et al. - 2016 - Bayesian two-stage dose finding for cytostatic agents via model adaptation.pdf}
}

@article{Cochran1968,
  title = {The {{Effectiveness}} of {{Adjustment}} by {{Subclassification}} in {{Removing Bias}} in {{Observational Studies}}},
  volume = {24},
  number = {2},
  journal = {Biometrics},
  author = {Cochran, W.G.},
  year = {1968},
  pages = {295-313},
  file = {/Users/k/Zotero/storage/FRSVB6JA/Cochran - 1968 - The Effectiveness of Adjustment by Subclassification in Removing Bias in Observational Studies.pdf;/Users/k/Zotero/storage/GVYNMW5Y/Cochran - 1968 - The Effectiveness of Adjustment by Subclassification in Removing Bias in Observational Studies.pdf}
}

@article{Blazeby2015,
  title = {Core Information Set for Oesophageal Cancer Surgery},
  volume = {102},
  issn = {13652168},
  doi = {10.1002/bjs.9840},
  abstract = {BACKGROUND: Surgeons provide patients with information before surgery, although standards of information are lacking and practice varies. The development and use of a 'core information set' as baseline information before surgery may improve understanding. A core set is a minimum set of information to use in all consultations before a specific procedure. This study developed a core information set for oesophageal cancer surgery.$\backslash$n$\backslash$nMETHODS: Information was identified from the literature, observations of clinical consultations and patient interviews. This was integrated to create a questionnaire survey. Stakeholders (patients and professionals) were surveyed twice to assess views on importance of information from 'not essential' to 'absolutely essential' using Delphi methods. Items not meeting predefined criteria were discarded after each survey and the final retained items were voted on, in separate patient and professional stakeholder meetings, to agree the core set.$\backslash$n$\backslash$nRESULTS: Some 67 information items were identified initially from multiple sources. Survey response rates were 76$\cdot$5 per cent (185 of 242) and 54$\cdot$8 per cent (126 of 230) for patients and professionals respectively (first round), and over 83 per cent in both groups thereafter. Health professionals rated short-term clinical outcomes most highly (technical complications), whereas patients prioritized information related to long-term benefits. The consensus meetings agreed the final set, which consisted of: in-hospital milestones to recovery, rates of open-and-close surgery, in-hospital mortality, major complications (reoperation), milestones in recovery after discharge, longer-term eating and drinking and overall quality of life, and chances of survival.$\backslash$n$\backslash$nCONCLUSION: This study has established a core information set for surgery for oesophageal cancer.},
  number = {8},
  journal = {British Journal of Surgery},
  author = {Blazeby, J. M. and Macefield, R. and Blencowe, N. S. and Jacobs, M. and McNair, a. G K and Sprangers, M. and Brookes, S. T.},
  year = {2015},
  keywords = {Surgery,CoreOutcomeSets},
  pages = {936-943},
  file = {/Users/k/Zotero/storage/GG72IQUE/Blazeby et al. - 2015 - Core information set for oesophageal cancer surgery.pdf;/Users/k/Zotero/storage/KGDVKZ8P/Blazeby et al. - 2015 - Core information set for oesophageal cancer surgery.pdf},
  pmid = {25980524}
}

@article{Loke2015,
  title = {Acquired Isodisomy on Chromosome 13 at Diagnosis Results in Impaired Overall Survival in {{Patients}} with {{FLT3}}-{{ITD}} Mutant Acute Myeloid Leukaemia},
  volume = {25},
  issn = {0887-6924},
  doi = {10.1038/leu.2015.148},
  number = {June},
  journal = {Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K},
  author = {Loke, J C T and Akiki, S and Borrow, J and Ewing, J and Bokhari, S W and Chandra, D and Arrazi, J and Hazlewood, P and Arthur, K and Walsh, J and a Wandroo, F and Watts, a and Borg, a and Brock, K and Craddock, C and Griffiths, M and Raghavan, M and Arrazi, J and Hazlewood, P and Arthur, K and Walsh, J and Membwange, Y and Watts, a and Borg, a and Brock, K and Ferguson, P and Craddock, C and Griffiths, M and Raghavan, M},
  year = {2015},
  keywords = {MyPubs},
  pages = {1-7},
  file = {/Users/k/Zotero/storage/ETP8RVZZ/Loke et al. - 2015 - Acquired isodisomy on chromosome 13 at diagnosis results in impaired overall survival in Patients with FLT3-ITD mut.pdf;/Users/k/Zotero/storage/VVQ3FQUN/Loke et al. - 2015 - Acquired isodisomy on chromosome 13 at diagnosis results in impaired overall survival in Patients with FLT3-ITD mut.pdf}
}

@article{Smith2003,
  title = {Parachute Use to Prevent Death and Major Trauma Related to Gravitational Challenge: Systematic Review of Randomised Controlled Trials.},
  volume = {327},
  issn = {1468-5833},
  doi = {10.1136/bmj.327.7429.1459},
  abstract = {OBJECTIVES: To determine whether parachutes are effective in preventing major trauma related to gravitational challenge. DESIGN: Systematic review of randomised controlled trials. DATA SOURCES: Medline, Web of Science, Embase, and the Cochrane Library databases; appropriate internet sites and citation lists. STUDY SELECTION: Studies showing the effects of using a parachute during free fall. MAIN OUTCOME MEASURE: Death or major trauma, defined as an injury severity score $>$ 15. RESULTS: We were unable to identify any randomised controlled trials of parachute intervention. CONCLUSIONS: As with many interventions intended to prevent ill health, the effectiveness of parachutes has not been subjected to rigorous evaluation by using randomised controlled trials. Advocates of evidence based medicine have criticised the adoption of interventions evaluated by using only observational data. We think that everyone might benefit if the most radical protagonists of evidence based medicine organised and participated in a double blind, randomised, placebo controlled, crossover trial of the parachute.},
  number = {7429},
  journal = {BMJ (Clinical research ed.)},
  author = {Smith, Gordon C S. and Pell, Jill P},
  year = {2003},
  keywords = {Humans,Randomized Controlled Trials as Topic,Accidents,Aviation,Aviation: prevention \& control,Death,Odds Ratio,Protective Devices,Publication Bias,Sudden,Sudden: prevention \& control,Wit and Humor as Topic,Wounds and Injuries,Wounds and Injuries: prevention \& control},
  pages = {1459-61},
  file = {/Users/k/Zotero/storage/N3TMUQER/Smith, Pell - 2003 - Parachute use to prevent death and major trauma related to gravitational challenge systematic review of randomised.pdf;/Users/k/Zotero/storage/V9NNY233/Smith, Pell - 2003 - Parachute use to prevent death and major trauma related to gravitational challenge systematic review of randomised.pdf},
  pmid = {14684649}
}

@article{Ergina2013,
  title = {{{IDEAL}} Framework for Surgical Innovation 2: Observational Studies in the Exploration and Assessment Stages.},
  volume = {346},
  issn = {1756-1833},
  doi = {10.1136/bmj.f3011},
  abstract = {The IDEAL framework describes the stages of evaluation for surgical innovations. This paper considers the role of observational studies in the exploration and assessment stages. At the exploration stage, the surgical intervention is usually more widely used, and observational studies should collect prospective data from multiple surgeons, deal with factors such as case mix and learning, and prepare for a definitive evaluation at the next stage of assessment. Although a randomised controlled trial is preferable, a high quality observational study would be acceptable if a randomised trial is not feasible or, on rare occasions, deemed unnecessary.},
  number = {jun18\_3},
  journal = {BMJ (Clinical research ed.)},
  author = {Ergina, Patrick L and Barkun, Jeffrey S and McCulloch, Peter and a Cook, Jonathan and Altman, Douglas G},
  year = {2013},
  keywords = {Humans,Evaluation Studies as Topic,Inventions,Observation,Observation: methods,Operative,Operative: standards,Surgery,Surgical Procedures},
  pages = {f3011},
  file = {/Users/k/Zotero/storage/BCDD2ZKJ/Ergina et al. - 2013 - IDEAL framework for surgical innovation 2 observational studies in the exploration and assessment stages.pdf;/Users/k/Zotero/storage/CASZXNR3/Ergina et al. - 2013 - IDEAL framework for surgical innovation 2 observational studies in the exploration and assessment stages.pdf},
  pmid = {23778426}
}

@article{Wardlaw2015,
  title = {Noninferiority {{Trials}}: {{Is}} a {{New Treatment Almost}} as {{Effective}} as {{Another}}},
  volume = {313},
  issn = {01406736},
  doi = {10.1001/jama},
  abstract = {An editorial regarding the articles by Salminen et al (2015) and by Kaji et al (2015) on noninferiority testing of anitbiotics vs surgery for appendicitis.},
  number = {23},
  journal = {Jama},
  author = {Kaji, Amy and Lewis, Roger},
  year = {2015},
  keywords = {Appendectomy,Clinical Trials: methods,Clinical Trials: noninferiority,★},
  pages = {2327-8},
  file = {/Users/k/Zotero/storage/XKAFRG9Z/Kaji, Lewis - 2015 - Noninferiority Trials Is a New Treatment Almost as Effective as Another.pdf},
  pmid = {7637476}
}

@article{Wathen2008,
  title = {Accounting for Patient Heterogeneity in Phase {{II}} Clinical Trials {{J}}.},
  volume = {27},
  issn = {02776715},
  journal = {Statistics in medicine},
  author = {Wathen, J. Kyle and Thall, Peter F. and Cook, John D. and Estey, Elihu H},
  year = {2008},
  pages = {2802-2815},
  file = {/Users/k/Zotero/storage/R6GDYGP5/Wathen et al. - 2008 - Accounting for patient heterogeneity in phase II clinical trials J.pdf},
  pmid = {19455509}
}

@article{Thall1996a,
  title = {New Statistical Strategy for Monitoring Safety and Efficacy in Single- Arm Clinical Trials},
  volume = {14},
  issn = {0732-183X},
  abstract = {PURPOSE: Efficacy and toxicity are both important outcomes in cancer clinical trials. Nonetheless, most statistical designs for phase II trials only provide rules for evaluating treatment efficacy, and moreover only allow early stopping after fixed cohorts of patients have been treated. We illustrate a new statistical design strategy for monitoring both adverse and efficacy outcomes on a patient-by-patient basis in phase II and other single-arm clinical trials. DESIGN: The new strategy is used to design a phase II trial of the experimental regimen idarubicin plus cytarabine (ara-C) plus cyclosporine for treatment of patients with intermediate-prognosis acute myelogenous leukemia (AML). The design requires a maximum of 56 patients and provides continuous monitoring boundaries to terminate the trial if the toxicity rate is unacceptably high or the complete remission (CR) rate is unacceptably low compared with the rates of these events with the standard regimen of anthracycline plus ara-C. RESULTS: The design has an 88\% to 91\% probability of stopping the trial early with a median of 15 to 18 patients if the toxicity rate of the experimental regimen is .05 to .10 above that of the standard and there is no improvement in the CR rate. If there is a .15 improvement in the CR rate and the toxicity rate is no more than .05 above that of the standard, then there is at least an 83\% probability that the trial will run to completion. CONCLUSION: The proposed monitoring strategy provides a flexible, practical means to continuously monitor both safety and efficacy in single-arm cancer clinical trials. The design strategy can be implemented easily using a freely available menu-driven computer program, and provides a scientifically sound alternative to the use of ad hoc safety monitoring rules},
  number = {0732-183X SB - M SB - X},
  journal = {J.Clin.Oncol.},
  author = {Thall, P F and Simon, R M and Estey, E H},
  year = {1996},
  keywords = {phase ii,Leukemia,Antineoplastic Agents,Research Design,clinical trials,Monitoring,toxicity,Acute,administration \& dosage,adverse effects,Anthracyclines,Bayes Theorem,Combined,Comparative Study,Cyclosporine,Cytarabine,drug therapy,Human,Idarubicin,Mathematical Computing,methods,Myelocytic,Patients,Physiologic,Probability,Remission Induction,Safety,therapeutic use,United States,Antineoplastic Agents;Combined,Clinical Trials,Clinical Trials;Phase II,Leukemia;Myelocytic;Acute,Monitoring;Physiologic},
  pages = {296-303},
  file = {/Users/k/Zotero/storage/CAMJU3TG/Thall, Simon, Estey - 1996 - New statistical strategy for monitoring safety and efficacy in single- arm clinical trials.pdf;/Users/k/Zotero/storage/DTMG25TC/Thall, Simon, Estey - 1996 - New statistical strategy for monitoring safety and efficacy in single- arm clinical trials(2).pdf},
  pmid = {8558211}
}

@article{Thall1998,
  title = {Some Extensions and Applications of a {{Bayesian}} Strategy for Monitoring Multiple Outcomes in Clinical Trials},
  volume = {17},
  issn = {02776715},
  doi = {10.1002/(SICI)1097-0258(19980730)17:14<1563::AID-SIM873>3.0.CO;2-L},
  abstract = {We present some practical extensions and applications of a strategy proposed by Thall, Simon and Estey for designing and monitoring single-arm clinical trials with multiple outcomes. We show by application how the strategy may be applied to construct designs for phase IIA activity trials and phase II equivalence trials. We also show how it may be extended to incorporate the use of mixture priors in settings where a Dirichlet distribution does not adequately quantify prior experience, randomized phase II selection trials involving two or more experimental treatments, and trials with group-sequential monitoring for applications involving multiple institutions.},
  number = {14},
  journal = {Statistics in Medicine},
  author = {Thall, Peter F. and Sung, Hsi Guang},
  year = {1998},
  pages = {1563-1580},
  file = {/Users/k/Zotero/storage/MCFA8BRU/Thall, Sung - 1998 - Some extensions and applications of a Bayesian strategy for monitoring multiple outcomes in clinical trials.pdf;/Users/k/Zotero/storage/ZJ27ULU3/Thall, Sung - 1998 - Some extensions and applications of a Bayesian strategy for monitoring multiple outcomes in clinical trials.pdf},
  pmid = {9699230}
}

@article{Calvert2014,
  title = {Reporting of {{Patient}}-{{Reported Outcomes}} in {{Randomized Trials}}},
  author = {Calvert, Melanie and Blazeby, Jane and Altman, Douglas G and a Revicki, Dennis and Moher, David and Brundage, Michael D},
  year = {2014},
  keywords = {Outcomes},
  file = {/Users/k/Zotero/storage/7A5VM6Q5/Calvert et al. - 2014 - Reporting of Patient-Reported Outcomes in Randomized Trials.pdf;/Users/k/Zotero/storage/C826DNXK/Calvert et al. - 2014 - Reporting of Patient-Reported Outcomes in Randomized Trials.pdf}
}

@article{Morita2014,
  title = {Biomarker-Based {{Bayesian}} Randomized Phase {{II}} Clinical Trial Design to Identify a Sensitive Patient Subpopulation},
  volume = {33},
  issn = {10970258},
  doi = {10.1002/sim.6209},
  abstract = {The benefits and challenges of incorporating biomarkers into the development of anticancer agents have been increasingly discussed. In many cases, a sensitive subpopulation of patients is determined based on preclinical data and/or by retrospectively analyzing clinical trial data. Prospective exploration of sensitive subpopulations of patients may enable us to efficiently develop definitively effective treatments, resulting in accelerated drug development and a reduction in development costs. We consider the development of a new molecular-targeted treatment in cancer patients. Given preliminary but promising efficacy data observed in a phase I study, it may be worth designing a phase II clinical trial that aims to identify a sensitive subpopulation. In order to achieve this goal, we propose a Bayesian randomized phase II clinical trial design incorporating a biomarker that is measured on a graded scale. We compare two Bayesian methods, one based on subgroup analysis and the other on a regression model, to analyze a time-to-event endpoint such as progression-free survival (PFS) time. The two methods basically estimate Bayesian posterior probabilities of PFS hazard ratios in biomarker subgroups. Extensive simulation studies evaluate these methods' operating characteristics, including the correct identification probabilities of the desired subpopulation under a wide range of clinical scenarios. We also examine the impact of subgroup population proportions on the methods' operating characteristics. Although both methods' performance depends on the distribution of treatment effect and the population proportions across patient subgroups, the regression-based method shows more favorable operating characteristics. Copyright \textcopyright{} 2014 John Wiley \& Sons, Ltd.},
  number = {23},
  journal = {Statistics in medicine},
  author = {Morita, Satoshi and Yamamoto, Hideharu and Sugitani, Yasuo},
  year = {2014},
  keywords = {Biomarkers,randomized phase II trial,Bayesian statistics,biomarker,molecular-targeted agent,time-to-event data,biomarkers},
  pages = {4008-4016},
  file = {/Users/k/Zotero/storage/G5XNNZT3/Morita, Yamamoto, Sugitani - 2014 - Biomarker-based Bayesian randomized phase II clinical trial design to identify a sensitive patient s.pdf;/Users/k/Zotero/storage/UZT7E6CS/Morita, Yamamoto, Sugitani - 2014 - Biomarker-based Bayesian randomized phase II clinical trial design to identify a sensitive patient s.pdf},
  pmid = {24820639}
}

@article{Boers2005,
  title = {{{OMERACT}}: {{An}} International Initiative to Improve Outcome Measurement in Rheumatology},
  volume = {23},
  issn = {0392856X},
  doi = {10.1186/1745-6215-8-38},
  abstract = {OMERACT is the acronym for an international, informally organized network initiated in 1992 aimed at improving outcome measurement in rheumatology. Chaired by an executive committee, it organizes consensus conferences in a 2-yearly cycle that circles the globe. Data driven recommendations are prepared and updated by expert working groups. Recommendations include core sets of measures for most of the major rheumatologic conditions. Since 2002 patients have been actively engaged in the process.},
  number = {5 SUPPL. 39},
  journal = {Clinical and Experimental Rheumatology},
  author = {Boers, Maarten and Brooks, Peter and Simon, Lee S. and Strand, Vibeke and Tugwell, Peter},
  year = {2005},
  keywords = {clinical trial,Outcomes,Longitudinal observational study,Outcome measures,Rheumatology,Clinical trial},
  pages = {1-6},
  file = {/Users/k/Zotero/storage/3HVZUTY6/Boers et al. - 2005 - OMERACT An international initiative to improve outcome measurement in rheumatology.pdf;/Users/k/Zotero/storage/MRTIBDT9/Boers et al. - 2005 - OMERACT An international initiative to improve outcome measurement in rheumatology.pdf},
  pmid = {18039364}
}

@article{Meakins2009,
  title = {Surgical Research: Act 3, Answers},
  volume = {374},
  issn = {01406736},
  doi = {10.1016/S0140-6736(09)61681-0},
  number = {9695},
  journal = {The Lancet},
  author = {Meakins, Jonathan L.},
  year = {2009},
  pages = {1039-1040},
  file = {/Users/k/Zotero/storage/SBQHGNZ9/Meakins - 2009 - Surgical research act 3, answers.pdf;/Users/k/Zotero/storage/ZKXTKQPU/Meakins - 2009 - Surgical research act 3, answers.pdf},
  pmid = {19782853}
}

@article{Barker2004,
  title = {Is Surgical Science Dead?},
  volume = {198},
  issn = {10727515},
  doi = {10.1016/j.jamcollsurg.2003.08.021},
  number = {1},
  journal = {Journal of the American College of Surgeons},
  author = {Barker, Clyde F. and Kaiser, Larry R.},
  year = {2004},
  keywords = {Surgery},
  pages = {1-19},
  file = {/Users/k/Zotero/storage/H495GZIC/Barker, Kaiser - 2004 - Is surgical science dead.pdf;/Users/k/Zotero/storage/HSILUJQX/Barker, Kaiser - 2004 - Is surgical science dead.pdf},
  pmid = {14698306}
}

@article{Birkmeyer2004,
  title = {Measuring the Quality of Surgical Care: {{Structure}}, Process, or Outcomes?},
  volume = {198},
  issn = {10727515},
  doi = {10.1016/j.jamcollsurg.2003.11.017},
  number = {4},
  journal = {Journal of the American College of Surgeons},
  author = {Birkmeyer, John D. and Dimick, Justin B. and Birkmeyer, Nancy J O},
  year = {2004},
  keywords = {Surgery},
  pages = {626-632},
  file = {/Users/k/Zotero/storage/CPBUK2BV/Birkmeyer, Dimick, Birkmeyer - 2004 - Measuring the quality of surgical care Structure, process, or outcomes.pdf;/Users/k/Zotero/storage/S439A6QC/Birkmeyer, Dimick, Birkmeyer - 2004 - Measuring the quality of surgical care Structure, process, or outcomes.pdf},
  pmid = {15051016}
}

@article{Barkun2009,
  title = {Evaluation and Stages of Surgical Innovations},
  volume = {374},
  issn = {01406736},
  doi = {10.1016/S0140-6736(09)61083-7},
  abstract = {Surgical innovation is an important part of surgical practice. Its assessment is complex because of idiosyncrasies related to surgical practice, but necessary so that introduction and adoption of surgical innovations can derive from evidence-based principles rather than trial and error. A regulatory framework is also desirable to protect patients against the potential harms of any novel procedure. In this first of three Series papers on surgical innovation and evaluation, we propose a five-stage paradigm to describe the development of innovative surgical procedures. ?? 2009 Elsevier Ltd. All rights reserved.},
  number = {9695},
  journal = {The Lancet},
  author = {Barkun, Jeffrey S. and Aronson, Jeffrey K. and Feldman, Liane S. and Maddern, Guy J. and Strasberg, Steven M.},
  year = {2009},
  keywords = {Surgery,IDEAL},
  pages = {1089-1096},
  file = {/Users/k/Zotero/storage/HQ9WZE5J/Barkun et al. - 2009 - Evaluation and stages of surgical innovations.pdf;/Users/k/Zotero/storage/PMTAW9UH/Barkun et al. - 2009 - Evaluation and stages of surgical innovations.pdf},
  pmid = {19782874}
}

@article{Ergina2009,
  title = {Challenges in Evaluating Surgical Innovation},
  volume = {374},
  issn = {01406736},
  doi = {10.1016/S0140-6736(09)61086-2},
  abstract = {Research on surgical interventions is associated with several methodological and practical challenges of which few, if any, apply only to surgery. However, surgical evaluation is especially demanding because many of these challenges coincide. In this report, the second of three on surgical innovation and evaluation, we discuss obstacles related to the study design of randomised controlled trials and non-randomised studies assessing surgical interventions. We also describe the issues related to the nature of surgical procedures-for example, their complexity, surgeon-related factors, and the range of outcomes. Although difficult, surgical evaluation is achievable and necessary. Solutions tailored to surgical research and a framework for generating evidence on which to base surgical practice are essential. ?? 2009 Elsevier Ltd. All rights reserved.},
  number = {9695},
  journal = {The Lancet},
  author = {Ergina, Patrick L. and a. Cook, Jonathan and Blazeby, Jane M. and Boutron, Isabelle and Clavien, Pierre Alain and Reeves, Barnaby C. and Seiler, Christoph M.},
  year = {2009},
  keywords = {Surgery,IDEAL},
  pages = {1097-1104},
  file = {/Users/k/Zotero/storage/I3YA62DQ/Ergina et al. - 2009 - Challenges in evaluating surgical innovation.pdf;/Users/k/Zotero/storage/ZIW78CTP/Ergina et al. - 2009 - Challenges in evaluating surgical innovation.pdf},
  pmid = {19782875}
}

@article{GeeKee2013,
  title = {Comparison of Three Different Dressings for Partial Thickness Burns in Children: Study Protocol for a Randomised Controlled Trial.},
  volume = {14},
  issn = {1745-6215},
  doi = {10.1186/1745-6215-14-403},
  abstract = {BACKGROUND: In the paediatric population, pain and distress associated with burn injuries during wound care procedures remain a constant challenge. Although silver dressings are the gold standard for burn care in Australasia, very few high-level trials have been conducted that compare silver dressings to determine which will provide the best level of care clinically. Therefore, for paediatric patients in particular, identifying silver dressings that are associated with lower levels of pain and rapid wound re-epithelialisation is imperative. This study will determine whether there is a difference in time to re-epithelialisation and pain and distress experienced during wound care procedures among Acticoat\texttrademark, Acticoat\texttrademark{} combined with Mepitel\texttrademark{} and Mepilex Ag\texttrademark{} dressings for acute, paediatric partial thickness burns.$\backslash$n$\backslash$nMETHODS/DESIGN: Children aged 0 to 15 years with an acute partial thickness (superficial partial to deep partial thickness inclusive) burn injury and a burn total body surface area of $\leq$ 10\% will be eligible for the trial. Patients will be randomised to one of the three dressing groups: (1) Acticoat\texttrademark{} or (2) Acticoat\texttrademark{} combined with Mepitel\texttrademark{} or (3) Mepilex Ag\texttrademark. A minimum of 28 participants will be recruited for each treatment group. Primary measures of pain, distress and healing will be repeated at each dressing change until complete wound re-epithelialisation occurs or skin grafting is required. Additional data collected will include infection status at each dressing change, physical function, scar outcome and scar management requirements, cost effectiveness of each dressing and staff perspectives of the dressings.$\backslash$n$\backslash$nDISCUSSION: The results of this study will determine the effects of three commonly used silver and silicone burn dressing combinations on the rate of wound re-epithelialisation and pain experienced during dressing procedures in acute, paediatric partial thickness burn injuries.$\backslash$n$\backslash$nTRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12613000105741.},
  journal = {Trials},
  author = {Gee Kee, Emma and Kimble, Roy M and Cuttle, Leila and Stockton, Kellie},
  year = {2013},
  keywords = {burn injuries,Burns,child,distress,healing,pain,partial thickness,randomised clinical trial,silver dressings},
  pages = {403},
  file = {/Users/k/Zotero/storage/6WMMYYXU/Gee Kee et al. - 2013 - Comparison of three different dressings for partial thickness burns in children study protocol for a randomised.pdf;/Users/k/Zotero/storage/QMNC6I86/Gee Kee et al. - 2013 - Comparison of three different dressings for partial thickness burns in children study protocol for a randomised.pdf},
  pmid = {24274190}
}

@article{thallSINGLEARMCLINICALTRIALS1995,
  title = {{{SINGLE}}-{{ARM CLINICAL TRIALS WITH MULTIPLE OUTCOMES}}},
  volume = {14},
  number = {October 1993},
  author = {Thall, Peter F and Simon, Richard M and Estey, Elihu H},
  year = {1995},
  keywords = {★},
  pages = {357-379},
  file = {/Users/k/Zotero/storage/8C4F53RW/Thall, Simon, Estey - 1995 - Single-Arm Clinical Trials With Multiple Outcomes(2).pdf;/Users/k/Zotero/storage/JS7IEXFR/Thall, Simon, Estey - 1995 - SINGLE-ARM CLINICAL TRIALS WITH MULTIPLE OUTCOMES.pdf;/Users/k/Zotero/storage/YXHTD9DQ/Thall, Simon, Estey - 1995 - Single-Arm Clinical Trials With Multiple Outcomes(2).pdf}
}

@article{Billingham2004,
  title = {Modelling the {{Time}} to {{Recurrent Infections}} in a {{Randomised Double}}-{{Blind}} , {{Placebo}}- {{Controlled Trial}} of {{Antibacterial Prophylaxis Following Myelosuppressive Chemotherapy}} in {{Patients}} with {{Solid Tumours}} or {{Lymphoma Time}} to {{First Infection}} by {{Treatment Arm}}},
  abstract = {The risk of infection in patients with solid tumours or lymphoma is increased by treatment with chemotherapy and the role of prophylactic antibacterials has remained controversial. A placebo-controlled, double-blind, randomised trial using the antibacterial drug levofloxacin was designed to resolve this controversy and inform clinical practice. The trial has recently completed recruitment and some preliminary data are presented here.},
  author = {Billingham, Lucinda and Steven, Neil and Gaunt, Claire and Cullen, Michael},
  year = {2004},
  keywords = {RepeatedEvents},
  file = {/Users/k/Zotero/storage/EEIVWVX7/Billingham et al. - 2004 - Modelling the Time to Recurrent Infections in a Randomised Double-Blind , Placebo- Controlled Trial of Antiba.pdf;/Users/k/Zotero/storage/UHI5QXZL/Billingham et al. - 2004 - Modelling the Time to Recurrent Infections in a Randomised Double-Blind , Placebo- Controlled Trial of Antiba.pdf}
}

@article{Antoniou2016,
  title = {Biomarker-{{Guided Adaptive Trial Designs}} in {{Phase II}} and {{Phase III}}: {{A Methodological Review}}},
  volume = {11},
  issn = {1932-6203},
  doi = {10.1371/journal.pone.0149803},
  number = {2},
  journal = {Plos One},
  author = {Antoniou, Miranta and Jorgensen, Andrea L and {Kolamunnage-Dona}, Ruwanthi},
  year = {2016},
  keywords = {Biomarkers,biomarkers},
  pages = {e0149803},
  file = {/Users/k/Zotero/storage/LG7BVJ57/Antoniou, Jorgensen, Kolamunnage-Dona - 2016 - Biomarker-Guided Adaptive Trial Designs in Phase II and Phase III A Methodological Review.pdf}
}

@article{Brock2015,
  title = {Modelling Clinical Trial Recruitment Using Poisson Processes},
  volume = {16},
  issn = {1745-6215},
  doi = {10.1186/1745-6215-16-S2-P85},
  number = {Suppl 2},
  journal = {Trials},
  author = {Brock, Kristian and Yap, Christina and Middleton, Gary and Billingham, Lucinda},
  year = {2015},
  keywords = {MyPubs},
  pages = {P85},
  file = {/Users/k/Zotero/storage/BU5QUSKR/Brock et al. - 2015 - Modelling clinical trial recruitment using poisson processes.pdf}
}

@article{Jung2008,
  title = {Randomized Phase {{II}} Trials with a Prospective Control {{Sin}}-{{Ho}}},
  volume = {27},
  issn = {02776715},
  journal = {Statistics in medicine},
  author = {Jung, Sin-Ho},
  year = {2008},
  pages = {568-583},
  file = {/Users/k/Zotero/storage/GDH22XBF/Jung - 2008 - Randomized phase II trials with a prospective control Sin-Ho.pdf},
  pmid = {19455509}
}

@article{McGranahan2016,
  title = {Clonal Neoantigens Elicit {{T}} Cell Immunoreactivity and Sensitivity to Immune Checkpoint Blockade},
  volume = {Accepted f},
  issn = {1095-9203},
  doi = {10.1126/science.aaf1490},
  number = {March},
  journal = {Science},
  author = {McGranahan, Nicholas and Furness, Andrew J.S. and Rosenthal, Rachel and Ramskov, Sofie and Lyngaa, Rikke and Saini, Sunil Kumar and {Jamal-Hanjani}, Mariam and a. Wilson, Gareth and Birkbak, Nicolai J. and Hiley, Crispin T. and Watkins, Tom B.K. and Shafi, Seema and Murugaesu, Nirupa and Mitter, Richard and Akarca, Ayse U. and Linares, Joseph and Marafioti, Teresa and Henry, Jake Y. and Allen, Eliezer M. Van and Miao, Diana and Schilling, Bastian and Schadendorf, Dirk and a. Garraway, Levi and Makarov, Vladimir and a. Rizvi, Naiyer and Snyder, Alexandra and Hellmann, Matthew D. and Merghoub, Taha and Wolchok, Jedd D. and a. Shukla, Sachet and Wu, Catherine J. and Peggs, Karl S. and a. Chan, Timothy and Hadrup, Sine R. and a. Quezada, Sergio and Swanton, Charles},
  year = {2016},
  pages = {1-11},
  file = {/Users/k/Zotero/storage/EMVZDMPG/McGranahan et al. - 2016 - Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade.pdf;/Users/k/Zotero/storage/LNSNTWA7/McGranahan et al. - 2016 - Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade.pdf}
}

@article{Wages2013,
  title = {Using the Time-to-Event Continual Reassessment Method in the Presence of Partial Orders},
  volume = {72},
  issn = {1878-5832},
  doi = {10.1038/nature13314.A},
  abstract = {The time-to-event continual reassessment method (TITE-CRM) was proposed to handle the problem of long trial duration in Phase 1 trials as a result of late-onset toxicities. Here, we implement the TITE-CRM in dose\textendash{}finding trials of combinations of agents. When studying multiple agents, monotonicity of the dose-toxicity curve is not clearly defined. Therefore, the toxicity probabilities follow a partial order, meaning that there are pairs of treatments for which the ordering of the toxicity probabilities is not known at the start of the trial. A CRM design for partially ordered trials (PO-CRM) was recently proposed. Simulation studies show that extending the TITE-CRM to the partial order setting produces results similar to those of the PO-CRM in terms of maximum tolerated dose recommendation yet reduces the duration of the trial.},
  number = {2},
  author = {Wages, Nolan and Conaway, Mark and O'Quigley, John},
  year = {2013},
  keywords = {Continual reassessment method,Dose finding,CRM,drug combination,partial order,phase 1 trials,time-,TITE-CRM,continual reassessment method,dose finding},
  pages = {181-204},
  file = {/Users/k/Zotero/storage/XAZ8CQV9/Wages, Conaway, O'Quigley - 2013 - Using the time-to-event continual reassessment method in the presence of partial orders.pdf;/Users/k/Zotero/storage/ZHL3DYK5/Wages, Conaway, O'Quigley - 2013 - Using the time-to-event continual reassessment method in the presence of partial orders.pdf},
  pmid = {21959306}
}

@article{Polley2011,
  title = {Practical Modifications to the Time-to-Event Continual Reassessment Method for Phase {{I}} Cancer Trials with Fast Patient Accrual and Late-Onset Toxicities},
  volume = {30},
  issn = {02776715},
  doi = {10.1002/sim.4255},
  abstract = {The goal of phase I cancer trials is to determine the highest dose of a treatment regimen with an acceptable toxicity rate. Traditional designs for phase I trials, such as the Continual Reassessment Method (CRM) and the 3 + 3 design, require each patient or a cohort of patients to be fully evaluated for the dose-limiting toxicity (DLT) before new patients can be enrolled. As such, the trial duration may be prohibitively long. The Time-to-Event Continual Reassessment Method (TITE-CRM, Cheung and Chappell, 2000) circumvents this limitation by allowing staggered patient accrual without the need for complete DLT follow-up of previously treated patients. However, in the setting of fast patient accrual and late-onset toxicities, the TITE-CRM results in overly aggressive dose escalation and exposes a considerable number of patients to toxic doses. We examine a modification to the TITE-CRM proposed by the original TITE-CRM creator and propose an alternative approach useful in this setting by incorporating an accrual suspension rule. A simulation study designed based on a neuro-oncology trial indicates that the modified methods provide a much improved degree of safety than the TITE-CRM while maintaining desirable design accuracy. The practical aspects of the proposed designs are discussed. The modifications presented are useful when planning phase I trials involving chemoradiation therapy.},
  number = {17},
  journal = {Statistics in Medicine},
  author = {Polley, Mei Yin C},
  year = {2011},
  keywords = {adaptive design,Dose finding,Bayesian inference,CRM,TITE-CRM,Late-onset toxicity,Phase I clinical trials,Time-to-Event Continual Reassessment Method,Adaptive design},
  pages = {2130-2143},
  file = {/Users/k/Zotero/storage/4Z8VD94X/Polley - 2011 - Practical modifications to the time-to-event continual reassessment method for phase I cancer trials with fast patient a.pdf;/Users/k/Zotero/storage/Z2ANBHVE/Polley - 2011 - Practical modifications to the time-to-event continual reassessment method for phase I cancer trials with fast patient a.pdf},
  pmid = {21590790}
}

@article{Malottki2016,
  title = {Problems of Variable Biomarker Evaluation in Stratified Medicine Research\textemdash{{A}} Case Study of {{ERCC1}} in Non-Small-Cell Lung Cancer},
  volume = {92},
  issn = {01695002},
  doi = {10.1016/j.lungcan.2015.11.017},
  journal = {Lung Cancer},
  author = {Malottki, Kinga and Popat, Sanjay and Deeks, Jonathan J. and Riley, Richard D. and Nicholson, Andrew G. and Billingham, Lucinda},
  year = {2016},
  pages = {1-7},
  file = {/Users/k/Zotero/storage/EBNGQCX8/Malottki et al. - 2016 - Problems of variable biomarker evaluation in stratified medicine research—A case study of ERCC1 in non-small-.pdf;/Users/k/Zotero/storage/S37RSEQJ/Malottki et al. - 2016 - Problems of variable biomarker evaluation in stratified medicine research—A case study of ERCC1 in non-small-.pdf}
}

@article{Billingham2016,
  title = {Series {{Rare}} Cancers {{XX Research}} Methods to Change Clinical Practice for Patients with Rare Cancers},
  volume = {17},
  issn = {1470-2045},
  doi = {10.1016/S1470-2045(15)00396-4},
  abstract = {Rare cancers are a growing group as a result of reclassification of common cancers by molecular markers. There is therefore an increasing need to identify methods to assess interventions that are sufficiently robust to potentially affect clinical practice in this setting. Methods advocated for clinical trials in rare diseases are not necessarily applicable in rare cancers. This Series paper describes research methods that are relevant for rare cancers in relation to the sliding scale [A: please clarify this concept in the text] of rarity. Strategies that maximise recruitment, minimise sample size, or maximise the usefulness of the evidence could enable the application of conventional clinical trial design to rare cancer populations. Alternative designs that address specific challenges for rare cancers with the aim of potentially changing clinical practice include Bayesian designs, uncontrolled n-of-1 trials, and umbrella and basket trials. Pragmatic solutions must be sought to enable some level of evidence-based health care for patients with rare cancers.},
  number = {2},
  journal = {Lancet Oncology},
  author = {Billingham, Lucinda and Malottki, Kinga and Steven, Neil},
  year = {2016},
  keywords = {RareDiseases},
  pages = {e70-e80},
  file = {/Users/k/Zotero/storage/8EUU286G/Billingham, Malottki, Steven - 2016 - Series Rare cancers XX Research methods to change clinical practice for patients with rare cancers.pdf;/Users/k/Zotero/storage/ZTMTHK3A/Billingham, Malottki, Steven - 2016 - Series Rare cancers XX Research methods to change clinical practice for patients with rare cancers.pdf}
}

@article{Anthonissen2013,
  title = {Measurement of Elasticity and Transepidermal Water Loss Rate of Burn Scars with the {{Dermalab}}??},
  issn = {03054179},
  doi = {10.1016/j.burns.2012.07.026},
  abstract = {This cross-sectional study investigated the reproducibility of repeated elasticity and transepidermal water loss (TEWL) measurements with the DermaLab?? on 32 active burn scars and healthy skin. Intra- and inter-observer reproducibility was examined by means of intra-class correlation coefficients (ICC) and standard error of measurements (SEM). Results showed good ICC values and rather high SEM values for inter- and intra-observer reproducibility of elasticity measurements. For TEWL measurements, ICC values were good and SEM values were high for inter- and intra-observer reproducibility. There was a significant difference between the estimated mean elasticity values of normal skin and grafted scars and between normal skin and spontaneously healed scars (p ??? 0.003). For the estimated mean TEWL values, there was a significant difference between normal skin and spontaneously healed scars (p = 0.036). A significant negative relation was reported between mean TEWL and time after burn (p = 0.008). In clinical trials it is necessary to interpret patient-specific changes in elasticity and TEWL with caution, since the SEMs of both modes are rather high. We therefore recommend the use of a mean of repeated measurements of elasticity and TEWL to decrease the SEM. ?? 2012 Elsevier Ltd and ISBI. All rights reserved.},
  journal = {Burns},
  author = {Anthonissen, Mieke and Daly, Daniel and Fieuws, Steffen and Massag??, Patrick and Van Brussel, Michel and Vranckx, Jan and Van Den Kerckhove, Eric},
  year = {2013},
  keywords = {Burns,Burn scar,DermaLab??,Elasticity,Transepidermal water loss},
  file = {/Users/k/Zotero/storage/IUFWEZEB/Anthonissen et al. - 2013 - Measurement of elasticity and transepidermal water loss rate of burn scars with the Dermalab.pdf;/Users/k/Zotero/storage/MEGE7BCB/Anthonissen et al. - 2013 - Measurement of elasticity and transepidermal water loss rate of burn scars with the Dermalab.pdf},
  pmid = {23000371}
}

@article{OQuigley1996,
  title = {Continual Reassessment Method: A Likelihood Approach},
  volume = {52},
  issn = {0006-\{341X\}},
  doi = {10.2307/2532905},
  abstract = {The continual reassessment method as described by \{O'Quigley\}, Pepe, and Fisher (1990, Biometrics 46, 33-48) leans to a large extent upon a Bayesian methodology. Initial experimentation and sequential updating are carried out in a natural way within the context of a Bayesian framework. In this paper we argue that such a framework is easily changed to a more classic one leaning upon likelihood theory. The essential features of the continual reassessment method remain unchanged. In particular, large sample properties are the same unless the prior is degenerate. For small samples and as far as the final recommended dose level is concerned, simulations indicate that there is not much to choose between a likelihood approach and a Bayesian one. However, for in-trial allocation of dose levels to patients, there are some differences and these are discussed. In contrast to the Bayesian approach, a likelihood one requires some extra effort to get off the ground. This is because the likelihood equation has no solution until we observe a toxicity. Initially then we suggest working with either a standard Up-and-Down scheme or standard continual reassessment method until toxicity is observed and then switching to the new scheme.},
  number = {2},
  journal = {Biometrics},
  author = {O'Quigley, J and Shen, L Z},
  year = {1996},
  keywords = {Humans,Data Interpretation,Statistical,clinical trials,Phase I as Topic,Clinical Trials as Topic,Bayes Theorem,Biometry,Drug Toxicity,Likelihood Functions,Pharmaceutical Preparations,Phase {II} as Topic,Clinical Trials},
  pages = {673-684},
  file = {/Users/k/Zotero/storage/9J44DE6F/O'Quigley, Shen - 1996 - Continual reassessment method a likelihood approach.pdf;/Users/k/Zotero/storage/BR3W4TBN/O'Quigley, Shen - 1996 - Continual reassessment method a likelihood approach.pdf},
  pmid = {8672707}
}

@misc{clintrials,
  title = {Clintrials},
  abstract = {clintrials is a library of clinical trial designs and methods in Python. This library is intended to facilitate research.},
  howpublished = {GitHub},
  author = {Brock, Kristian},
  year = {2016},
  keywords = {Software}
}

@article{Qaqish2003,
  title = {A Family of Multivariate Binary Distributions for Simulating Correlated Binary Variables with Specified Marginal Means and Correlations},
  volume = {90},
  issn = {00063444},
  doi = {10.1093/biomet/90.2.455},
  abstract = {... The latter step generally requires a Choleski decomposition and generation of n standard normal variates ... i in (3) is maximised over the 2i-1 possible y 1 ,...,y i-1 sequences  ... This is not a big limitation since the difficulty in simulating correlated  binary observations lies mainly with ... $\backslash$n},
  number = {2},
  journal = {Biometrika},
  author = {Qaqish, Bahjat F.},
  year = {2003},
  keywords = {Autoregressive correlation structure,Clustered data,Correlated Bernoulli variates,Exchangeable correlation structure,Simulation},
  pages = {455-463},
  file = {/Users/k/Zotero/storage/2WBI3BAC/Qaqish - 2003 - A family of multivariate binary distributions for simulating correlated binary variables with specified marginal means a.pdf;/Users/k/Zotero/storage/WERVKGBP/Qaqish - 2003 - A family of multivariate binary distributions for simulating correlated binary variables with specified marginal means a.pdf}
}

@misc{binarySimCLF,
  title = {{{binarySimCLF}}},
  abstract = {Simulates correlated binary data in R. The algorithm is based on Qaqish (2003)},
  howpublished = {CRAN},
  author = {By, Kunthel and Qaqish, Bahjat F.},
  keywords = {Software},
  file = {/Users/k/Zotero/storage/BKUXQGA2/By, Qaqish - Unknown - binarySimCLF.gz}
}

@misc{EffTox,
  title = {{{EffTox}}},
  abstract = {This computer program provides a basis for constructing, simulating, and conducting the EffTox phase I-II clinical trial design described in the paper ``Dose-finding based on efficacy-toxicity trade-offs'', Thall and Cook, Biometrics 60:684-693,2004 [1]. Please read this paper before using this program, which implements the trial design, simulation, and conduct. Please note that very important improvements/refinements have been made in two key elements, (1) the prior and (2) the trade-off contour. These are explained in the tutorial, available here and in the computer program.},
  howpublished = {MD Anderson Cancer Center},
  author = {Herrick, R and Norris, C and Cook, JD and Venier, J},
  year = {2015},
  keywords = {EfficacyToxicity,Software}
}

@article{Schiller2002,
  title = {Comparison of Four Chemotherapy Regimens for Advanced Non-Small-Cell Lung Cancer.},
  volume = {346},
  issn = {1533-4406},
  doi = {10.1056/NEJMoa011954},
  abstract = {BACKGROUND: We conducted a randomized study to determine whether any of three chemotherapy regimens was superior to cisplatin and paclitaxel in patients with advanced non-small-cell lung cancer.$\backslash$n$\backslash$nMETHODS: A total of 1207 patients with advanced non-small-cell lung cancer were randomly assigned to a reference regimen of cisplatin and paclitaxel or to one of three experimental regimens: cisplatin and gemcitabine, cisplatin and docetaxel, or carboplatin and paclitaxel.$\backslash$n$\backslash$nRESULTS: The response rate for all 1155 eligible patients was 19 percent, with a median survival of 7.9 months (95 percent confidence interval, 7.3 to 8.5), a 1-year survival rate of 33 percent (95 percent confidence interval, 30 to 36 percent), and a 2-year survival rate of 11 percent (95 percent confidence interval, 8 to 12 percent). The response rate and survival did not differ significantly between patients assigned to receive cisplatin and paclitaxel and those assigned to receive any of the three experimental regimens. Treatment with cisplatin and gemcitabine was associated with a significantly longer time to the progression of disease than was treatment with cisplatin and paclitaxel but was more likely to cause grade 3, 4, or 5 renal toxicity (in 9 percent of patients, vs. 3 percent of those treated with cisplatin plus paclitaxel). Patients with a performance status of 2 had a significantly lower rate of survival than did those with a performance status of 0 or 1.$\backslash$n$\backslash$nCONCLUSIONS: None of four chemotherapy regimens offered a significant advantage over the others in the treatment of advanced non-small-cell lung cancer.},
  number = {2},
  journal = {The New England journal of medicine},
  author = {Schiller, Joan H and Harrington, David and Belani, Chandra P and Langer, Corey and Sandler, Alan and Krook, James and Zhu, Junming and Johnson, David H},
  year = {2002},
  keywords = {Adult,Female,Humans,Middle Aged,NSCLC,Male,80 and over,Aged,Antineoplastic Combined Chemotherapy Protocols,Antineoplastic Combined Chemotherapy Protocols: ad,Antineoplastic Combined Chemotherapy Protocols: th,Carcinoma,Chemo,Cisplatin,Cisplatin: administration \& dosage,Deoxycytidine,Deoxycytidine: administration \& dosage,Deoxycytidine: analogs \& derivatives,Disease-Free Survival,Lung Neoplasms,Lung Neoplasms: drug therapy,Lung Neoplasms: mortality,Non-Small-Cell Lung,Non-Small-Cell Lung: drug therapy,Non-Small-Cell Lung: mortality,Paclitaxel,Paclitaxel: administration \& dosage,Paclitaxel: analogs \& derivatives,Survival Analysis,Taxoids,Aged; 80 and over,Carcinoma; Non-Small-Cell Lung,Carcinoma; Non-Small-Cell Lung: drug therapy,Carcinoma; Non-Small-Cell Lung: mortality},
  pages = {92-8},
  file = {/Users/k/Zotero/storage/FI3X4YD9/Schiller et al. - 2002 - Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.pdf;/Users/k/Zotero/storage/KZXEWJJM/Schiller et al. - 2002 - Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.pdf},
  pmid = {11784875}
}

@article{Details2000,
  title = {Tests for {{Two Proportions}} in a {{Repeated Measures Design}}},
  number = {1},
  journal = {Power},
  author = {Details, Technical},
  year = {2000},
  keywords = {AssociationsInCategoricalData},
  pages = {1-13},
  file = {/Users/k/Zotero/storage/YJZMV9FD/Details - 2000 - Tests for Two Proportions in a Repeated Measures Design.pdf}
}

@article{Lachin2011,
  title = {Power and Sample Size Evaluation for the {{Cochran}}-{{Mantel}}-{{Haenszel}} Mean Score ({{Wilcoxon}} Rank Sum) Test and the {{Cochran}}-{{Armitage}} Test for Trend},
  issn = {02776715},
  doi = {10.1002/sim.4330},
  abstract = {The power of a chi-square test, and thus the required sample size, are a function of the noncentrality parameter that can be obtained as the limiting expectation of the test statistic under an alternative hypothesis specification. Herein, we apply this principle to derive simple expressions for two tests that are commonly applied to discrete ordinal data. The Wilcoxon rank sum test for the equality of distributions in two groups is algebraically equivalent to the Mann-Whitney test. The Kruskal-Wallis test applies to multiple groups. These tests are equivalent to a Cochran-Mantel-Haenszel mean score test using rank scores for a set of C-discrete categories. Although various authors have assessed the power function of the Wilcoxon and Mann-Whitney tests, herein it is shown that the power of these tests with discrete observations, that is, with tied ranks, is readily provided by the power function of the corresponding Cochran-Mantel-Haenszel mean scores test for two and R $>$ 2 groups. These expressions yield results virtually identical to those derived previously for rank scores and also apply to other score functions. The Cochran-Armitage test for trend assesses whether there is an monotonically increasing or decreasing trend in the proportions with a positive outcome or response over the C-ordered categories of an ordinal independent variable, for example, dose. Herein, it is shown that the power of the test is a function of the slope of the response probabilities over the ordinal scores assigned to the groups that yields simple expressions for the power of the test.},
  journal = {Statistics in Medicine},
  author = {Lachin, John M.},
  year = {2011},
  keywords = {AssociationsInCategoricalData,Cochran-Armitage test for trend,Cochran-Mantel-Haenszel mean score test,Kruskal-Wallis test,Power,sample size,Wilcoxon rank sum test,Sample size},
  file = {/Users/k/Zotero/storage/BA9IPHJF/Lachin - 2011 - Power and sample size evaluation for the Cochran-Mantel-Haenszel mean score (Wilcoxon rank sum) test and the Cochran-Arm.pdf;/Users/k/Zotero/storage/GGQDNH2L/Lachin - 2011 - Power and sample size evaluation for the Cochran-Mantel-Haenszel mean score (Wilcoxon rank sum) test and the Cochran-Arm.pdf},
  pmid = {22006667}
}

@article{Gelman2013,
  archivePrefix = {arXiv},
  eprinttype = {arxiv},
  eprint = {1307.5928v1},
  title = {Understanding Predictive Information Criteria for {{Bayesian}} Models},
  issn = {09603174},
  doi = {10.1007/s11222-013-9416-2},
  abstract = {We review the Akaike, deviance, and Watanabe-Akaike information criteria from a Bayesian$\backslash$nperspective, where the goal is to estimate expected out-of-sample-prediction error using a biascorrected adjustment of within-sample error. We focus on the choices involved in setting up these$\backslash$nmeasures, and we compare them in three simple examples, one theoretical and two applied. The$\backslash$ncontribution of this paper is to put all these information criteria into a Bayesian predictive$\backslash$ncontext and to better understand, through small examples, how these methods can apply in$\backslash$npractice.},
  journal = {Statistics and Computing},
  author = {Gelman, Andrew and Hwang, Jessica and Vehtari, Aki},
  year = {2013},
  keywords = {AIC,Bayes,Cross-validation,DIC,Prediction,WAIC},
  pages = {1-20},
  file = {/Users/k/Zotero/storage/CXRYIBQR/Gelman, Hwang, Vehtari - 2013 - Understanding predictive information criteria for Bayesian models.pdf;/Users/k/Zotero/storage/JWBAQKHQ/Gelman, Hwang, Vehtari - 2013 - Understanding predictive information criteria for Bayesian models.pdf}
}

@article{Roberts2015a,
  title = {Targeting {{BCL2}} with {{Venetoclax}} in {{Relapsed Chronic Lymphocytic Leukemia}}},
  issn = {0028-4793},
  doi = {10.1056/NEJMoa1513257},
  journal = {New England Journal of Medicine},
  author = {Roberts, Andrew W. and Davids, Matthew S. and Pagel, John M. and Kahl, Brad S. and Puvvada, Soham D. and Gerecitano, John F. and Kipps, Thomas J. and Anderson, Mary Ann and Brown, Jennifer R. and Gressick, Lori and Wong, Shekman and Dunbar, Martin and Zhu, Ming and Desai, Monali B. and Cerri, Elisa and Enschede, Sari Heitner and a. Humerickhouse, Rod and Wierda, William G. and Seymour, John F.},
  year = {2015},
  keywords = {CLL,BCL-2},
  pages = {151206090218007},
  file = {/Users/k/Zotero/storage/6KIPFZSM/Roberts et al. - 2015 - Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia(2).pdf;/Users/k/Zotero/storage/CUV42K7V/Roberts et al. - 2015 - Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia(2).pdf},
  pmid = {26639348}
}

@article{Spiegelhalter2005,
  title = {Funnel Plots for Comparing Institutional Performance},
  volume = {24},
  issn = {02776715},
  doi = {10.1002/sim.1970},
  abstract = {'Funnel plots' are recommended as a graphical aid for institutional comparisons, in which an estimate of an underlying quantity is plotted against an interpretable measure of its precision. 'Control limits' form a funnel around the target outcome, in a close analogy to standard Shewhart control charts. Examples are given for comparing proportions and changes in rates, assessing association between outcome and volume of cases, and dealing with over-dispersion due to unmeasured risk factors. We conclude that funnel plots are flexible, attractively simple, and avoid spurious ranking of institutions into 'league tables'.},
  number = {8},
  journal = {Statistics in Medicine},
  author = {Spiegelhalter, David J.},
  year = {2005},
  keywords = {Heterogeneity,Control charts,Institutional profiling,Outliers,Over-dispersion,Ranking},
  pages = {1185-1202},
  file = {/Users/k/Zotero/storage/C8LIA8QA/Spiegelhalter - 2005 - Funnel plots for comparing institutional performance.pdf},
  pmid = {15568194}
}

@article{Spiegelhalter2003,
  title = {Risk-Adjusted Sequential Probability Ratio Tests: {{Applications}} to {{Bristol}}, {{Shipman}} and Adult Cardiac Surgery},
  volume = {15},
  issn = {13534505},
  doi = {10.1093/intqhc/15.1.7},
  abstract = {OBJECTIVE: To investigate the use of the risk-adjusted sequential probability ratio test in monitoring the cumulative occurrence of adverse clinical outcomes. DESIGN: Retrospective analysis of three longitudinal datasets. SUBJECTS: Patients aged 65 years and over under the care of Harold Shipman between 1979 and 1997, patients under 1 year of age undergoing paediatric heart surgery in Bristol Royal Infirmary between 1984 and 1995, adult patients receiving cardiac surgery from a team of cardiac surgeons in London,UK. MAIN OUTCOME MEASURE: Annual and 30-day mortality rates. RESULTS: Using reasonable boundaries, the procedure could have indicated an 'alarm' in Bristol after publication of the 1991 Cardiac Surgical Register, and in 1985 or 1997 for Harold Shipman depending on the data source and the comparator. The cardiac surgeons showed no significant deviation from expected performance. CONCLUSIONS: The risk-adjusted sequential probability test is simple to implement, can be applied in a variety of contexts, and might have been useful to detect specific instances of past divergent performance. The use of this and related techniques deserves further attention in the context of prospectively monitoring adverse clinical outcomes.},
  number = {1},
  journal = {International Journal for Quality in Health Care},
  author = {Spiegelhalter, David and Grigg, Olivia and Kinsman, Robin and Treasure, Tom},
  year = {2003},
  keywords = {Surgery,Adverse clinical outcomes,General practitioners,Heterogeneity,Monitoring,Mortality,Paediatric and adult cardiac surgery,Risk-adjustment,Sequential probability ratio tests},
  pages = {7-13},
  file = {/Users/k/Zotero/storage/XFVIDZCF/Spiegelhalter et al. - 2003 - Risk-adjusted sequential probability ratio tests Applications to Bristol, Shipman and adult cardiac surger.pdf},
  pmid = {12630796}
}

@article{White2009,
  title = {Accounting for Regression-to-the-Mean in Tests for Recent Changes in Institutional Performance: {{Analysis}} and Power},
  volume = {28},
  issn = {02776715},
  abstract = {Although sample size calculations have become an important element in the design of research projects, such methods for studies involving current status data are scarce. Here, we propose a method for calculating power and sample size for studies using current status data. This method is based on a Weibull survival model for a two-group comparison. The Weibull model allows the investigator to specify a group difference in terms of a hazards ratio or a failure time ratio. We consider exponential, Weibull and uniformly distributed censoring distributions. We base our power calculations on a parametric approach with the Wald test because it is easy for medical investigators to conceptualize and specify the required input variables. As expected, studies with current status data have substantially less power than studies with the usual right-censored failure time data. Our simulation results demonstrate the merits of these proposed power calculations.},
  number = {15},
  journal = {Statistics in medicine},
  author = {Jones, Hayley E. and Spiegelhalter, David J.},
  year = {2009},
  keywords = {Heterogeneity,missing covariates,missing data,multiple imputation,proportional hazards model},
  pages = {1982-1998},
  file = {/Users/k/Zotero/storage/J4DCIHJI/Jones, Spiegelhalter - 2009 - Accounting for regression-to-the-mean in tests for recent changes in institutional performance Analysis an.pdf},
  pmid = {19455509}
}

@article{Borghaei2015,
  title = {Nivolumab versus {{Docetaxel}} in {{Advanced Squamous}}-{{Cell Non}}-{{Small}}-{{Cell Lung Cancer}}.},
  volume = {373},
  issn = {1533-4406},
  doi = {10.1056/NEJMoa1504627},
  abstract = {Background Patients with advanced squamous-cell non-small-cell lung cancer (NSCLC) who have disease progression during or after first-line chemotherapy have limited treatment options. This randomized, open-label, international, phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, as compared with docetaxel in this patient population. Methods We randomly assigned 272 patients to receive nivolumab, at a dose of 3 mg per kilogram of body weight every 2 weeks, or docetaxel, at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival. Results The median overall survival was 9.2 months (95\% confidence interval [CI], 7.3 to 13.3) with nivolumab versus 6.0 months (95\% CI, 5.1 to 7.3) with docetaxel. The risk of death was 41\% lower with nivolumab than with docetaxel (hazard ratio, 0.59; 95\% CI, 0.44 to 0.79; P$<$0.001). At 1 year, the overall survival rate was 42\% (95\% CI, 34 to 50) with nivolumab versus 24\% (95\% CI, 17 to 31) with docetaxel. The response rate was 20\% with nivolumab versus 9\% with docetaxel (P=0.008). The median progression-free survival was 3.5 months with nivolumab versus 2.8 months with docetaxel (hazard ratio for death or disease progression, 0.62; 95\% CI, 0.47 to 0.81; P$<$0.001). The expression of the PD-1 ligand (PD-L1) was neither prognostic nor predictive of benefit. Treatment-related adverse events of grade 3 or 4 were reported in 7\% of the patients in the nivolumab group as compared with 55\% of those in the docetaxel group. Conclusions Among patients with advanced, previously treated squamous-cell NSCLC, overall survival, response rate, and progression-free survival were significantly better with nivolumab than with docetaxel, regardless of PD-L1 expression level. (Funded by Bristol-Myers Squibb; CheckMate 017 ClinicalTrials.gov number, NCT01642004 .).},
  journal = {The New England journal of medicine},
  author = {Borghaei, H. and {Paz-Ares}, L. and Horn, L. and Spigel, D.R. and Steins, M. and Ready, N.E. and Chow, L.Q. and Vokes, E.E. and Felip, E. and Holgado, E. and Barlesi, F. and Kohlh\"aufl, M. and Arrieta, O. and Burgio, M.A. and Fayette, J. and Lena, H. and Poddubskaya, E. and Gerber, D.E. and Gettinger, S.N. and Rudin, C.M. and Rizvi, N. and Crin\`o, L. and G.R. Blumenschein, Jr. and Antonia, S.J. and Dorange, C. and Harbison, C.T. and Finckenstein, F. Graf and Brahmer, J.R.},
  year = {2015},
  keywords = {Aged,Antibodies,Antigens,Antineoplastic Agents,Antineoplastic Agents: adverse effects,Antineoplastic Agents: therapeutic use,Carcinoma,CD274,CD274: antagonists \& inhibitors,CD274: immunology,CD274: metabolism,Female,Humans,Lung Neoplasms,Lung Neoplasms: drug therapy,Lung Neoplasms: mortality,Male,Middle Aged,Monoclonal,Monoclonal: adverse effects,Monoclonal: therapeutic use,Nivolumab,Non-Small-Cell Lung,Non-Small-Cell Lung: drug therapy,Non-Small-Cell Lung: mortality,NSCLC,PD1,Survival Analysis,Taxoids,Taxoids: adverse effects,Taxoids: therapeutic use},
  pages = {123-135},
  file = {/Users/k/Zotero/storage/BVAGP5R3/Borghaei et al. - 2015 - Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer.pdf;/Users/k/Zotero/storage/JZDHBSDV/Borghaei et al. - 2015 - Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer.pdf;/Users/k/Zotero/storage/NBASIEZ4/Borghaei et al. - 2015 - Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer.pdf;/Users/k/Zotero/storage/P95WHBFG/Borghaei et al. - 2015 - Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer.pdf},
  pmid = {26028407}
}

@article{Garon2015,
  title = {Pembrolizumab for the Treatment of Non-Small-Cell Lung Cancer.},
  volume = {372},
  issn = {1533-4406},
  doi = {10.1056/NEJMoa1501824},
  abstract = {BACKGROUND We assessed the efficacy and safety of programmed cell death 1 (PD-1) inhibition with pembrolizumab in patients with advanced non-small-cell lung cancer enrolled in a phase 1 study. We also sought to define and validate an expression level of the PD-1 ligand 1 (PD-L1) that is associated with the likelihood of clinical benefit. METHODS We assigned 495 patients receiving pembrolizumab (at a dose of either 2 mg or 10 mg per kilogram of body weight every 3 weeks or 10 mg per kilogram every 2 weeks) to either a training group (182 patients) or a validation group (313 patients). We assessed PD-L1 expression in tumor samples using immunohistochemical analysis, with results reported as the percentage of neoplastic cells with staining for membranous PD-L1 (proportion score). Response was assessed every 9 weeks by central review. RESULTS Common side effects that were attributed to pembrolizumab were fatigue, pruritus, and decreased appetite, with no clear difference according to dose or schedule. Among all the patients, the objective response rate was 19.4\%, and the median duration of response was 12.5 months. The median duration of progression-free survival was 3.7 months, and the median duration of overall survival was 12.0 months. PD-L1 expression in at least 50\% of tumor cells was selected as the cutoff from the training group. Among patients with a proportion score of at least 50\% in the validation group, the response rate was 45.2\%. Among all the patients with a proportion score of at least 50\%, median progression-free survival was 6.3 months; median overall survival was not reached. CONCLUSIONS Pembrolizumab had an acceptable side-effect profile and showed antitumor activity in patients with advanced non-small-cell lung cancer. PD-L1 expression in at least 50\% of tumor cells correlated with improved efficacy of pembrolizumab. (Funded by Merck; KEYNOTE-001 ClinicalTrials.gov number, NCT01295827.).},
  number = {21},
  journal = {The New England journal of medicine},
  author = {Garon, Edward B and a Rizvi, Naiyer and Hui, Rina and Leighl, Natasha and Balmanoukian, Ani S and Eder, Joseph Paul and Patnaik, Amita and Aggarwal, Charu and Gubens, Matthew and Horn, Leora and Carcereny, Enric and Ahn, Myung-ju and Felip, Enriqueta and Lee, Jong-seok and Hellmann, Matthew D and Hamid, Omid and Goldman, Jonathan W and Soria, Jean-charles and {Dolled-Filhart}, Marisa and Rutledge, Ruth Z and Zhang, Jin and Lunceford, Jared K and Rangwala, Reshma and Lubiniecki, Gregory M and Roach, Charlotte and Emancipator, Kenneth and Gandhi, Leena and {KEYNOTE-001 Investigators}},
  year = {2015},
  keywords = {NSCLC,PD1,Pembrolizumab,pembrolizumab},
  pages = {2018-28},
  file = {/Users/k/Zotero/storage/FX6YHWVD/Garon et al. - 2015 - Pembrolizumab for the treatment of non-small-cell lung cancer.pdf;/Users/k/Zotero/storage/M2G82ZUR/Garon et al. - 2015 - Pembrolizumab for the treatment of non-small-cell lung cancer.pdf;/Users/k/Zotero/storage/WZG8ZXVG/Garon et al. - 2015 - Supplement - Pembrolizumab for the treatment of non-small-cell lung cancer.pdf;/Users/k/Zotero/storage/XJCGD99B/Garon et al. - 2015 - Pembrolizumab for the treatment of non-small-cell lung cancer(2).pdf},
  pmid = {25891174}
}

@article{Guilhot2015,
  title = {Analyzing Molecular Response in Chronic Myeloid Leukemia Clinical Trials: {{Pitfalls}} and Golden Rules},
  volume = {121},
  issn = {10970142},
  doi = {10.1002/cncr.29053},
  number = {4},
  journal = {Cancer},
  author = {Guilhot, Joelle and Preudhomme, Claude and Mahon, Francois Xavier and Guilhot, Fran??ois},
  year = {2015},
  keywords = {SurrogateOutcomes,CML,BCR-ABL1,Chronic myeloid leukemia,Molecular response,Statistical analyses},
  pages = {490-497},
  file = {/Users/k/Zotero/storage/GSTWQTGP/Guilhot et al. - 2015 - Analyzing molecular response in chronic myeloid leukemia clinical trials Pitfalls and golden rules.pdf}
}

@article{philipsonExperimentsSubjectSampling1997,
  title = {Experiments and Subject Sampling},
  author = {Philipson, B Y Tomas},
  year = {1997},
  pages = {619-630},
  file = {/Users/k/Zotero/storage/CGQIAD3Y/Philipson - 1997 - Experiments and subject sampling.pdf}
}

@article{Plimack2017,
  title = {Safety and Activity of Pembrolizumab in Patients with Locally Advanced or Metastatic Urothelial Cancer ({{KEYNOTE}}-012): A Non-Randomised, Open-Label, Phase 1b Study},
  volume = {2045},
  issn = {14702045},
  doi = {10.1016/S1470-2045(17)30007-4},
  number = {17},
  journal = {The Lancet Oncology},
  author = {Plimack, Elizabeth R and Bellmunt, Joaquim and Gupta, Shilpa and Berger, Raanan and Chow, Laura Q M and Juco, Jonathan and Lunceford, Jared and Saraf, Sanatan and Perini, Rodolfo F and O'Donnell, Peter H},
  year = {2017},
  pages = {1-8},
  file = {/Users/k/Zotero/storage/K8LTPLYN/Plimack et al. - 2017 - Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEYNOTE-.pdf}
}

@article{Shashok2017,
  title = {Can Scientists and Their Institutions Become Their Own Open Access Publishers?},
  abstract = {This article offers a personal perspective on the current state of academic publishing, and posits that the scientific community is beset with journals that contribute little valuable knowledge, overload the community's capacity for high-quality peer review, and waste resources. Open access publishing can offer solutions that benefit researchers and other information users, as well as institutions and funders, but commercial journal publishers have influenced open access policies and practices in ways that favor their economic interests over those of other stakeholders in knowledge creation and sharing. One way to free research from constraints on access is the diamond route of open access publishing, in which institutions and funders that produce new knowledge reclaim responsibility for publication via institutional journals or other open platforms. I argue that research journals (especially those published for profit) may no longer be fit for purpose, and hope that readers will consider whether the time has come to put responsibility for publishing back into the hands of researchers and their institutions. The potential advantages and challenges involved in a shift away from for-profit journals in favor of institutional open access publishing are explored.},
  author = {Shashok, Karen and Ruiz, Compositor},
  year = {2017},
  keywords = {academic publishing,diamond,editors,ethics,funders,gold,green,institutions,journals,open access,peer review,research center,research quality,researchers,stakeholders},
  pages = {1-23},
  file = {/Users/k/Zotero/storage/UR6FBHCM/Shashok, Ruiz - 2017 - Can scientists and their institutions become their own open access publishers.pdf}
}

@article{Soverini2006,
  title = {Contribution of {{ABL}} Kinase Domain Mutations to Imatinib Resistance in Different Subsets of {{Philadelphia}}-Positive Patients: {{By}} the {{GIMEMA}} Working Party on Chronic Myeloid Leukemia},
  volume = {12},
  issn = {10780432},
  doi = {10.1158/1078-0432.CCR-06-1516},
  abstract = {PURPOSE: ABL kinase domain mutations have been implicated in the resistance to the BCR-ABL inhibitor imatinib mesylate of Philadelphia-positive (Ph+) leukemia patients. EXPERIMENTAL DESIGN: Using denaturing high-performance liquid chromatography and sequencing, we screened for ABL kinase domain mutations in 370 Ph+ patients with evidence of hematologic or cytogenetic resistance to imatinib. RESULTS: Mutations were found in 127 of 297 (43\%) evaluable patients. Mutations were found in 27\% of chronic-phase patients (14\% treated with imatinib frontline; 31\% treated with imatinib post-IFN failure), 52\% of accelerated-phase patients, 75\% of myeloid blast crisis patients, and 83\% of lymphoid blast crisis/Ph+ acute lymphoblastic leukemia (ALL) patients. Mutations were associated in 30\% of patients with primary resistance (44\% hematologic and 28\% cytogenetic) and in 57\% of patients with acquired resistance (23\% patients who lost cytogenetic response; 55\% patients who lost hematologic response; and 87\% patients who progressed to accelerated phase/blast crisis). P-loop and T315I mutations were particularly frequent in advanced-phase chronic myeloid leukemia and Ph+ ALL patients, and often accompanied progression from chronic phase to accelerated phase/blast crisis. CONCLUSIONS: We conclude that (a) amino acid substitutions at seven residues (M244V, G250E, Y253F/H, E255K/V, T315I, M351T, and F359V) account for 85\% of all resistance-associated mutations; (b) the search for mutations is important both in case of imatinib failure and in case of loss of response at the hematologic or cytogenetic level; (c) advanced-phase chronic myeloid leukemia and Ph+ ALL patients have a higher likelihood of developing imatinib-resistant mutations; and (d) the presence of either P-loop or T315I mutations in imatinib-treated patients should warn the clinician to reconsider the therapeutic strategy.},
  number = {24},
  journal = {Clinical Cancer Research},
  author = {Soverini, Simona and Colarossi, Sabrina and Gnani, Alessandra and Rosti, Gianantonio and Castagnetti, Fausto and Poerio, Angela and Iacobucci, Ilaria and Amabile, Marilina and Abruzzese, Elisabetta and Orlandi, Ester and Radaelli, Franca and Ciccone, Fabrizio and Tiribelli, Mario and Di Lorenzo, Roberto and Caracciolo, Clementina and Izzo, Barbara and Pane, Fabrizio and Saglio, Giuseppe and Baccarani, Michele and Martinelli, Giovanni},
  year = {2006},
  pages = {7374-7379},
  file = {/Users/k/Zotero/storage/MTL5CU3M/Soverini et al. - 2006 - Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positiv.pdf},
  pmid = {17189410}
}

@article{Jain2011,
  title = {Chronic {{Myelogenous Leukemia}}: {{Role}} of {{Stem Cell Transplant}} in the {{Imatinib Era}}},
  volume = {25},
  issn = {08898588},
  doi = {10.1016/j.hoc.2011.09.003},
  abstract = {In the pre-tyrosine kinase (TKI) era, allogeneic stem cell transplant (allo-SCT) was the front-line treatment of choice for young patients with chronic myelogenous leukemia (CML). Today, imatinib is well established as front-line therapy for CML, with excellent long-term outcomes. This has changed the role of allo-SCT and the number of patients undergoing allo-SCT has declined dramatically. Allo-SCT is currently recommended for patients in accelerated/blast phase disease, those who have failed a second-generation TKI and those with TKI-resistant mutations such as T315I. The role of allo-SCT in the management of CML will require continual reappraisal as medical therapies continue to evolve. ?? 2011 Elsevier Inc.},
  number = {5},
  journal = {Hematology/Oncology Clinics of North America},
  author = {Jain, Nitin and Van Besien, Koen},
  year = {2011},
  keywords = {Allogeneic stem cell transplant,Chronic myelogenous leukemia,Imatinib,Tyrosine kinase inhibitors},
  pages = {1025-1048},
  file = {/Users/k/Zotero/storage/RWVSCKZP/Jain, Van Besien - 2011 - Chronic Myelogenous Leukemia Role of Stem Cell Transplant in the Imatinib Era.pdf},
  pmid = {22054733}
}

@article{saglioHHSPublicAccess2016,
  title = {{{HHS Public Access}}},
  volume = {116},
  doi = {10.1002/cncr.25123.Dasatinib},
  number = {16},
  author = {Saglio, Giuseppe and Hochhaus, Andreas and Goh, Yeow Tee and Masszi, Tamas and Pasquini, Ricardo and Maloisel, Frederic and Erben, Philipp and Cortes, Jorge and Paquette, Ronald and {Bradley-garelik}, M Brigid and Zhu, Chao and Sciences, Biological and Jena, Universitaetsklinikum and Curitiba, De Clinicas De and Clinic, Medical and Angeles, Los},
  year = {2016},
  pages = {3852-3861},
  file = {/Users/k/Zotero/storage/TQ9D3N2N/Saglio et al. - 2016 - HHS Public Access.pdf}
}

@article{Saglio2010,
  title = {Dasatinib in Imatinib-Resistant or Imatinib-Intolerant Chronic Myeloid Leukemia in Blast Phase after 2 Years of Follow-up in a Phase 3 Study: {{Efficacy}} and Tolerability of 140 Milligrams Once Daily and 70 Milligrams Twice Daily},
  volume = {116},
  issn = {0008543X},
  doi = {10.1002/cncr.25123},
  abstract = {BACKGROUND: In a phase 3 study, the authors assessed the effects of dasatinib at doses of 140 mg once daily and 70 mg twice daily in patients who had either chronic myeloid leukemia (CML) in advanced phases or Philadelphia chromosome-positive acute lymphoblastic leukemia and were resistant or intolerant to imatinib. In the current report, the results for patients with CML in blast phase after 2 years of follow-up are reported.$\backslash$n$\backslash$nMETHODS: Patients were stratified according to whether they had CML in myeloid blast phase (MBP-CML) or in lymphoid blast phase (LBP-CML) and were randomized (1:1) within each stratum to receive either oral dasatinib 140 mg once daily or 70 mg twice daily.$\backslash$n$\backslash$nRESULTS: In patients with MBP-CML, the major hematologic response rate was 28\% for both regimens; and, in patients with LBP-CML, the major hematologic response rate was 42\% for once-daily dasatinib and 32\% for twice-daily dasatinib. The major cytogenetic response rates were 25\% for once-daily dasatinib and 28\% for twice-daily dasatinib in patients with MBP-CML, and the respective rates in patients with LBP-CML were 50\% and 40\%. The overall survival rate at 24 months was 24\% for once-daily dasatinib and 28\% for twice-daily dasatinib in patients with MBP-CML, and the respective values in patients with LBP-CML were 21\% and 16\%. Adverse events indicated a trend toward improved tolerability for the once-daily regimen.$\backslash$n$\backslash$nCONCLUSIONS: The current results suggested that dasatinib 140 mg once daily had similar efficacy and improved tolerability relative to the 70-mg twice-daily regimen in patients with imatinib-resistant, blast phase CML.},
  number = {16},
  journal = {Cancer},
  author = {Saglio, Giuseppe and Hochhaus, Andreas and Goh, Yeow Tee and Masszi, Tamas and Pasquini, Ricardo and Maloisel, Frederic and Erben, Philipp and Cortes, Jorge and Paquette, Ronald and {Bradley-Garelik}, M. Brigid and Zhu, Chao and Dombret, Herve},
  year = {2010},
  keywords = {Chronic myeloid leukemia,Imatinib,Blast crisis,Dasatinib,Drug resistance},
  pages = {3852-3861},
  file = {/Users/k/Zotero/storage/PANCSDLJ/Saglio et al. - 2010 - Dasatinib in imatinib-resistant or imatinib-intolerant chronic myeloid leukemia in blast phase after 2 years of f.pdf},
  pmid = {20564086}
}

@article{Druker2001,
  title = {Activity of a Specific Inhibitor of the {{BCR}}-{{ABL}} Tyrosine Kinase in the Blast Crisis of {{Chronic Myeloid Leukemia}} and {{Acute Lymphoblastic Leukemia}} with the {{Philadelphia}} Chromosome},
  volume = {344},
  number = {14},
  journal = {New England Journal of Medicine},
  author = {Druker, Brian J. and Sawyers, Charles L. and Kantarjian, Hagop and Resta, Debra J. and Reese, Sofia Fernandes and Ford, John M. and Capdeville, Renaud and Talpaz, Moshe},
  year = {2001},
  keywords = {CML},
  pages = {1038-1042},
  file = {/Users/k/Zotero/storage/CI29ERZ7/Druker et al. - 2001 - Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of Chronic Myeloid Leukemia a.pdf}
}

@article{Hehlmann2012,
  title = {How {{I}} Treat {{CML}} Blast Crisis {{How I}} Treat {{How I}} Treat {{CML}} Blast Crisis},
  volume = {120},
  doi = {10.1182/blood-2012-03-380147},
  abstract = {http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml\#repub\_requests Information about reproducing this article in parts or in its entirety may be found online at: http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml\#reprints Information about ordering reprints may be found online at: http://bloodjournal.hematologylibrary.org/site/subscriptions/index.xhtml Information about subscriptions and ASH membership may be found online at: Blast crisis (BC) remains the major chal-lenge in the management of chronic my-eloid leukemia (CML). It is now generally accepted that BC is the consequence of continued BCR-ABL activity leading to genetic instability, DNA damage, and im-paired DNA repair. Most patients with BC carry multiple mutations, and up to 80\% show additional chromosomal aber-rations in a nonrandom pattern. Treat-ment with tyrosine kinase inhibitors has improved survival in BC modestly, but most long-term survivors are those who have been transplanted. Patients in BC should be treated with a tyrosine kinase inhibitor according to mutation profile, with or without chemotherapy, with the goal of achieving a second chronic phase and proceeding to allogeneic stem cell transplantation as quickly as possible. Although long-term remissions are rare, allogeneic stem cell transplantation pro-vides the best chance of a cure in BC. Investigational agents are not likely to provide an alternative in the near future. In view of these limited options, preven-tion of BC by a rigorous and early elimina-tion of BCR-ABL is recommended. Early response indicators should be used to select patients for alternative therapies and early transplantation. Every attempt should be made to reduce or eliminate BCR-ABL consistent with good patient care as far as possible. (Blood. 2012; 120(4):737-747)},
  number = {4},
  journal = {Blood},
  author = {Hehlmann, Ruediger},
  year = {2012},
  pages = {737-748},
  file = {/Users/k/Zotero/storage/2BCP884L/Hehlmann - 2012 - How I treat CML blast crisis How I treat How I treat CML blast crisis.pdf}
}

@article{Palandri2008,
  title = {Chronic Myeloid Leukemia in Blast Crisis Treated with Imatinib 600 Mg: {{Outcome}} of the Patients Alive after a 6-Year Follow-Up},
  volume = {93},
  issn = {03906078},
  doi = {10.3324/haematol.13068},
  abstract = {BACKGROUND:Imatinib mesylate is the first line treatment for chronic myeloid leukemia. In patients with advanced phase of the disease, the advent of imatinib significantly increased survival. However, few long-term data, based on large, prospective and controlled trials are available on the outcome of these patients. DESIGN AND METHODS:We conducted a phase II trial of imatinib 600 mg daily in patients with chronic myeloid leukemia in blast crisis. The return to chronic phase was defined as $<$15\% blasts and $<$30\% blasts plus promyelocytes in blood or bone marrow and $<$20\% peripheral basophils. A complete hematologic response required the normalization of platelet and white cell differential counts and absence of extramedullary involvement. Cytogenetic response was assessed by the standard banding technique and rated as usual. RESULTS:Ninety-two patients were enrolled (20 with lymphoid blast crisis and 72 with myeloid blast crisis). Forty-six patients (50\%) returned to chronic phase, and 24 patients (26\%) achieved also a complete hematologic response. Sixteen patients (17\%) had a cytogenetic response (9 complete, 1 partial, and 6 minor or minimal). The complete cytogenetic response was subsequently lost by all but two patients between 2 and 12 months after first having achieved it: the median duration of complete cytogenetic response was 7 months. All responses were sustained for a minimum of 4 weeks. The median survival of all the patients was 7 months. After a median observation time of 66 months, seven (8\%) patients are alive. Three of these patients are on imatinib treatment (1 in complete hematologic remission, 1 in partial cytogenetic response and 1 in complete cytogenetic remission). Three patients are in complete remission after allogeneic stem cell transplantation. One patient is alive in blast crisis, on therapy with a second-generation tyrosine kinase inhibitor. CONCLUSIONS:Imatinib was effective and safe in the short-term treatment of chronic myeloid leukemia in blast crisis, but longer-term outcome was not significantly influenced (ClinicalTrials.gov identifier: NCT00514969).},
  number = {12},
  journal = {Haematologica},
  author = {Palandri, Francesca and Castagnetti, Fausto and Testoni, Nicoletta and Luatti, Simona and Marzocchi, Giulia and Bassi, Simona and Breccia, Massimo and Alimena, Giuliana and Pungolino, Ester and {Rege-Cambrin}, Giovanna and Varaldo, Riccardo and Miglino, Maurizio and Specchia, Giorgina and Zuffa, Eliana and Ferrara, Felicetto and Bocchia, Monica and Saglio, Giuseppe and Pane, Fabrizio and Alberti, Daniele and Martinelli, Giovanni and Baccarani, Michele and Rosti, Gianantonio},
  year = {2008},
  keywords = {Chronic myeloid leukemia,Imatinib,Blast crisis,Long-term,Outcome},
  pages = {1792-1796},
  file = {/Users/k/Zotero/storage/APHB7K4H/Palandri et al. - 2008 - Chronic myeloid leukemia in blast crisis treated with imatinib 600 mg Outcome of the patients alive after a 6-y.pdf},
  pmid = {18838477}
}

@article{Giles2012,
  title = {Nilotinib Is Effective in Imatinib-Resistant or -Intolerant Patients with Chronic Myeloid Leukemia in Blastic Phase.},
  volume = {26},
  issn = {1476-5551},
  doi = {10.1038/leu.2011.355},
  abstract = {Nilotinib is a selective inhibitor of BCR-ABL approved for use in newly diagnosed and imatinib-resistant or -intolerant patients with chronic myeloid leukemia (CML) in chronic phase. In this study, 400 mg of nilotinib was administered twice daily to the patients with myeloid (MBP, n=105) or lymphoid blastic phase (LBP, n=31) CML. After a minimum follow-up of 24 months, major hematologic responses were observed in 60\% (MBP) and 59\% (LBP) of patients. Major cytogenetic responses (MCyR) were attained in 38\% (MBP) and 52\% (LBP) of patients; and complete cytogenetic responses in 30\% and 32\%, respectively. Median duration of MCyR was 10.8 (MBP) and 3.2 months (LBP). Median overall survival was 10.1 (MBP) and 7.9 (LBP) months with 12- and 24-month survival of 42\% (MBP 44\%, LBP 35\%) and 27\% (MBP 32\%, LBP 10\%), respectively. Twelve MBP patients and two LBP patients received subsequent stem cell transplantation. Myelosuppression was frequent, with grade 3/4 neutropenia, thrombocytopenia, and anemia in 68\%, 63\% and 47\% of patients, respectively. Grade 3/4 hypophosphatemia, hyperbilirubinemia and lipase elevation were observed in 15\%, 11\% and 11\% of patients, respectively. Nilotinib has significant efficacy in patients with BP CML, but given the limited long-term survival of these patients, novel agents are needed.},
  number = {5},
  journal = {Leukemia},
  author = {Giles, F J and Kantarjian, H M and {le Coutre}, P D and Baccarani, M and Mahon, F X and Blakesley, R E and Gallagher, N J and Gillis, K and Goldberg, S L and Larson, R A and Hochhaus, A and Ottmann, O G},
  year = {2012},
  keywords = {bcr-abl,blastic phase,chronic myeloid leukemia,imatinib resistance,mutations,nilotinib},
  pages = {959-962},
  file = {/Users/k/Zotero/storage/UIA8HF8U/Giles et al. - 2012 - Nilotinib is effective in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blastic phas.pdf},
  pmid = {22157807}
}

@article{Larson2012,
  title = {Nilotinib vs Imatinib in Patients with Newly Diagnosed {{Philadelphia}} Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase : {{ENESTnd}} 3-Year Follow-up {{This}} Article Has Been Corrected since {{Advance Online Publication}} and a Corrigendum Is Also Printed},
  volume = {26},
  doi = {10.1038/leu.2012.134},
  journal = {Leukemia},
  author = {Larson, RA and Hochhaus, A and Hughes, TP and Clark, RE and Etienne, G and Kim, D-W and Flinn, IW and Kurokawa, M and Moiraghi, B and Yu, R and Blakesley, RE and Gallagher, NJ and Saglio, G and Kantarjian, HM},
  year = {2012},
  keywords = {chronic myeloid leukemia,nilotinib,enestnd,imatinib,newly diagnosed,progression},
  pages = {2197-2203},
  file = {/Users/k/Zotero/storage/2H9BUU9K/Larson et al. - 2012 - Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia.pdf}
}

@article{Jabbour2014,
  title = {Early Response with Dasatinib or Imatinib in Chronic Myeloid Leukemia : 3-Year Follow-up from a Randomized Phase 3 Trial ( {{DASISION}} )},
  volume = {123},
  doi = {10.1182/blood-2013-06-511592.The},
  number = {4},
  journal = {Blood},
  author = {Jabbour, Elias and Kantarjian, Hagop M. and Saglio, Giuseppe and Steegmann, Juan Luis and Shah, Neil P. and Boque, Concepcion and Chuah, Charles and Pavlovsky, Carolina and Mayer, Jir and Cortes, Jorge and Baccarani, Michele and Kim, Dong-Wook and {Bradley-Garelik}, M. Brigid and Mohamed, Hesham and Wildgust, Mark and Hochhaus, Andreas},
  year = {2014},
  pages = {494-501},
  file = {/Users/k/Zotero/storage/TZ2RBW5Y/Jabbour et al. - 2014 - Early response with dasatinib or imatinib in chronic myeloid leukemia 3-year follow-up from a randomized phase.pdf}
}

@article{Druker2006,
  title = {Five-{{Year Follow}}-up of {{Patients Receiving Imatinib}} for {{Chronic Myeloid Leukemia}}},
  volume = {355},
  number = {23},
  journal = {New England Journal of Medicine},
  author = {Druker, Brian J. and Guilhot, Fran{\c c}ois and O'Brien, Stephen G. and Gathmann, Insa and Kantarjian, Hagop and Gattermann, Norbert and Deininger, Michael W.N. and Silver, Richard T. and Goldman, John M. and Stone, Richard M. and Cervantes, Francisco and Hochhaus, Andreas and Powell, Bayard L. and Gabrilove, Janice L. and Rousselot, Philippe and Reiffers, Josy and Cornelissen, Jan J. and Hughes, Timothy and Agis, Hermine and Fischer, Thomas and Verhoef, Gregor and Shepherd, John and Saglio, Giuseppe and Gratwohl, Alois and Nielsen, Johan L. and Radich, Jerald P. and Simonsson, Bengt and Taylor, Kerry and Baccarani, Michele and So, Charlene and Letvak, Laurie and Larson, Richard A.},
  year = {2006},
  pages = {2408-17},
  file = {/Users/k/Zotero/storage/X53SQNZD/Druker et al. - 2006 - Five-Year Follow-up of Patients Receiving Imatinib for Chronic Myeloid Leukemia.pdf}
}

@article{Gonzalez-Cao2017,
  title = {Pembrolizumab for Advanced Melanoma: Experience from the {{Spanish Expanded Access Program}}},
  issn = {1699-048X},
  doi = {10.1007/s12094-016-1602-1},
  abstract = {BACKGROUND The programmed death (PD-1) inhibitor pembrolizumab has been recently approved for the treatment of advanced melanoma. We evaluated the clinical activity of pembrolizumab in melanoma patients treated under the Spanish Expanded Access Program. METHODS Advanced melanoma patients who failed to previous treatment lines were treated with pembrolizumab 2~mg/kg every three weeks. Patients with brain metastases were not excluded if they were asymptomatic. Data were retrospectively collected from 21 centers in the Spanish Melanoma Group. RESULTS Sixty-seven advanced melanoma patients were analyzed. Most patients were stage M1c (73.1\%), had high LDH levels (55.2\%) and had ECOG PS 1 or higher (59.7\%). For cutaneous melanoma patients, median overall survival was 14.0~months; the 18-month overall survival rate was 47.1\%. Overall response rate was 27\%, including three patients with complete responses (6.5\%). Median response duration was not reached, with 83.3\% of responses ongoing (3.5~m+ to 20.4~m+). From ten patients included with brain metastases, four (40\%) had an objective response, two (20\%) of them achieved a complete response. Significant prognostic factors for overall survival were LDH level, ECOG PS and objective response. There were no serious adverse events. CONCLUSION Although this was a heavily pretreated cohort, pembrolizumab activity at the approved dose and schedule was confirmed in the clinical setting with long-term responders, also including patients with brain metastases.},
  journal = {Clinical and Translational Oncology},
  author = {{Gonz\'alez-Cao}, M. and Arance, A. and Piulats, J. M. and {Marquez-Rodas}, I. and Manzano, J. L. and Berrocal, A. and Crespo, G. and Rodriguez, D. and {Perez-Ruiz}, E. and Berciano, M. and Soria, A. and Castano, A. G. and Espinosa, E. and Montagut, C. and Alonso, L. and Puertolas, T. and Aguado, C. and Royo, M. A. and Blanco, R. and Rodr\'iguez, J. F. and Mu\~noz, E. and Mut, P. and Barron, F. and {Martin-Algarra}, S. and {Spanish Melanoma Group}},
  year = {2017},
  keywords = {Pembrolizumab,Melanoma,Survival,CNS metastases,Expanded access program},
  file = {/Users/k/Zotero/storage/ILH9FFAT/González-Cao et al. - 2017 - Pembrolizumab for advanced melanoma experience from the Spanish Expanded Access Program.pdf},
  pmid = {28054320}
}

@article{Brock2016,
  title = {Relationships between Paranoid Thinking, Self-Esteem and the Menstrual Cycle},
  volume = {19},
  issn = {14351102},
  doi = {10.1007/s00737-015-0558-4},
  abstract = {This study aimed to investigate whether paranoid experiences and levels of self-esteem fluctuate over the menstrual cycle and whether levels of self-esteem are lower when perceived persecution is felt to be deserved. Measures of anxiety, depression, persecution, deservedness and self-esteem were completed on-line by 278 women over their menstrual cycle. Responses were compared at the paramenstrual (3~days before and after menses onset) and mid-cycle phase. At the paramenstrual phase persecution, negative self-esteem, anxiety and depression were higher and positive self-esteem was lower than at mid-cycle. A greater proportion of women experienced persecution as deserved at the paramenstrual phase. This was associated with higher depression and negative self-esteem scores. Increased levels of deservedness significantly strengthened the relationship between persecution and negative, but not positive, self-esteem. These findings suggest that the paramenstrual phase is a time of vulnerability to increased paranoid experiences, an increased likelihood that feelings of persecution will feel deserved and lowered self-esteem. The findings support the view that interpersonal sensitivities may be key to menstrual cycle symptoms and have an impact on relationships. Further, the study illustrated that ideas developed for psychosis could make a valuable contribution to understanding and managing this aspect of menstruation-related distress.},
  number = {2},
  journal = {Archives of Women's Mental Health},
  author = {Brock, Rosalind and Rowse, Georgina and Slade, Pauline},
  year = {2016},
  keywords = {Deservedness,Menstruation,Paranoia,Premenstrual,Self-esteem},
  pages = {271-279},
  file = {/Users/k/Zotero/storage/DFIEK6RQ/Brock, Rowse, Slade - 2016 - Relationships between paranoid thinking, self-esteem and the menstrual cycle.pdf},
  pmid = {26260035}
}

@misc{McNair2016,
  title = {The {{NCRI Future}} of {{Surgery}} Initiative: {{Defining}} a Research Agenda for Outcomes of Surgical Randomized Controlled Trials},
  journal = {NCRI Abstracts},
  howpublished = {http://abstracts.ncri.org.uk/abstract/the-ncri-future-of-surgery-initiative-defining-a-research-agenda-for-outcomes-of-surgical-randomized-controlled-trials/},
  author = {McNair, Angus and Brock, Kristian and Jones, Terry and Francis, Adele and Blazeby, Jane and Bach, Simon and Avery, Kerry and Fairhurst, Kathrine and Shaw, Richard},
  year = {2016},
  keywords = {MyPubs}
}

@misc{Rawstron2015,
  title = {{{THE LLR TAP ICICLLE TRIAL ASSESSING BIOLOGICAL RESPONSE TO IBRUTINIB IN CLL}}: {{IMMEDIATE DISEASE REDISTRIBUTION PRECEDES CELL CYCLE ARREST BY}} 2 {{WEEKS WITH REDUCED BONE MARROW INFILTRATION BY}} 6 {{MONTHS}}},
  howpublished = {http://learningcenter.ehaweb.org/eha/2015/20th/103132/andy.rawstron.the.llr.tap.iciclle.trial.assessing.biological.response.to.html?f=m3},
  author = {Rawstron, Andy and Munir, Talha and Dalal, Surita and Thompson, Jonny and Yap, Christina and Brock, Kristian and Yates, Francesca and Ogburn, Emma and Fox, Christopher and MacDonald, Donald and Fegan, Christopher and Bloor, Adrian and Hillmen, Peter},
  year = {2015},
  keywords = {MyPubs}
}

@inproceedings{Rawstron2016b,
  title = {Compartment {{Effect}} on the {{Prognostic Significance}} of {{MRD Detection}} in {{CLL}}: {{Impact}} of {{Treatment Type}} and {{Duration}} of {{Follow}}-Up},
  booktitle = {Blood},
  author = {Rawstron, Andy C and Howard, Dena and McParland, Lucy and {de Tute}, Ruth and Collett, Laura and Phillips, David and Chalmers, Anna and Varghese, Abraham Mullasseril and Munir, Talha and Gregory, Walter M and Bishop, Rebecca and Yates, Francesca J and Brock, Kristian and {Mu\~noz-Vicente}, Samuel and Hillmen, Peter},
  year = {2016},
  keywords = {MyPubs},
  pages = {3226}
}

@misc{Cook2016,
  title = {Immune {{Biomarkers Identify Sustained Quantitative}} and {{Functional Immune Reconstitution}} in the {{Setting}} of {{Adjunctive Lenalidomide Following T}}-{{Depleted RIC}}-{{Allo SCT}} for {{Multiple Myeloma}}},
  howpublished = {https://ash.confex.com/ash/2016/webprogram/Paper94823.html},
  author = {Cook, Gordon and Carter, Clive R and Brock, Kristian and McQuaker, Grant and Snowden, John A and Crawley, Charles and Hunter, Hannah and Cavenagh, Jamie D. and Lobb, Mark and Cullen, Katherine and Hodgkinson, Andrea and Sirovica, Mirjana and Cook, Mark},
  year = {2016},
  keywords = {MyPubs}
}

@misc{trialr,
  title = {Trialr - Clinical Trial Designs in {{R}} \& {{Stan}}},
  author = {Brock, Kristian},
  year = {2017},
  keywords = {Software,MyPubs}
}

@article{Shu2016,
  title = {Into the {{Clinic With Nivolumab}} and {{Pembrolizumab}}.},
  volume = {21},
  issn = {1549-490X},
  doi = {10.1634/theoncologist.2016-0099},
  number = {5},
  journal = {The oncologist},
  author = {Shu, Catherine A and Rizvi, Naiyer A},
  year = {2016},
  keywords = {NSCLC,Pembrolizumab,pembrolizumab},
  pages = {527-8},
  file = {/Users/k/Zotero/storage/NIFGYS7F/Shu, Rizvi - 2016 - Into the Clinic With Nivolumab and Pembrolizumab.pdf},
  pmid = {27026678}
}

@article{Nagy1998,
  title = {The Cell Division Cycle and the Pathophysiology of {{Alzheimer}}'s Disease.},
  volume = {87},
  issn = {0306-4522},
  doi = {S0306452298002930 [pii]},
  abstract = {Evidence is growing of a role of apoptosis in neurodegenerative disorders including Alzheimer's disease. Recent research indicates that cell cycle disturbances may promote apoptosis in neurodegenerative diseases. In this commentary we will discuss the control of the cell cycle in mammalian cells in general and in the central nervous system in particular. We then summarize the evidence for cell cycle perturbations in Alzheimer's disease and discuss the possible significance these may have for the development of pathological changes in this disease. Our working hypothesis is that, contrary to previous belief, neurons in the adult human brain are capable of re-entering the cell division cycle. The progression of the cell cycle is normally arrested at an early stage and neurons are able to re-differentiate. However, in Alzheimer's disease the cell cycle is allowed to progress into the G2 phase. At this stage re-differentiation is not possible and the neurons will suffer one of two fates: either they will die via an apoptotic pathway or they may produce Alzheimer-type pathology.},
  number = {4},
  journal = {Neuroscience},
  author = {Nagy, Z and Esiri, M M and Smith, A D},
  year = {1998},
  keywords = {alzheimer,apoptosis,cell cycle,cyclin,down,s disease,s syndrome,temporal lobe epilepsy},
  pages = {731-9},
  file = {/Users/k/Zotero/storage/JF8LU55K/Nagy, Esiri, Smith - 1998 - The cell division cycle and the pathophysiology of Alzheimer's disease.pdf},
  pmid = {9759963}
}

@article{Barrett1997,
  title = {Wolfram ({{DIDMOAD}}) Syndrome},
  volume = {34},
  journal = {Journal of Medical Genetics},
  author = {Barrett, T G and Bundey, S E},
  year = {1997},
  keywords = {Wolfram},
  pages = {838-841},
  file = {/Users/k/Zotero/storage/R4JAZ8YL/Barrett, Bundey - 1997 - Wolfram (DIDMOAD) syndrome.pdf}
}

@techreport{Wolfram1938,
  title = {Diabetes Mellitus and Simple Optic Atrophy among Siblings: Report of Four Cases},
  institution = {{MAYO CLINIC PROCEEDINGS}},
  author = {Wolfram, DJ and Wagener, HP},
  year = {1938},
  keywords = {Wolfram}
}

@article{Abdel-rahman2016,
  title = {Evaluation of Efficacy and Safety of Different Pembrolizumab Dose / Schedules in Treatment of Non-Small-Cell Lung Cancer and Melanoma : A Systematic Review},
  issn = {1750-743X},
  doi = {10.2217/imt-2016-0075},
  number = {December},
  author = {{Abdel-rahman}, Omar},
  year = {2016},
  keywords = {Pembrolizumab,dose,SystematicReview,melanoma,nsclc,pembrolizumab},
  file = {/Users/k/Zotero/storage/MQU937RG/Abdel-rahman - 2016 - Evaluation of efficacy and safety of different pembrolizumab dose schedules in treatment of non-small-cell lung c.pdf}
}

@article{Azzouzi2016a,
  title = {Padeliporfin Vascular-Targeted Photodynamic Therapy versus Active Surveillance in Men with Low-Risk Prostate Cancer ({{CLIN1001 PCM301}}): An Open-Label, Phase 3, Randomised Controlled Trial},
  volume = {2045},
  issn = {14702045},
  doi = {10.1016/S1470-2045(16)30661-1},
  number = {16},
  journal = {The Lancet Oncology},
  author = {Azzouzi, Abdel-Rahm\`ene and Vincendeau, S\'ebastien and Barret, Eric and Cicco, Antony and Kleinclauss, Fran{\c c}ois and {van der Poel}, Henk G and Stief, Christian G and Rassweiler, Jens and Salomon, Georg and Solsona, Eduardo and Alcaraz, Antonio and Tammela, Teuvo T and Rosario, Derek J and {Gomez-Veiga}, Francisco and Ahlgren, G\"oran and Benzaghou, Fawzi and Gaillac, Bertrand and Amzal, Billy and Debruyne, Frans M J and Fromont, Ga\"elle and Gratzke, Christian and Emberton, Mark},
  year = {2016},
  pages = {1-11},
  file = {/Users/k/Zotero/storage/UF32EBZF/Azzouzi et al. - 2016 - Padeliporfin vascular-targeted photodynamic therapy versus active surveillance in men with low-risk prostate can.pdf}
}

@article{Cheung2005,
  title = {Coherence {{Principles}} in {{Dose}}-{{Finding Studies}}},
  volume = {92},
  number = {4},
  journal = {Biometrika},
  author = {Cheung, Ying Kuen},
  year = {2005},
  keywords = {DoseFinding},
  pages = {863-873},
  file = {/Users/k/Zotero/storage/LNPFJPTH/Cheung - 2005 - Coherence Principles in Dose-Finding Studies.pdf}
}

@article{Main2015,
  title = {The Role of High-Dose Myeloablative Chemotherapy with Haematopoietic Stem Cell Transplantation ({{HSCT}}) in Children with Central Nervous System ({{CNS}}) Tumours: Protocol for a Systematic Review and Meta-Analysis.},
  volume = {4},
  issn = {2046-4053},
  doi = {10.1186/s13643-015-0155-7},
  abstract = {OBJECTIVES The objective of the study is to conduct a systematic review to compare the effects of high-dose chemotherapy (HDCT) with autologous haematopoietic stem cell transplantation (HSCT) versus standard-dose chemotherapy (SDCT) in children with malignant central nervous system (CNS) tumours. METHODS Standard systematic review methods aimed at minimising bias will be employed for study identification, selection and data extraction. Ten electronic databases will be searched, along with citation searching and reference checking. Studies assessing the effects of HDCT with HSCT in children with CNS tumours will be included. The outcomes are survival (overall, progression-free, event-free, disease-free), response rates, short- and long-term adverse events and health-related quality of life (HRQoL). Two reviewers will independently screen and select randomised and non-randomised controlled trials and controlled and uncontrolled observational studies for inclusion. Quality assessment will be tailored to the different study designs. Where possible data will be summarised using combined estimates of effect for the hazard ratio for survival outcomes and the risk ratio for response rates. A fixed effect model will be used; sub-group analyses and meta-regression will be used to explore potential sources of heterogeneity between studies. DISCUSSION Given the poor prognosis of malignant brain tumours in children in terms of survival and quality of life, this review will help guide clinical practice by summarising the current evidence on the use of high-dose myeloblative chemotherapy with stem cell support in children with CNS tumours.},
  journal = {Systematic reviews},
  author = {Main, Caroline and Wilson, Jayne S and Stevens, Simon P and Houlton, Aimee E and English, Martin and Kearns, Pamela R and Phillips, Bob and Pizer, Barry and Wilne, Sophie and Wheatley, Keith},
  year = {2015},
  keywords = {Systematic review,uk,ac,correspondence,SystematicReview,bham,c,central nervous system tumours,Central nervous system tumours,children,Children,haematopoietic stem cell,Haematopoietic stem cell transplantation,high-dose chemotherapy,High-dose chemotherapy,main,systematic review,transplantation},
  pages = {168},
  file = {/Users/k/Zotero/storage/DFXNDJPZ/Main et al. - 2015 - The role of high-dose myeloablative chemotherapy with haematopoietic stem cell transplantation (HSCT) in children w.pdf},
  pmid = {26589619}
}

@article{Grigg2016,
  title = {{{PD}}-{{L1}} Biomarker Testing for Non-Small Cell Lung Cancer: Truth or Fiction?},
  volume = {4},
  issn = {2051-1426},
  doi = {10.1186/s40425-016-0153-x},
  abstract = {Research in cancer immunology is currently accelerating following a series of cancer immunotherapy breakthroughs during the last 5 years. Various monoclonal antibodies which block the interaction between checkpoint molecules PD-1 on immune cells and PD-L1 on cancer cells have been used to successfully treat non-small cell lung cancer (NSCLC), including some durable responses lasting years. Two drugs, nivolumab and pembrolizumab, are now FDA approved for use in certain patients who have failed or progressed on platinum-based or targeted therapies while agents targeting PD-L1, atezolizumab and durvalumab, are approaching the final stages of clinical testing. Despite impressive treatment outcomes in a subset of patients who receive these immune therapies, many patients with NSCLC fail to respond to anti-PD-1/PD-L1 and the identification of a biomarker to select these patients remains highly sought after. In this review, we discuss the recent clinical trial results of pembrolizumab, nivolumab, and atezolizumab for NSCLC, and the significance of companion diagnostic testing for tumor PD-L1 expression.},
  journal = {Journal for immunotherapy of cancer},
  author = {Grigg, Claud and Rizvi, Naiyer A},
  year = {2016},
  keywords = {NSCLC,Pembrolizumab,Immunotherapy,Lung cancer,biomarker,Nivolumab,pd-l1,nsclc,pembrolizumab,Biomarker,immune checkpoint inhibitor,Immune checkpoint inhibitor,immunotherapy,lung cancer,nivolumab,pd-1,PD-1,PD-L1},
  pages = {48},
  file = {/Users/k/Zotero/storage/3RZEET52/Grigg, Rizvi - 2016 - PD-L1 biomarker testing for non-small cell lung cancer truth or fiction.pdf},
  pmid = {27532023}
}

@article{Rupp2016,
  title = {Quality of {{Life}}, {{Overall Survival}}, and {{Costs}} of {{Cancer Drugs Approved Based}} on {{Surrogate Endpoints}}},
  issn = {2168-6106},
  doi = {10.1001/jamainternmed.2016.7761},
  journal = {JAMA Internal Medicine},
  author = {Rupp, Tracy and Zuckerman, Diana},
  year = {2016},
  pages = {4-6},
  file = {/Users/k/Zotero/storage/X5JYTPYM/Rupp, Zuckerman - 2016 - Quality of Life, Overall Survival, and Costs of Cancer Drugs Approved Based on Surrogate Endpoints.pdf},
  pmid = {27898978}
}

@article{Carbognin2015,
  title = {Differential Activity of Nivolumab, Pembrolizumab and {{MPDL3280A}} According to the Tumor Expression of Programmed Death-Ligand-1 ({{PD}}-{{L1}}): {{Sensitivity}} Analysis of Trials in Melanoma, Lung and Genitourinary Cancers},
  volume = {10},
  issn = {19326203},
  doi = {10.1371/journal.pone.0130142},
  abstract = {BACKGROUND: The potential predictive role of programmed death-ligand-1 (PD-L1) expression on tumor cells in the context of solid tumor treated with checkpoint inhibitors targeting the PD-1 pathway represents an issue for clinical research. METHODS: Overall response rate (ORR) was extracted from phase I-III trials investigating nivolumab, pembrolizumab and MPDL3280A for advanced melanoma, non-small cell lung cancer (NSCLC) and genitourinary cancer, and cumulated by adopting a fixed and random-effect model with 95\% confidence interval (CI). Interaction test according to tumor PD-L1 was accomplished. A sensitivity analysis according to adopted drug, tumor type, PD-L1 cut-off and treatment line was performed. RESULTS: Twenty trials (1,475 patients) were identified. A significant interaction (p$<$0.0001) according to tumor PD-L1 expression was found in the overall sample with an ORR of 34.1\% (95\% CI 27.6-41.3\%) in the PD-L1 positive and 19.9\% (95\% CI 15.4-25.3\%) in the PD-L1 negative population. ORR was significantly higher in PD-L1 positive in comparison to PD-L1 negative patients for nivolumab and pembrolizumab, with an absolute difference of 16.4\% and 19.5\%, respectively. A significant difference in activity of 22.8\% and 8.7\% according to PD-L1 was found for melanoma and NSCLC, respectively, with no significant difference for genitourinary cancer. CONCLUSION: Overall, the three antibodies provide a significant differential effect in terms of activity according to PD-L1 expression on tumor cells. The predictive value of PD-L1 on tumor cells seems to be more robust for anti-PD-1 antibody (nivolumab and pembrolizumab), and in the context of advanced melanoma and NSCLC.},
  number = {6},
  journal = {PLoS ONE},
  author = {Carbognin, Luisa and Pilotto, Sara and Milella, Michele and Vaccaro, Vanja and Brunelli, Matteo and Cali\`o, Anna and Cuppone, Federica and Sperduti, Isabella and Giannarelli, Diana and Chilosi, Marco and Bronte, Vincenzo and Scarpa, Aldo and Bria, Emilio and Tortora, Giampaolo},
  year = {2015},
  keywords = {Pembrolizumab,pembrolizumab},
  file = {/Users/k/Zotero/storage/8B8VJBGS/Carbognin et al. - 2015 - Differential activity of nivolumab, pembrolizumab and MPDL3280A according to the tumor expression of programme.pdf},
  pmid = {26086854}
}

@article{Parmar2016,
  title = {How Do You Design Randomised Trials for Smaller Populations? {{A}} Framework},
  volume = {14},
  doi = {10.1186/s12916-016-0722-3},
  abstract = {How should we approach trial design when we can get some, but not all, of the way to the numbers required for a randomised phase III trial? We present an ordered framework for designing randomised trials to address the problem when the ideal sample size is considered larger than the number of participants that can be recruited in a reasonable time frame. Staying with the frequentist approach that is well accepted and understood in large trials, we propose a framework that includes small alterations to the design parameters. These aim to increase the numbers achievable and also potentially reduce the sample size target. The first step should always be to attempt to extend collaborations, consider broadening eligibility criteria and increase the accrual time or follow-up time. The second set of ordered considerations are the choice of research arm, outcome measures, power and target effect. If the revised design is still not feasible, in the third step we propose moving from two-to one-sided significance tests, changing the type I error rate, using covariate information at the design stage, re-randomising patients and borrowing external information. We discuss the benefits of some of these possible changes and warn against others. We illustrate, with a worked example based on the Euramos-1 trial, the application of this framework in designing a trial that is feasible, while still providing a good evidence base to evaluate a research treatment. This framework would allow appropriate evaluation of treatments when large-scale phase III trials are not possible, but where the need for high-quality randomised data is as pressing as it is for common diseases.},
  number = {183},
  journal = {BMC Medicine},
  author = {Parmar, Mahesh K B and Sydes, Matthew R and Morris, Tim P},
  year = {2016},
  keywords = {Trial design,RareDiseases,Randomised trials,Smaller populations,Uncommon diseases},
  file = {/Users/k/Zotero/storage/ZG9LV6AN/Parmar, Sydes, Morris - 2016 - How do you design randomised trials for smaller populations A framework.pdf}
}

@article{IOANNIDIS2016,
  title = {The {{Mass Production}} of {{Redundant}}, {{Misleading}}, and {{Conflicted Systematic Reviews}} and {{Meta}}-Analyses},
  volume = {94},
  issn = {0887378X},
  doi = {10.1111/1468-0009.12210},
  number = {3},
  journal = {The Milbank Quarterly},
  author = {IOANNIDIS, JOHN P.A.},
  year = {2016},
  pages = {485-514},
  file = {/Users/k/Zotero/storage/C6AGJFJK/IOANNIDIS - 2016 - The Mass Production of Redundant, Misleading, and Conflicted Systematic Reviews and Meta-analyses.pdf},
  pmid = {27620683}
}

@misc{clintrials-v0.1.4,
  title = {Clintrials v0.1.4},
  abstract = {clintrials is a library of clinical trial designs and methods in Python. This library is intended to facilitate research.},
  howpublished = {GitHub, Zenodo},
  author = {Brock, Kristian},
  year = {2016},
  keywords = {Software,MyPubs},
  doi = {10.5281/zenodo.164621}
}

@article{Chen2016,
  title = {Anti\textendash{}Programmed Cell Death ({{PD}})-1 Immunotherapy for Malignant Tumor: {{A}} Systematic Review and Meta-Analysis},
  volume = {9},
  issn = {19365233},
  doi = {10.1016/j.tranon.2015.11.010},
  abstract = {This systematic review and meta-analysis evaluated anti\textendash{}programmed cell death (PD)-1 immunotherapy (nivolumab or pembrolizumab) for overall efficacy, safety, and effective dose relative to standard chemotherapy or other conventional drugs in the treatment of malignant tumors. We searched the following databases, PubMed, Medline, Embase, Cochrane, Wangfang Data, Weipu, and China National Knowledge Infrastructure, and the reference lists of the selected articles for randomized controlled trials (RCTs) of anti\textendash{}PD-1 therapies in humans. The outcome measures were overall survival, treatment response, and adverse events. Only four randomized controlled trials met our inclusion criteria. Three of these evaluated responses to nivolumab, whereas one tested pembrolizumab. The result of our analysis suggested that nivolumab may improve the overall response rate in treating melanoma relative to chemotherapy and has few associated adverse events. Similarly, in metastatic melanoma patients, nivolumab had a significant advantage over dacarbazine in terms of 1-year survival, progression-free survival, and objective response rate. Regarding dose levels of nivolumab for patients with metastatic renal cell carcinoma, the outcomes in response to 2 and 10 mg/kg were similar, but both had significant advantages over 0.3 mg/kg. In addition, pembrolizumab showed similar outcomes in response to 2- and 10-mg/kg treatment. Anti\textendash{}PD-1 immunotherapy appears to be safe and effective for patients with melanoma or metastatic renal cell carcinoma. Our meta-analysis is limited, but additional clinical trials are warranted to verify this preliminary evidence of positive outcomes and before anti\textendash{}PD-1 therapy can be recommended for routine clinical use.},
  number = {1},
  journal = {Translational Oncology},
  author = {Chen, Ran and Peng, Pei Chun and Wen, Bin and Li, Fu Ying and Xie, Sheng and Chen, Guozhong and Lu, Jiefu and Peng, Zhuoyu and Tang, Shao Bo and Liang, Yu Mei and Deng, Xin},
  year = {2016},
  keywords = {Pembrolizumab,pembrolizumab},
  pages = {32-40},
  file = {/Users/k/Zotero/storage/DBAA8SPC/Chen et al. - 2016 - Anti–programmed cell death (PD)-1 immunotherapy for malignant tumor A systematic review and meta-analysis.pdf},
  pmid = {26947879}
}

@article{Yap2015,
  title = {Dose Transition Pathways: A Design, Analysis and Operational Tool for Dose-Finding Trials Using Model-Based Designs},
  volume = {16},
  issn = {1745-6215},
  doi = {10.1186/1745-6215-16-S2-O13},
  number = {S2},
  journal = {Trials},
  author = {Yap, Christina and Billingham, Lucinda and Craddock, Charles and O'Quigley, John},
  year = {2015},
  pages = {O13},
  file = {/Users/k/Zotero/storage/CWK6M584/Yap et al. - 2015 - Dose transition pathways a design, analysis and operational tool for dose-finding trials using model-based designs.pdf}
}

@article{Simon2016,
  title = {Genomic Alteration-Driven Clinical Trial Designs in Oncology},
  volume = {165},
  issn = {15393704},
  doi = {10.7326/M15-2413},
  abstract = {The established molecular heterogeneity of human cancers necessitates the development of new paradigms to serve as a reliable basis for precision medicine. The assumptions underlying some of the conventional approaches to clinical trial design and analysis are no longer appropriate because of the molecular heterogeneity of tumors of a given primary site. This article reviews some clinical trial designs that have been actively applied in the codevelopment of therapeutics and predictive biomarkers to inform their use in oncology. These include the enrichment design, the basket design, and the umbrella design. Oncology leads most other therapeutic areas in development of personalized or precision medicine. Personalized or precision medicine is practiced daily in oncology on the basis of tumor genomics and may evolve in other therapeutic areas as it has in oncology, rather than according to inherited polymorphisms as so often imagined. Consequently, some of the clinical trial designs described here may serve as a possible blueprint for therapeutic development in fields other than oncology.},
  number = {4},
  journal = {Annals of Internal Medicine},
  author = {Simon, Richard},
  year = {2016},
  pages = {270-278},
  file = {/Users/k/Zotero/storage/28LTV9Q3/Simon - 2016 - Genomic alteration-driven clinical trial designs in oncology.pdf},
  pmid = {27214515}
}

@article{Shah2015,
  title = {Phase {{I}}/{{II}} Trial of Lenalidomide and High Dose Melphalan with Autologous Stem Cell Transplantation for Relapsed Myeloma},
  volume = {29},
  doi = {10.1038/leu.2015.54},
  number = {9},
  journal = {Leukemia},
  author = {Shah, Nina and Thall, Peter F. and Fox, Patricia S. and Bashir, Qaiser and Shah, Jatin J. and Parmar, Simrit and Lin, Pei and Kebriaei, Partow and Nieto, Yago and Popat, Uday R. and Hosing, Chitra M. and Cornelison, Amanda and Shpall, Elizabeth J. and Orlowski, Robert Z. and Champlin, Richard E. and Qazilbash, Muzaffar H.},
  year = {2015},
  keywords = {EffToxCiter},
  pages = {1945-48},
  file = {/Users/k/Zotero/storage/ZB5R3TEW/Shah et al. - 2015 - Phase III trial of lenalidomide and high dose melphalan with autologous stem cell transplantation for relapsed myel.pdf},
  pmid = {25931448}
}

@article{Chen2013,
  title = {Cyclosporine {{Modulation}} of {{Multidrug Resistance}} in {{Combination}} with {{Pravastatin}}, {{Mitoxantrone}}, and {{Etoposide}} for {{Adult Patients}} with {{Relapsed}}/{{Refractory Acute Myeloid Leukemia}} ({{AML}}): {{A Phase}} 1/2 {{Study}}},
  volume = {54},
  issn = {15378276},
  doi = {10.3109/10428194.2013.777836},
  number = {11},
  journal = {Leuk Lymphoma},
  author = {Chen, Tara L. and Estey, Elihu H. and Othus, Megan and Gardner, Kelda M. and Markle, Lauren J. and Walter, Roland B.},
  year = {2013},
  keywords = {EffToxCiter,cyp6d1 transcription,hr96,musca domestica,phenobarbital induction,pyrethroid resistance},
  pages = {2534-6},
  file = {/Users/k/Zotero/storage/SYBF59BK/Chen et al. - 2013 - Cyclosporine Modulation of Multidrug Resistance in Combination with Pravastatin, Mitoxantrone, and Etoposide for Ad.pdf},
  pmid = {1000000221}
}

@article{Briasoulis2013,
  title = {Dose Selection Trial of Metronomic Oral Vinorelbine Monotherapy in Patients with Metastatic Cancer: A Hellenic Cooperative Oncology Group Clinical Translational Study.},
  volume = {13},
  issn = {1471-2407},
  doi = {10.1186/1471-2407-13-263},
  abstract = {BACKGROUND: Metronomic chemotherapy is considered an anti-angiogenic therapy that involves chronic administration of low-dose chemotherapy at regular short intervals. We investigated the optimal metronomic dose of oral vinorelbine when given as monotherapy in patients with metastatic cancer.$\backslash$n$\backslash$nMETHODS: Patients with recurrent metastatic breast (BC), prostate (PC) or non-small cell lung cancer (NSCLC) and adequate organ functions were randomly assigned to 30, 40 or 50 mg vinorelbine, taken orally three times a week. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent or maximum 24 months. Primary endpoint was time-to-treatment failure (TTF) and secondary were progression-free survival (PFS), toxicity, changes in blood concentrations of angiogenesis-associated biomarkers and pharmacokinetics.$\backslash$n$\backslash$nRESULTS: Seventy-three patients were enrolled. Four-month TTF rate did not differ between the three arms: 25.9\% (11.1\%-46.2\% 95\% Confidence Interval), 33.3\% (15.6\%-55.3\%) and 18.2\% (5.2\%-40.3\%) for the 30 mg, 40 mg and 50 mg arms (p-value = 0.56). Objective response was seen in 2 patients with NSCLC (treated at 30 and 50 mg respectively), one with BC (at 40 m g) and one with PC (at 50 mg) and lasted from 4 to 100 weeks, with maximum response duration achieved at 50 mg. Adverse events were mild and negligible and did not differ between the three arms. Blood levels of vinorelbine reached steady state from the second week of treatment and mean values for the 30, 40 and 50 mg were respectively 1.8 ng/ml (SD 1.10), 2.2 ng/ml (SD 1.87) and 2.6 ng/ml (SD 0.69). Low pre-treatment blood concentrations of FGF2 and IL8 predicted favorable response to therapy (p values 0.02 and 0.006, respectively), while high levels of TEK gene transcript predicted treatment resistance.$\backslash$n$\backslash$nCONCLUSIONS: Considering the antitumor activity and response duration, the negligible toxicity of the highest dose investigated and the lack of drug accumulation over time, we suggest that 50 mg given three times a week is the optimal dose for metronomic oral vinorelbine. Further investigation of metronomic oral vinorelbine (MOVIN) at this dose is warranted in combination with conventional chemotherapy regimens and targeted therapies.$\backslash$n$\backslash$nTRIAL REGISTRATION: Clinicaltrials.gov NCT00278070.},
  number = {1},
  journal = {BMC Cancer},
  author = {Briasoulis, Evangelos and Aravantinos, Gerasimos and Kouvatseas, George and Pappas, Periklis and Biziota, Eirini and Sainis, Ioannis and Makatsoris, Thomas and Varthalitis, Ioannis and Xanthakis, Ioannis and Vassias, Antonios and Klouvas, George and Boukovinas, Ioannis and Fountzilas, George and Syrigos, Kostantinos N and Kalofonos, Haralambos and Samantas, Epaminontas},
  year = {2013},
  keywords = {Adult,Female,Humans,Biomarkers,Follow-Up Studies,Middle Aged,Antineoplastic Agents,Prognosis,Male,Dose-Response Relationship,Drug,Adolescent,Aged,Young Adult,Carcinoma,Lung Neoplasms,Lung Neoplasms: drug therapy,Lung Neoplasms: mortality,Non-Small-Cell Lung,Non-Small-Cell Lung: drug therapy,Non-Small-Cell Lung: mortality,EffToxCiter,Administration,Bone Neoplasms,Bone Neoplasms: drug therapy,Bone Neoplasms: secondary,Breast Neoplasms,Breast Neoplasms: drug therapy,Breast Neoplasms: mortality,Breast Neoplasms: pathology,Enzyme-Linked Immunosorbent Assay,Liver Neoplasms,Liver Neoplasms: drug therapy,Liver Neoplasms: mortality,Liver Neoplasms: secondary,Lung Neoplasms: pathology,Messenger,Messenger: genetics,Neoplasm Staging,Non-Small-Cell Lung: pathology,Oral,Phytogenic,Phytogenic: administration,Prostatic Neoplasms,Prostatic Neoplasms: drug therapy,Prostatic Neoplasms: mortality,Prostatic Neoplasms: pathology,Real-Time Polymerase Chain Reaction,Reverse Transcriptase Polymerase Chain Reaction,RNA,Survival Rate,Time-to-Treatment,Translational Medical Research,Tumor,Tumor: genetics,Tumor: metabolism,Vinblastine,Vinblastine: administration \& dosage,Vinblastine: analogs \& derivatives},
  pages = {263},
  file = {/Users/k/Zotero/storage/RZT4B9H2/Briasoulis et al. - 2013 - Dose selection trial of metronomic oral vinorelbine monotherapy in patients with metastatic cancer a hellenic.pdf},
  pmid = {23718900}
}

@article{Anderlini2015,
  title = {Cyclophosphamide Conditioning in Patients with Severe Aplastic Anaemia given Unrelated Marrow Transplantation: A Phase 1\textendash{}2 Dose de-Escalation Study},
  volume = {2},
  doi = {10.1016/S2352-3026(15)00147-7},
  number = {9},
  journal = {Lancet Haematology},
  author = {Anderlini, Paolo and Wu, Juan and Gersten, Iris and Ewell, Marian and Tolar, Jakob and Antin, Joseph H. and Adams, Roberta and Arai, Sally and Eames, Gretchen and Horwitz, Mitchell E. and McCarty, John and Nakamura, Ryotaro and Pulsipher, Michael A. and Rowley, Scott and Leifer, Eric and Carter, Shelly L. and DiFronzo, Nancy L. and Horowitz, Mary M. and Confer, Dennis and Deeg, H. Joachim and Eapen, Mary},
  year = {2015},
  keywords = {EffToxCiter},
  pages = {367-375},
  file = {/Users/k/Zotero/storage/F5EY853W/Anderlini et al. - 2015 - Cyclophosphamide conditioning in patients with severe aplastic anaemia given unrelated marrow transplantatio.pdf},
  pmid = {25931448}
}

@article{eichlerThresholdcrossingUsefulWay,
  title = {" {{Threshold}}-Crossing " : {{A Useful Way}} to {{Establish}} the {{Counterfactual}} in {{Clinical Trials}}?},
  doi = {10.1002/cpt.515},
  abstract = {10 , MM Lumpkin 11 , MJ Murphy 12 , F Pignatti 1 , M Posch 3 , S Schneeweiss 13 , M Trusheim 14 and F Koenig 3 A central question in the assessment of benefit/harm of new treatments is: how does the average outcome on the new treatment (the factual) compare to the average outcome had patients received no treatment or a different treatment known to be effective (the counterfactual)? Randomized controlled trials (RCTs) are the standard for comparing the factual with the counterfactual. Recent developments necessitate and enable a new way of determining the counterfactual for some new medicines. For select situations, we propose a new framework for evidence generation, which we call " threshold-crossing. " This framework leverages the wealth of information that is becoming available from completed RCTs and from real world data sources. Relying on formalized procedures, information gleaned from these data is used to esti-mate the counterfactual, enabling efficacy assessment of new drugs. We propose future (research) activities to enable " threshold-crossing " for carefully selected products and indications in which RCTs are not feasible. What is the counterfactual? The human condition is an uncontrolled experiment. Socrates once advised a young man who asked whether he should get mar-ried: " Do as you wish, you will likely regret, no matter what you choose. " Why would the sage expect his friend to have postdeci-sion blues? Whatever road the young man takes, he would cer-tainly experience the consequences of his action (the factual) but there is no way he could learn the\textemdash{}possibly superior\textemdash{} consequences of the road not taken (the counterfactual). One might argue that the young man could still explore the counter-factual by marrying later in life or getting a divorce. However, this argument is flawed because the comparison between an early-in-life event with a late-in-life event is inadmissible; in modern research terms, the comparison is confounded. Alas, we shall rare-ly know the counterfactuals in our lives, the road not taken. The assessment of the causal effects (benefits and harms) of any treatment revolves around the same question: how does the outcome of (test) treatment (the factual) compare to " what would have happened [if patients] had not received the test treatment or if they had received a different treatment known to be effective " 1 (the counterfactual)? The question is asked by clinicians treating individual patients and by population-level decision-makers, including drug developers, regulators, health technology assessment (HTA) bodies, and payers of health care. However, the counterfactual outcomes of individual patients can rarely be observed. Decision-makers must instead focus on comparing average population counterfactual outcomes between different interventions (which are estimable) to deduce causal effects on a population (see Table 1 2\textendash{}11 for review of the con-cept of the counterfactual and how it underpins the definition of a causal treatment effect). How does the concept of the counterfactual underpin the defi-nition of a causal treatment effect? Here, we review the current ways of estimating the counterfactual to enable the assessment of causal treatment effects. We reflect on how scientific and societal developments necessitate and enable a new way of determining the counterfactual for some new medicines. We then propose a new framework for evidence generation, which we will refer to as " threshold-crossing. " Finally, we propose future research and oth-er activities to enable a move toward threshold-crossing for},
  author = {Eichler, H-G and {Bloechl-Daum}, B and Bauer, P and Bretz, F and Brown, J and Hampson, Lv and Honig, P and Krams, M and Leufkens, H and Lim, R},
  file = {/Users/k/Zotero/storage/C44I7YF6/Eichler et al. - Unknown - Threshold-crossing A Useful Way to Establish the Counterfactual in Clinical Trials.pdf}
}

@article{Ivanova2005,
  title = {Continuous Toxicity Monitoring in Phase {{II}} Trials in Oncology},
  volume = {61},
  issn = {0006341X},
  doi = {10.1111/j.1541-0420.2005.00311.x},
  abstract = {The goal of a phase II trial in oncology is to evaluate the efficacy of a new therapy. The dose investigated in a phase II trial is usually an estimate of a maximum-tolerated dose obtained in a preceding phase I trial. Because this estimate is imprecise, stopping rules for toxicity are used in many phase II trials. We give recommendations on how to construct stopping rules to monitor toxicity continuously. A table is provided from which Pocock stopping boundaries can be easily obtained for a range of toxicity rates and sample sizes. Estimation of the probability of toxicity and response is also discussed.},
  number = {2},
  journal = {Biometrics},
  author = {Ivanova, Anastasia and Qaqish, Bahjat F. and Schell, Michael J.},
  year = {2005},
  keywords = {Phase II trial,Pocock boundary,Sequential monitoring,Unbiased estimate},
  pages = {540-545},
  file = {/Users/k/Zotero/storage/CJ74KREG/Ivanova, Qaqish, Schell - 2005 - Continuous toxicity monitoring in phase II trials in oncology.pdf},
  pmid = {16011702}
}

@article{Dewan2012,
  title = {{{CRASH}}-3 - Tranexamic Acid for the Treatment of Significant Traumatic Brain Injury: Study Protocol for an International Randomized, Double-Blind, Placebo-Controlled Trial.},
  volume = {13},
  abstract = {BACKGROUND: Worldwide, over 10 million people are killed or hospitalized because of traumatic brain injury each year. About 90\% of deaths occur in low- and middle-income countries. The condition mostly affects young adults, and many experience long lasting or permanent disability. The social and economic burden is considerable. Tranexamic acid (TXA) is commonly given to surgical patients to reduce bleeding and the need for blood transfusion. It has been shown to reduce the number of patients receiving a blood transfusion by about a third, reduces the volume of blood transfused by about one unit, and halves the need for further surgery to control bleeding in elective surgical patients. METHODS/DESIGN: The CRASH-3 trial is an international, multicenter, pragmatic, randomized, double-blind, placebo-controlled trial to quantify the effects of the early administration of TXA on death and disability in patients with traumatic brain injury. Ten thousand adult patients who fulfil the eligibility criteria will be randomized to receive TXA or placebo. Adults with traumatic brain injury, who are within 8 h of injury and have any intracranial bleeding on computerized tomography (CT scan) or Glasgow Coma Score (GCS) of 12 or less can be included if the responsible doctor is substantially uncertain as to whether or not to use TXA in this patient. Patients with significant extracranial bleeding will be excluded since there is evidence that TXA improves outcome in these patients. Treatment will entail a 1 g loading dose followed by a 1 g maintenance dose over 8 h.The main analyses will be on an 'intention-to-treat' basis, irrespective of whether the allocated treatment was received. Results will be presented as appropriate effect estimates with a measure of precision (95\% confidence intervals). Subgroup analyses for the primary outcome will be based on time from injury to randomization, the severity of the injury, location of the bleeding, and baseline risk. Interaction tests will be used to test whether the effect of treatment differs across these subgroups. A study with 10,000 patients will have approximately 90\% power to detect a 15\% relative reduction from 20\% to 17\% in all-cause mortality. TRIAL REGISTRATION: Current Controlled Trials ISRCTN15088122; Clinicaltrials.gov NCT01402882.},
  journal = {Trials},
  author = {Dewan, Y},
  year = {2012},
  keywords = {clinical trial,antifibrinolytic,emergency care,intracranial bleeding,TBI,tranexamic acid,traumatic brain},
  pages = {87},
  file = {/Users/k/Zotero/storage/2NVHEC3L/Dewan - 2012 - CRASH-3 - tranexamic acid for the treatment of significant traumatic brain injury study protocol for an international ran.pdf}
}

@article{He2015,
  title = {Dimension of {{Model Parameter Space}} and {{Operating Characteristics}} in {{Adaptive Dose}}-{{Finding Studies}}},
  volume = {35},
  issn = {1527-5418},
  number = {21},
  journal = {Statistics in Medicine},
  author = {Iasonos, Alexia and Wages, Nolan A. and Conaway, Mark R. and Cheung, Ken and Yuan, Ying and O'Quigley, John},
  year = {2016},
  pages = {3760-3775},
  file = {/Users/k/Zotero/storage/4ETIUJUD/Iasonos et al. - 2016 - Dimension of Model Parameter Space and Operating Characteristics in Adaptive Dose-Finding Studies.pdf},
  pmid = {24655651}
}

@article{Tao2013,
  title = {Dose-{{Finding Based}} on {{Bivariate Efficacy}}-{{Toxicity Outcome Using Archimedean Copula}}},
  volume = {8},
  issn = {1932-6203},
  doi = {10.1371/journal.pone.0078805},
  number = {11},
  journal = {PLoS ONE},
  author = {Tao, Yuxi and Liu, Junlin and Li, Zhihui and Lin, Jinguan and Lu, Tao and Yan, Fangrong},
  year = {2013},
  pages = {e78805},
  file = {/Users/k/Zotero/storage/V8MIK6VH/Tao et al. - 2013 - Dose-Finding Based on Bivariate Efficacy-Toxicity Outcome Using Archimedean Copula.pdf}
}

@article{Boonstra2015,
  title = {A Statistical Evaluation of Dose Expansion Cohorts in Phase {{I}} Clinical Trials.},
  volume = {107},
  issn = {1460-2105},
  doi = {10.1093/jnci/dju429},
  abstract = {BACKGROUND: Phase I trials often include a dose expansion cohort (DEC), in which additional patients are treated at the estimated maximum tolerated dose (MTD) after dose escalation, with the goal of ensuring that data are available from more than six patients at a single dose level. However, protocols do not always detail how, or even if, the additional toxicity data will be used to reanalyze the MTD or whether observed toxicity in the DEC will warrant changing the assigned dose. A DEC strategy has not been statistically justified.$\backslash$n$\backslash$nMETHODS: We conducted a simulation study of two phase I designs: the "3+3" and the Continual Reassessment Method (CRM). We quantified how many patients are assigned the true MTD using a 10 to 20 patient DEC and how a sensible reanalysis using the DEC changes the probability of selecting the true MTD. We compared these results with those from an equivalently sized larger CRM that does not include a DEC.$\backslash$n$\backslash$nRESULTS: With either the 3+3 or CRM, reanalysis with the DEC increased the probability of identifying the true MTD. However, a large CRM without a DEC was more likely to identify the true MTD while still treating 10 or 15 patients at this dose level.$\backslash$n$\backslash$nCONCLUSIONS: Where feasible, a CRM design with no explicit DEC is preferred to designs that fix a dose for all patients in a DEC.},
  number = {3},
  journal = {Journal of the National Cancer Institute},
  author = {Boonstra, Philip S and Shen, Jincheng and Taylor, Jeremy M G and Braun, Thomas M and a Griffith, Kent and Daignault, Stephanie and Kalemkerian, Gregory P and Lawrence, Theodore S and Schipper, Matthew J},
  year = {2015},
  keywords = {Humans,Antineoplastic Agents,Research Design,clinical trials,Antineoplastic Agents: administration \& dosage,Antineoplastic Agents: adverse effects,Dose-Response Relationship,Drug,Maximum Tolerated Dose,Phase I as Topic,Phase I as Topic: methods,Clinical Trials; Phase I as Topic,Clinical Trials; Phase I as Topic: methods,Dose-Response Relationship; Drug},
  pages = {1-6},
  file = {/Users/k/Zotero/storage/84TYVLWJ/Boonstra et al. - 2015 - A statistical evaluation of dose expansion cohorts in phase I clinical trials.pdf},
  pmid = {25710960}
}

@article{Thall2010,
  title = {Bayesian {{Models}} and {{Decision Algorithms}} for {{Complex Early Phase Clinical Trials}}},
  volume = {25},
  doi = {10.1214/09-STS315.Bayesian},
  abstract = {An early phase clinical trial is the first step in evaluating the effects in humans of a potential new anti-disease agent or combination of agents. Usually called ``phase I'' or ``phase I/II'' trials, these experiments typically have the nominal scientific goal of determining an acceptable dose, most often based on adverse event probabilities. This arose from a tradition of phase I trials to evaluate cytotoxic agents for treating cancer, although some methods may be applied in other medical settings, such as treatment of stroke or immunological diseases. Most modern statistical designs for early phase trials include model-based, outcome-adaptive decision rules that choose doses for successive patient cohorts based on data from previous patients in the trial. Such designs have seen limited use in clinical practice, however, due to their complexity, the requirement of intensive, computer-based data monitoring, and the medical community's resistance to change. Still, many actual applications of model-based outcome-adaptive designs have been remarkably successful in terms of both patient benefit and scientific outcome. In this paper, I will review several Bayesian early phase trial designs that were tailored to accommodate specific complexities of the treatment regime and patient outcomes in particular clinical settings.},
  number = {2},
  journal = {Statistical Science},
  author = {Thall, Peter F},
  year = {2010},
  keywords = {adaptive design,DoseFinding,clinical trial,dose-finding,and phrases,bayesian design,ii trial,phase i,phase i trial},
  pages = {227-244},
  file = {/Users/k/Zotero/storage/V8IAXPKU/Thall - 2010 - Bayesian Models and Decision Algorithms for Complex Early Phase Clinical Trials.pdf}
}

@article{Reck2016,
  title = {Pembrolizumab versus {{Chemotherapy}} for {{PD}}-{{L1}}\textendash{{Positive Non}}\textendash{{Small}}-{{Cell Lung Cancer}}},
  issn = {0028-4793},
  doi = {10.1056/NEJMoa1606774},
  journal = {New England Journal of Medicine},
  author = {Reck, Martin and {Rodr\'iguez-Abreu}, Delvys and Robinson, Andrew G. and Hui, Rina and Cs{\H o}szi, Tibor and F\"ul\"op, Andrea and Gottfried, Maya and Peled, Nir and Tafreshi, Ali and Cuffe, Sinead and O'Brien, Mary and Rao, Suman and Hotta, Katsuyuki and Leiby, Melanie A. and Lubiniecki, Gregory M. and Shentu, Yue and Rangwala, Reshma and Brahmer, Julie R.},
  year = {2016},
  keywords = {NSCLC,Pembrolizumab,pembrolizumab},
  file = {/Users/k/Zotero/storage/P8I3WFUZ/Reck et al. - 2016 - Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer(2).pdf;/Users/k/Zotero/storage/QURQZY9K/Reck et al. - 2016 - Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer.pdf},
  pmid = {27718847}
}

@article{Vachhani2016,
  title = {Spotlight on Pembrolizumab in Non-Small Cell Lung Cancer: The Evidence to Date},
  doi = {10.2147/OTT.S97746},
  journal = {OncoTargets and Therapy},
  author = {Vachhani, Pankit and Chen, Hongbin},
  keywords = {Pembrolizumab,pembrolizumab,KEYNOTE,non-small cell lung cancer},
  file = {/Users/k/Zotero/storage/6JYCSJGV/Vachhani, Chen - Unknown - Spotlight on pembrolizumab in non-small cell lung cancer the evidence to date.pdf}
}

@article{manderProductIndependentBeta2015,
  title = {A Product of Independent Beta Probabilities Dose Escalation Design for Dual-Agent Phase {{I}} Trials},
  issn = {10970258},
  doi = {10.1002/sim.6434},
  abstract = {Dual-agent trials are now increasingly common in oncology research, and many proposed dose-escalation designs are available in the statistical literature. Despite this, the translation from statistical design to practical application is slow, as has been highlighted in single-agent phase I trials, where a 3\,+\,3 rule-based design is often still used. To expedite this process, new dose-escalation designs need to be not only scientifically beneficial but also easy to understand and implement by clinicians. In this paper, we propose a curve-free (nonparametric) design for a dual-agent trial in which the model parameters are the probabilities of toxicity at each of the dose combinations. We show that it is relatively trivial for a clinician's prior beliefs or historical information to be incorporated in the model and updating is fast and computationally simple through the use of conjugate Bayesian inference. Monotonicity is ensured by considering only a set of monotonic contours for the distribution of the maximum tolerated contour, which defines the dose-escalation decision process. Varied experimentation around the contour is achievable, and multiple dose combinations can be recommended to take forward to phase II. Code for R, Stata and Excel are available for implementation.},
  journal = {Statistics in Medicine},
  author = {Mander, Adrian P. and Sweeting, Michael J.},
  year = {2015},
  keywords = {Adaptive design,Dose escalation,Dual-agent trial,Nonparametric,Phase I clinical trial},
  file = {/Users/k/Zotero/storage/VQXBTCIW/Mander, Sweeting - 2015 - A product of independent beta probabilities dose escalation design for dual-agent phase I trials.pdf},
  pmid = {25630638}
}

@article{Salminen2015,
  title = {Antibiotic {{Therapy}} vs {{Appendectomy}} for {{Treatment}} of {{Uncomplicated Acute Appendicitis}}},
  volume = {313},
  issn = {0098-7484},
  doi = {10.1001/jama.2015.6154},
  abstract = {IMPORTANCE An increasing amount of evidence supports the use of antibiotics instead of surgery for treating patients with uncomplicated acute appendicitis. OBJECTIVE To compare antibiotic therapy with appendectomy in the treatment of uncomplicated acute appendicitis confirmed by computed tomography (CT). CONCLUSIONS AND RELEVANCE Among patients with CT-proven, uncomplicated appendicitis, antibiotic treatment did not meet the prespecified criterion for noninferiority compared with appendectomy. Most patients randomized to antibiotic treatment for uncomplicated appendicitis did not require appendectomy during the 1-year follow-up period, and those who required appendectomy did not experience significant complications.},
  number = {23},
  journal = {Jama},
  author = {Salminen, Paulina and Paajanen, Hannu and Rautio, Tero and Nordstr\"om, Pia and Aarnio, Markku and Rantanen, Tuomo and Tuominen, Risto and Hurme, Saija and Virtanen, Johanna and Mecklin, Jukka-Pekka and Sand, Juhani and Jartti, Airi and {Rinta-Kiikka}, Irina and Gr\"onroos, Juha M.},
  year = {2015},
  keywords = {Surgery,Appendectomy,Clinical Trials: methods,Clinical Trials: noninferiority},
  pages = {2340},
  file = {/Users/k/Zotero/storage/H6Y5VJW2/Salminen et al. - 2015 - Antibiotic Therapy vs Appendectomy for Treatment of Uncomplicated Acute Appendicitis.pdf},
  pmid = {26080338}
}

@article{Edwards2009,
  title = {Effect of {{Spironolactone}} on {{Left Ventricular Mass}} and {{Aortic Stiffness}} in {{Early}}-{{Stage Chronic Kidney Disease}}. {{A Randomized Controlled Trial}}},
  volume = {54},
  issn = {07351097},
  doi = {10.1016/j.jacc.2009.03.066},
  abstract = {Objectives: We sought to determine whether the addition of spironolactone to angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) improves left ventricular mass and arterial stiffness in early-stage chronic kidney disease (CKD). Background: Chronic kidney disease is associated with a high risk of cardiovascular disease and a high prevalence of left ventricular hypertrophy and arterial stiffness that confer an adverse prognosis. It is believed that these abnormalities are in part a result of activation of the renin-angiotensin-aldosterone system. Methods: After an active run-in phase with spironolactone 25 mg once daily, 112 patients with stage 2 and 3 CKD with good blood pressure control (mean daytime ambulatory blood pressure $<$130/85 mm Hg) on established treatment with ACE inhibitors or ARBs were randomized to continue spironolactone or to receive a matching placebo. Left ventricular mass (cardiac magnetic resonance) and arterial stiffness (pulse wave velocity/analysis, aortic distensibility) were measured before run in and after 40 weeks of treatment. Results: Compared with placebo, the use of spironolactone resulted in significant improvements in left ventricular mass (-14 ?? 13 g vs. +3 ?? 11 g, p $<$ 0.01), pulse wave velocity (-0.8 ?? 1.0 m/s vs. -0.1 ?? 0.9 m/s, p $<$ 0.01), augmentation index (-5.2 ?? 6.1\% vs. -1.4 ?? 5.9\%, p $<$ 0.05), and aortic distensibility (0.69 ?? 0.86 ?? 10-3 mm Hg vs. 0.04 ?? 1.04 ?? 10-3 mm Hg, p $<$ 0.01). Conclusions: The use of spironolactone reduces left ventricular mass and improves arterial stiffness in early-stage CKD. These effects suggest that aldosterone exerts adverse cardiovascular effects in CKD and that spironolactone is worthy of further study as a treatment that could reduce adverse cardiovascular events. (Is Spironolactone Safe and Effective in the Treatment of Cardiovascular Disease in Mild Chronic Renal Failure; NCT00291720). ?? 2009 American College of Cardiology Foundation.},
  number = {6},
  journal = {Journal of the American College of Cardiology},
  author = {Edwards, Nicola C. and Steeds, Richard P. and Stewart, Paul M. and Ferro, Charles J. and Townend, Jonathan N.},
  year = {2009},
  keywords = {arterial stiffness,chronic kidney disease,CKD,left ventricular mass,renin-angiotensin-aldosterone system,spironolactone},
  pages = {505-512},
  file = {/Users/k/Zotero/storage/7HMCMTBR/Edwards et al. - 2009 - Effect of Spironolactone on Left Ventricular Mass and Aortic Stiffness in Early-Stage Chronic Kidney Disease. A.pdf},
  pmid = {19643310}
}

@article{Chow2016,
  title = {Antitumor {{Activity}} of {{Pembrolizumab}} in {{Biomarker}}-{{Unselected Patients With Recurrent}} and/or {{Metastatic Head}} and {{Neck Squamous Cell Carcinoma}}: {{Results From}} the {{Phase Ib KEYNOTE}}-012 {{Expansion Cohort}}},
  issn = {0732-183X},
  doi = {10.1200/JCO.2016.68.1478},
  journal = {Journal of Clinical Oncology},
  author = {Chow, L. Q. M. and Haddad, R. and Gupta, S. and Mahipal, A. and Mehra, R. and Tahara, M. and Berger, R. and Eder, J. P. and Burtness, B. and Lee, S.-H. and Keam, B. and Kang, H. and Muro, K. and Weiss, J. and Geva, R. and Lin, C.-C. and Chung, H. C. and Meister, A. and {Dolled-Filhart}, M. and Pathiraja, K. and Cheng, J. D. and Seiwert, T. Y.},
  year = {2016},
  keywords = {Pembrolizumab,pembrolizumab},
  file = {/Users/k/Zotero/storage/A4EU6MEK/Chow et al. - 2016 - Antitumor Activity of Pembrolizumab in Biomarker-Unselected Patients With Recurrent andor Metastatic Head and Neck.pdf}
}

@article{Srinivasan2012a,
  title = {The {{Steroids}} for {{Corneal Ulcers Trial}}: {{Study Design}} and {{Baseline Characteristics}}},
  volume = {130},
  issn = {1946-6242},
  doi = {10.1001/archophthalmol.2011.303},
  number = {2},
  journal = {Archives of Ophthalmology},
  author = {Srinivasan, Muthiah and Mascarenhas, Jeena and Rajaraman, Revathi and Ravindran, Meenakshi and Lalitha, Prajna and Glidden, David V. and Ray, Kathryn J. and Hong, Kevin C. and Oldenburg, Catherine E. and Lee, Salena M. and Zegans, Michael E. and McLeod, Stephen D. and Lietman, Thomas M. and Acharya, Nisha R.},
  year = {2012},
  keywords = {Corneal,33447,44-207-794-0500 ext 35123 or,address correspondence to dr,centre for nephrology and,dengue,disease severity,e-mail,ethnic thais,genetic associations,henry stephens,hla,london nw3 2pf,lta,rowland hill street,royal free hospital campus,tel,the,the anthony nolan trust,tnf,uk,university college london},
  pages = {151-7},
  file = {/Users/k/Zotero/storage/D7I8SVI5/Srinivasan et al. - 2012 - The Steroids for Corneal Ulcers Trial Study Design and Baseline Characteristics.pdf},
  pmid = {20371490}
}

@article{Srinivasan2014,
  title = {The Steroids for Corneal Ulcers Trial ({{SCUT}}): {{Secondary}} 12-Month Clinical Outcomes of a Randomized Controlled Trial},
  volume = {157},
  issn = {00029394},
  doi = {10.1016/j.ajo.2013.09.025},
  abstract = {Purpose To determine whether topical corticosteroids as adjunctive therapy for bacterial keratitis improves long-term clinical outcomes. Design Randomized, placebo-controlled, double-masked clinical trial. Methods This multicenter trial compared 1.0\% prednisolone sodium phosphate to placebo in the treatment of bacterial keratitis among 500 patients with culture-positive ulcers receiving 48 hours of moxifloxacin before randomization. The primary endpoint was 3 months from enrollment, and 399 patients were evaluated at 12 months. The outcomes examined were best spectacle-corrected visual acuity (BSCVA) and scar size at 12 months. Based on previous results, regression models with adjustments for baseline status and/or causative organism were used for analysis. Results No significant differences in clinical outcomes by treatment group were seen with the prespecified regression models (BSCVA: -0.04 logMAR, 95\% CI, -0.12 to 0.05, P =.39; scar size: 0.03 mm, 95\% CI, -0.12 to 0.18, P =.69). A regression model including a Nocardia-treatment arm interaction found corticosteroid use associated with a mean 1-line improvement in BSCVA at 12 months among patients with non-Nocardia ulcers (-0.10 logMAR, 95\% CI, -0.19 to -0.02, P =.02). No significant difference was observed in 12-month BSCVA for Nocardia ulcers (0.18 logMAR, 95\% CI, -0.04 to 0.41, P =.16). Corticosteroids were associated with larger mean scar size at 12 months among Nocardia ulcers (0.47 mm, 95\% CI, 0.06-0.88, P =.02) and no significant difference was identified by treatment for scar size for non-Nocardia ulcers (-0.06 mm, 95\% CI, -0.21 to 0.10, P =.46). Conclusions Adjunctive topical corticosteroid therapy may be associated with improved long-term clinical outcomes in bacterial corneal ulcers not caused by Nocardia species. ?? 2014 BY ELSEVIER INC. ALL RIGHTS RESERVED.},
  number = {2},
  journal = {American Journal of Ophthalmology},
  author = {Srinivasan, Muthiah and Mascarenhas, Jeena and Rajaraman, Revathi and Ravindran, Meenakshi and Lalitha, Prajna and O'Brien, Kieran S. and Glidden, David V. and Ray, Kathryn J. and Oldenburg, Catherine E. and Zegans, Michael E. and Whitcher, John P. and McLeod, Stephen D. and Porco, Travis C. and Lietman, Thomas M. and Acharya, Nisha R.},
  year = {2014},
  keywords = {Corneal},
  pages = {327-333.e3},
  file = {/Users/k/Zotero/storage/QH3F852M/Srinivasan et al. - 2014 - The steroids for corneal ulcers trial (SCUT) Secondary 12-month clinical outcomes of a randomized controlled.pdf},
  pmid = {24315294}
}

@article{Deerenberg2015,
  title = {Small Bites versus Large Bites for Closure of Abdominal Midline Incisions ({{STITCH}}): {{A}} Double-Blind, Multicentre, Randomised Controlled Trial},
  volume = {386},
  issn = {1474547X},
  doi = {10.1016/S0140-6736(15)60459-7},
  abstract = {Background Incisional hernia is a frequent complication of midline laparotomy and is associated with high morbidity, decreased quality of life, and high costs. We aimed to compare the large bites suture technique with the small bites technique for fascial closure of midline laparotomy incisions. Methods We did this prospective, multicentre, double-blind, randomised controlled trial at surgical and gynaecological departments in ten hospitals in the Netherlands. Patients aged 18 years or older who were scheduled to undergo elective abdominal surgery with midline laparotomy were randomly assigned (1:1), via a computer-generated randomisation sequence, to receive small tissue bites of 5 mm every 5 mm or large bites of 1 cm every 1 cm. Randomisation was stratified by centre and between surgeons and residents with a minimisation procedure to ensure balanced allocation. Patients and study investigators were masked to group allocation. The primary outcome was the occurrence of incisional hernia; we postulated a reduced incidence in the small bites group. We analysed patients by intention to treat. This trial is registered at Clinicaltrials.gov, number NCT01132209 and with the Nederlands Trial Register, number NTR2052. Findings Between Oct 20, 2009, and March 12, 2012, we randomly assigned 560 patients to the large bites group (n=284) or the small bites group (n=276). Follow-up ended on Aug 30, 2013; 545 (97\%) patients completed follow-up and were included in the primary outcome analysis. Patients in the small bites group had fascial closures sutured with more stitches than those in the large bites group (mean number of stitches 45 [SD 12] vs 25 [10]; p$<$0??0001), a higher ratio of suture length to wound length (5??0 [1??5] vs 4??3 [1??4]; p$<$0??0001) and a longer closure time (14 [6] vs 10 [4] min; p$<$0??0001). At 1 year follow-up, 57 (21\%) of 277 patients in the large bites group and 35 (13\%) of 268 patients in the small bites group had incisional hernia (p=0??0220, covariate adjusted odds ratio 0??52, 95\% CI 0??31-0??87; p=0??0131). Rates of adverse events did not differ significantly between groups. Interpretation Our findings show that the small bites suture technique is more effective than the traditional large bites technique for prevention of incisional hernia in midline incisions and is not associated with a higher rate of adverse events. The small bites technique should become the standard closure technique for midline incisions. Funding Erasmus University Medical Center and Ethicon.},
  number = {10000},
  journal = {The Lancet},
  author = {Deerenberg, Eva B. and Harlaar, Joris J. and Steyerberg, Ewout W. and Lont, Harold E. and Van Doorn, Helena C. and Heisterkamp, Joos and Wijnhoven, Bas P L and Schouten, Willem R. and Cense, Huib A. and Stockmann, Hein B A C and Berends, Frits J. and Dijkhuizen, F. Paul Hlj and Dwarkasing, Roy S. and Jairam, An P. and Van Ramshorst, Gabrielle H. and Kleinrensink, Gert Jan and Jeekel, Johannes and Lange, Johan F.},
  year = {2015},
  keywords = {Surgery},
  pages = {1254-1260},
  file = {/Users/k/Zotero/storage/NVIUP2FP/Deerenberg et al. - 2015 - Small bites versus large bites for closure of abdominal midline incisions (STITCH) A double-blind, multicentr.pdf;/Users/k/Zotero/storage/YSU2D2VZ/Deerenberg et al. - 2015 - Small bites versus large bites for closure of abdominal midline incisions (STITCH) A double-blind, multicentr.pdf},
  pmid = {26188742}
}

@article{Gruenbaum2016,
  title = {Pharmacologic {{Neuroprotection}} for {{Functional Outcomes After Traumatic Brain Injury}}: {{A Systematic Review}} of the {{Clinical Literature}}},
  volume = {30},
  issn = {1172-7047},
  doi = {10.1007/s40263-016-0355-2},
  number = {9},
  journal = {CNS Drugs},
  author = {Gruenbaum, Shaun E. and Zlotnik, Alexander and Gruenbaum, Benjamin F. and Hersey, Denise and Bilotta, Federico},
  year = {2016},
  keywords = {TBI},
  pages = {1-16},
  file = {/Users/k/Zotero/storage/SMSD4HTW/Gruenbaum et al. - 2016 - Pharmacologic Neuroprotection for Functional Outcomes After Traumatic Brain Injury A Systematic Review of the.pdf;/Users/k/Zotero/storage/VHKHNSV4/Gruenbaum et al. - 2016 - Pharmacologic Neuroprotection for Functional Outcomes After Traumatic Brain Injury A Systematic Review of the.pdf},
  pmid = {27339615}
}

@article{Burke2016,
  title = {Clarification on {{Tartari}} et Al: {{Economic}} Sustainability of Anti-{{PD}}-1 Agents Nivolumab and Pembrolizumab in Cancer Patients},
  issn = {03057372},
  doi = {10.1016/j.ctrv.2016.08.009},
  journal = {Cancer Treatment Reviews},
  author = {Burke, Tom},
  year = {2016},
  keywords = {Pembrolizumab,pembrolizumab},
  file = {/Users/k/Zotero/storage/JAH92WUW/Burke - 2016 - Clarification on Tartari et al Economic sustainability of anti-PD-1 agents nivolumab and pembrolizumab in cancer patients.pdf;/Users/k/Zotero/storage/M5QNDBY8/Burke - 2016 - Clarification on Tartari et al Economic sustainability of anti-PD-1 agents nivolumab and pembrolizumab in cancer patients.pdf}
}

@article{Tartari2016,
  title = {Economic Sustainability of Anti-{{PD}}-1 Agents Nivolumab and Pembrolizumab in Cancer Patients: {{Recent}} Insights and Future Challenges.},
  volume = {48},
  issn = {1532-1967},
  doi = {10.1016/j.ctrv.2016.06.002},
  abstract = {Anti-programmed death (PD)-1 agents pembrolizumab and nivolumab have recently obtained enthusiastic results in terms of progression-free survival (PFS), overall survival (OS) and tolerability in cancer patients. Despite these promising data, the high cost of these agents needs careful consideration. Indeed, the evaluation of cost-effectiveness analysis (CEA) and quality-adjusted life year (QALY), as well as different drug reimbursement modalities, will represent fundamental tools in order to guarantee the economic sustainability of health system and the access to care for all cancer patients. In this review, we discussed the recent results obtained by immunotherapy in cancer patients and we evaluated the economic impact of recently approved nivolumab and pembrolizumab in patients with advanced melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC).},
  journal = {Cancer treatment reviews},
  author = {Tartari, Francesca and Santoni, Matteo and Burattini, Luciano and Mazzanti, Paola and Onofri, Azzurra and Berardi, Rossana},
  year = {2016},
  keywords = {Pembrolizumab,Immunotherapy,Melanoma,Economic sustainability,Lung cancer,Per patient cost,Renal cell carcinoma,pembrolizumab},
  pages = {20-24},
  file = {/Users/k/Zotero/storage/GAAUWPZS/Tartari et al. - 2016 - Economic sustainability of anti-PD-1 agents nivolumab and pembrolizumab in cancer patients Recent insights and f.pdf;/Users/k/Zotero/storage/HUBHPRYC/Tartari et al. - 2016 - Economic sustainability of anti-PD-1 agents nivolumab and pembrolizumab in cancer patients Recent insights and f.pdf},
  pmid = {27310708}
}

@article{Tan2003,
  title = {Strategy for Randomised Clinical Trials in Rare Cancers},
  volume = {327},
  issn = {0959-8138},
  doi = {10.1136/bmj.327.7405.47},
  abstract = {Proving that a new treatment is more effective than current treatment can be difficult for rare conditions. Data from small randomised trials could, however, be made more robust by taking other related research into account},
  number = {7405},
  journal = {BMJ : British Medical Journal},
  author = {Tan, Say-Beng and Dear, Keith B G and Bruzzi, Paolo and Machin, David},
  year = {2003},
  pages = {47-49},
  file = {/Users/k/Zotero/storage/4622FIFW/Tan et al. - 2003 - Strategy for randomised clinical trials in rare cancers.pdf},
  pmid = {12842959}
}

@article{Hemming2013,
  title = {A {{Systematic Review}} of {{Systematic Reviews}} and {{Panoramic Meta}}-{{Analysis}}: {{Staples}} versus {{Sutures}} for {{Surgical Procedures}}},
  volume = {8},
  issn = {19326203},
  doi = {10.1371/journal.pone.0075132},
  abstract = {OBJECTIVE: To systematically evaluate the evidence across surgical specialties as to whether staples or sutures better improve patient and provider level outcomes.$\backslash$n$\backslash$nDESIGN: A systematic review of systematic reviews and panoramic meta-analysis of pooled estimates.$\backslash$n$\backslash$nRESULTS: Eleven systematic reviews, including 13,661 observations, met the inclusion criteria. In orthopaedic surgery sutures were found to be preferable, and for appendicial stump sutures were protective against both surgical site infection and post surgical complications. However, staples were protective against leak in ilecolic anastomosis. For all other surgery types the evidence was inconclusive with wider confidence intervals including the possibly of preferential outcomes for surgical site infection or post surgical complication for either staples or sutures. Whilst reviews showed substantial variation in mean differences in operating time (I(2) 94\%) there was clear evidence of a reduction in average operating time across all surgery types. Few reviews reported on length of stay, but the three reviews that did (I(2) 0\%, including 950 observations) showed a non significant reduction in length of stay, but showed evidence of publication bias (P-value for Egger test 0.05).$\backslash$n$\backslash$nCONCLUSIONS: Evidence across surgical specialties indicates that wound closure with staples reduces the mean operating time. Despite including several thousand observations, no clear evidence of superiority emerged for either staples or sutures with respect to surgical site infection, post surgical complications, or length of stay.},
  number = {10},
  journal = {PLoS ONE},
  author = {Hemming, Karla and Pinkney, Thomas and Futaba, Kay and Pennant, Mary and Morton, Dion G. and Lilford, Richard J.},
  year = {2013},
  keywords = {SystematicReview},
  file = {/Users/k/Zotero/storage/UZJ6AIVJ/Hemming et al. - 2013 - A Systematic Review of Systematic Reviews and Panoramic Meta-Analysis Staples versus Sutures for Surgical Proced.pdf},
  pmid = {24116028}
}

@article{Hemming2012,
  title = {Pooling Systematic Reviews of Systematic Reviews: {{A Bayesian}} Panoramic Meta-Analysis},
  volume = {31},
  issn = {02776715},
  doi = {10.1002/sim.4372},
  abstract = {Systematic reviews and meta-analyses usually synthesise evidence from studies reporting outcomes from particular interventions in specific diseases. For example, a meta-analysis of prophylactic antibiotics (intervention) in elective arterial reconstruction (disease) for rates of wound infection (outcome). However, because systematic reviews and meta-analyses are so widespread, a body of evidence often exists around specific intervention effects on particular outcomes over a range of diseases. So for example, a multitude of independent meta-analyses have evaluated rates of wound infection with and without the use of prophylactic antibiotics over multiple surgery types. A systematic review of systematic reviews is a means of synthesising evidence for the same intervention over multiple disease types. We propose a panoramic meta-analysis as a means of pooling effect estimates over systematic reviews of systematic reviews. We explore several methods ranging from a simple two-step approach, to a meta-regression or mixed effects approach, where variation between diseases are modelled as fixed covariate effects and between-study variation by random effects, and to a three-level hierarchical model in which exchangeability is assumed, which allows both a between-disease component of variance and a between-study (within disease) component of variance. In the surgery example, we pool 18 meta-analyses (each including between 4 and 26 studies) of prophylactic antibiotics reporting rates of wound infection from 18 different surgery sites to obtain a single pooled estimate of effect and estimates of between-disease, within-disease and within-study variability.},
  number = {3},
  journal = {Statistics in Medicine},
  author = {Hemming, Karla and Bowater, Russell James and Lilford, Richard J.},
  year = {2012},
  keywords = {Meta-analysis,Panoramic meta-analysis,Random effects models,Systematic reviews,SystematicReview},
  pages = {201-216},
  file = {/Users/k/Zotero/storage/IM3BC84Q/Hemming, Bowater, Lilford - 2012 - Pooling systematic reviews of systematic reviews A Bayesian panoramic meta-analysis.pdf},
  pmid = {21965138}
}

@article{Ribas2015b,
  title = {P0116 {{Updated}} Clinical Efficacy of the Anti-{{PD}}-1 Monoclonal Antibody Pembrolizumab ({{MK}}-3475) in 411 Patients with Melanoma},
  volume = {51},
  issn = {09598049},
  doi = {10.1016/j.ejca.2015.06.072},
  journal = {European Journal of Cancer},
  author = {Ribas, A. and Wolchok, J.D. and Robert, C. and Kefford, R. and Hamid, O. and Daud, A. and Hwu, W-J. and Weber, J.S. and Joshua, A.M. and Gangadhar, T.C. and Patnaik, A. and Hersey, P. and Dronca, R. and Zarour, H. and Gergich, K. and Lindia, J.A. and Giannotti, M. and Li, X.N. and Ebbinghaus, S. and Kang, S.P. and Hodi, F.S.},
  year = {2015},
  keywords = {Pembrolizumab,Melanoma,pembrolizumab},
  pages = {e24},
  file = {/Users/k/Zotero/storage/FRI376FU/Ribas et al. - 2015 - P0116 Updated clinical efficacy of the anti-PD-1 monoclonal antibody pembrolizumab (MK-3475) in 411 patients with.pdf;/Users/k/Zotero/storage/PKDP2ZIB/Ribas et al. - 2015 - P0116 Updated clinical efficacy of the anti-PD-1 monoclonal antibody pembrolizumab (MK-3475) in 411 patients with.pdf}
}

@article{Patnaik2015,
  title = {Phase {{I}} Study of Pembrolizumab ({{MK}}-3475; {{Anti}}-{{PD}}-1 Monoclonal Antibody) in Patients with Advanced Solid Tumors},
  volume = {21},
  issn = {15573265},
  doi = {10.1158/1078-0432.CCR-14-2607},
  abstract = {PURPOSE This phase I study evaluated the safety, maximum tolerated dose, antitumor activity, and pharmacokinetics and pharmacodynamics of pembrolizumab in patients with advanced solid tumors. EXPERIMENTAL DESIGN In a 3 + 3 dose escalation study, 10 patients received pembrolizumab 1, 3, or 10 mg/kg intravenously every 2 weeks until progression or intolerable toxicity. Seven additional patients received 10 mg/kg every 2 weeks. Thirteen patients participated in a 3-week intrapatient dose escalation (dose range, 0.005-10 mg/kg) followed by 2 or 10 mg/kg every 3 weeks. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. RESULTS No dose-limiting toxicities were observed. Maximum administered dose was 10 mg/kg every 2 weeks. One patient with melanoma and one with Merkel cell carcinoma experienced complete responses of 57 and 56+ weeks' duration, respectively. Three patients with melanoma experienced partial responses. Fifteen patients with various malignancies experienced stable disease. One patient died of cryptococcal infection 92 days after pembrolizumab discontinuation, following prolonged corticosteroid use for grade 2 gastritis considered drug related. Pembrolizumab exhibited pharmacokinetic characteristics typical of humanized monoclonal antibodies. Maximum serum target engagement was reached with trough levels of doses greater than or equal to 1 mg/kg every 3 weeks. Mechanism-based translational models with a focus on intratumor exposure prediction suggested robust clinical activity would be observed at doses $\geq$2 mg/kg every 3 weeks. CONCLUSIONS Pembrolizumab was well tolerated and associated with durable antitumor activity in multiple solid tumors. The lowest dose with full potential for antitumor activity was 2 mg/kg every 3 weeks.},
  number = {19},
  journal = {Clinical Cancer Research},
  author = {Patnaik, Amita and Kang, S. Peter and Rasco, Drew and Papadopoulos, Kyriakos P. and {Elassaiss-Schaap}, Jeroen and Beeram, Muralidhar and Drengler, Ronald and Chen, Cong and Smith, Lon and Espino, Guillermo and Gergich, Kevin and Delgado, Liliana and Daud, Adil and Lindia, Jill A. and Nicole Li, Xiaoyun and Pierce, Robert H. and Yearley, Jennifer H. and Wu, Dianna and Laterza, Omar and Lehnert, Manfred and Iannone, Robert and Tolcher, Anthony W.},
  year = {2015},
  keywords = {Pembrolizumab,★,pembrolizumab},
  pages = {4286-4293},
  file = {/Users/k/Zotero/storage/9N2XSBT2/Patnaik et al. - 2015 - Phase I study of pembrolizumab (MK-3475 Anti-PD-1 monoclonal antibody) in patients with advanced solid tumors.pdf;/Users/k/Zotero/storage/NT3AVUEN/Patnaik et al. - Unknown - Supplementary - Phase I study of pembrolizumab (MK-3475 Anti-PD-1 monoclonal antibody) in patients with adva.docx},
  pmid = {25977344}
}

@article{Herbst2016a,
  title = {Supplementary {{Appendix}} - {{Pembrolizumab}} versus Docetaxel for Previously Treated, {{PD}}-{{L1}}-Positive, Advanced Non-Small-Cell Lung Cancer ({{KEYNOTE}}-010): A Randomised Controlled Trial},
  volume = {6736},
  number = {15},
  author = {{Herbst} and {Baas} and {Kim} and {...}},
  year = {2015},
  keywords = {NSCLC,Pembrolizumab,pembrolizumab},
  file = {/Users/k/Zotero/storage/YLZR68HU/Herbst et al. - 2015 - Supplementary Appendix - Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-smal.pdf}
}

@article{Dalgleish2016,
  title = {Randomised, Open-Label, Phase {{II}} Study of Gemcitabine with and without {{IMM}}-101 for Advanced Pancreatic Cancer},
  doi = {10.1038/bjc.2016.271},
  abstract = {Background: Immune Modulation and Gemcitabine Evaluation-1, a randomised, open-label, phase II, first-line, proof of concept study (NCT01303172), explored safety and tolerability of IMM-101 (heat-killed Mycobacterium obuense; NCTC 13365) with gemcitabine (GEM) in advanced pancreatic ductal adenocarcinoma. Methods: Patients were randomised (2 : 1) to IMM-101 (10 mg ml \`A l intradermally) \th{} GEM (1000 mg m \`A 2 intravenously; n \textonequarter{} 75), or GEM alone (n \textonequarter{} 35). Safety was assessed on frequency and incidence of adverse events (AEs). Overall survival (OS), progression-free survival (PFS) and overall response rate (ORR) were collected. Results: IMM-101 was well tolerated with a similar rate of AE and serious adverse event reporting in both groups after allowance for exposure. Median OS in the intent-to-treat population was 6.7 months for IMM-101 \th{} GEM v 5.6 months for GEM; while not significant, the hazard ratio (HR) numerically favoured IMM-101 \th{} GEM (HR, 0.68 (95\% CI, 0.44\textendash{}1.04, P \textonequarter{} 0.074). In a pre-defined metastatic subgroup (84\%), OS was significantly improved from 4.4 to 7.0 months in favour of IMM-101 \th{} GEM (HR, 0.54, 95\% CI 0.33\textendash{}0.87, P \textonequarter{} 0.01). Conclusions: IMM-101 with GEM was as safe and well tolerated as GEM alone, and there was a suggestion of a beneficial effect on survival in patients with metastatic disease. This warrants further evaluation in an adequately powered confirmatory study.},
  journal = {British journal of cancer},
  author = {Dalgleish, Angus G and Stebbing, Justin and Adamson, Douglas JA and Safia Arif, Seema and Bidoli, Paolo and Chang, David and Cheeseman, Sue and {Diaz-Beveridge}, Robert and {Fernandez-Martos}, Carlos and {Glynne-Jones}, Rob and Granetto, Cristina and Massuti, Bartomeu and McAdam, Karen and McDermott, Raymond and {Mu\~n oz Mart\'in}, Andr\'e J and Papamichael, Demetris and {Pazo-Cid}, Roberto and Vieitez, Jose M and Zaniboni, Alberto and Carroll, Kevin J and Wagle, Shama and Gaya, Andrew and Mudan, Satvinder S},
  year = {2016},
  keywords = {Immunotherapy,IMM-101,Pancreatic},
  pages = {1-8},
  file = {/Users/k/Zotero/storage/6CT6PKVU/Dalgleish et al. - 2016 - Randomised, open-label, phase II study of gemcitabine with and without IMM-101 for advanced pancreatic cancer.pdf;/Users/k/Zotero/storage/9Z4XAFGL/Dalgleish et al. - 2016 - Randomised, open-label, phase II study of gemcitabine with and without IMM-101 for advanced pancreatic cancer.pdf}
}

@article{Muro2016,
  title = {Pembrolizumab for Patients with {{PD}}-{{L1}}-Positive Advanced Gastric Cancer ({{KEYNOTE}}-012): A Multicentre, Open-Label, Phase 1b Trial},
  volume = {17},
  issn = {14702045},
  doi = {10.1016/S1470-2045(16)00175-3},
  journal = {The Lancet Oncology},
  author = {Muro, Kei and Chung, Hyun Cheol and Shankaran, Veena and Geva, Ravit and Catenacci, Daniel and Gupta, Shilpa and Eder, Joseph Paul and Golan, Talia and Le, Dung T and Burtness, Barbara and McRee, Autumn J and Lin, Chia-Chi and Pathiraja, Kumudu and Lunceford, Jared and Emancipator, Kenneth and Juco, Jonathan and Koshiji, Minori and Bang, Yung-Jue},
  year = {2016},
  keywords = {Pembrolizumab,pembrolizumab},
  pages = {717-726},
  file = {/Users/k/Zotero/storage/JTHQ8KQ4/Muro et al. - 2016 - Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012) a multicentre, open-label, pha.pdf},
  pmid = {27157491}
}

@article{Seiwert2016,
  title = {Safety and Clinical Activity of Pembrolizumab for Treatment of Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck ({{KEYNOTE}}-012): An Open-Label, Multicentre, Phase 1b Trial},
  volume = {17},
  issn = {14702045},
  doi = {10.1016/S1470-2045(16)30066-3},
  number = {7},
  journal = {The Lancet Oncology},
  author = {Seiwert, Tanguy Y and Burtness, Barbara and Mehra, Ranee and Weiss, Jared and Berger, Raanan and Eder, Joseph Paul and Heath, Karl and McClanahan, Terrill and Lunceford, Jared and Gause, Christine and Cheng, Jonathan D and Chow, Laura Q},
  year = {2016},
  keywords = {Pembrolizumab,pembrolizumab},
  pages = {956-965},
  file = {/Users/k/Zotero/storage/42MTLHWD/Seiwert et al. - 2016 - Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma o.pdf},
  pmid = {27247226}
}

@article{Nanda2016,
  title = {Pembrolizumab in {{Patients With Advanced Triple}}-{{Negative Breast Cancer}}: {{Phase Ib KEYNOTE}}-012 {{Study}}.},
  issn = {1527-7755},
  doi = {10.1200/JCO.2015.64.8931},
  abstract = {PURPOSE Immune checkpoint inhibition has been demonstrated to be an effective anticancer strategy. Several lines of evidence support the study of immunotherapy in triple-negative breast cancer (TNBC). We assessed the safety and antitumor activity of the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab in patients with advanced TNBC. METHODS KEYNOTE-012 (ClinicalTrials.gov identifier: NCT01848834) was a multicenter, nonrandomized phase Ib trial of single-agent pembrolizumab given intravenously at 10 mg/kg every 2 weeks to patients with advanced PD-L1-positive (expression in stroma or $\geq$ 1\% of tumor cells by immunohistochemistry) TNBC, gastric cancer, urothelial cancer, and head and neck cancer. This report focuses on the TNBC cohort. RESULTS Among 111 patients with TNBC whose tumor samples were screened for PD-L1 expression, 58.6\% had PD-L1-positive tumors. Thirty-two women (median age, 50.5 years; range, 29 to 72 years) were enrolled and assessed for safety and antitumor activity. The median number of doses administered was five (range, 1 to 36 doses). Common toxicities were mild and similar to those observed in other tumor cohorts (eg, arthralgia, fatigue, myalgia, and nausea), and included five (15.6\%) patients with grade $\geq$ 3 toxicity and one treatment-related death. Among the 27 patients who were evaluable for antitumor activity, the overall response rate was 18.5\%, the median time to response was 17.9 weeks (range, 7.3 to 32.4 weeks), and the median duration of response was not yet reached (range, 15.0 to $\geq$ 47.3 weeks). CONCLUSION This phase Ib study describes preliminary evidence of clinical activity and a potentially acceptable safety profile of pembrolizumab given every 2 weeks to patients with heavily pretreated, advanced TNBC. A single-agent phase II study examining a 200-mg dose given once every 3 weeks (ClinicalTrials.gov identifier: NCT02447003) is ongoing.},
  journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology},
  author = {Nanda, Rita and Chow, Laura Q M and Dees, E Claire and Berger, Raanan and Gupta, Shilpa and Geva, Ravit and Pusztai, Lajos and Pathiraja, Kumudu and Aktan, Gursel and Cheng, Jonathan D and Karantza, Vassiliki and Buisseret, Laurence},
  year = {2016},
  keywords = {Pembrolizumab,pembrolizumab},
  pages = {1-10},
  file = {/Users/k/Zotero/storage/RPUQGXU8/Nanda et al. - 2016 - Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer Phase Ib KEYNOTE-012 Study.pdf},
  pmid = {27138582}
}

@article{Ribas2015,
  title = {Pembrolizumab versus Investigator-Choice Chemotherapy for Ipilimumab-Refractory Melanoma ({{KEYNOTE}}-002): {{A}} Randomised, Controlled, Phase 2 Trial},
  volume = {16},
  issn = {14745488},
  doi = {10.1016/S1470-2045(15)00083-2},
  abstract = {Background: Patients with melanoma that progresses on ipilimumab and, if BRAFV600 mutant-positive, a BRAF or MEK inhibitor or both, have few treatment options. We assessed the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma. Methods: We carried out a randomised phase 2 trial of patients aged 18 years or older from 73 hospitals, clinics, and academic medical centres in 12 countries who had confirmed progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAFV600 mutant-positive, previous treatment with a BRAF or MEK inhibitor or both. Patients had to have resolution of all ipilimumab-related adverse events to grade 0-1 and prednisone 10 mg/day or less for at least 2 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and at least one measurable lesion to be eligible. Using a centralised interactive voice response system, we randomly assigned (1:1:1) patients in a block size of six to receive intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or oral temozolomide). Randomisation was stratified by ECOG performance status, lactate dehydrogenase concentration, and BRAFV600 mutation status. Individual treatment assignment between pembrolizumab and chemotherapy was open label, but investigators and patients were masked to assignment of the dose of pembrolizumab. We present the primary endpoint at the prespecified second interim analysis of progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01704287. The study is closed to enrolment but continues to follow up and treat patients. Findings: Between Nov 30, 2012, and Nov 13, 2013, we enrolled 540 patients: 180 patients were randomly assigned to receive pembrolizumab 2 mg/kg, 181 to receive pembrolizumab 10 mg/kg, and 179 to receive chemotherapy. Based on 410 progression-free survival events, progression-free survival was improved in patients assigned to pembrolizumab 2 mg/kg (HR 0$\cdot$57, 95\% CI 0$\cdot$45-0$\cdot$73; p},
  number = {8},
  journal = {The Lancet Oncology},
  author = {Ribas, Antoni and Puzanov, Igor and Dummer, Reinhard and Schadendorf, Dirk and Hamid, Omid and Robert, Caroline and Hodi, F. Stephen and Schachter, Jacob and Pavlick, Anna C. and Lewis, Karl D. and Cranmer, Lee D. and Blank, Christian U. and O'Day, Steven J. and Ascierto, Paolo A. and Salama, April K S and Margolin, Kim A. and Loquai, Carmen and Eigentler, Thomas K. and Gangadhar, Tara C. and Carlino, Matteo S. and Agarwala, Sanjiv S. and Moschos, Stergios J. and Sosman, Jeffrey A. and Goldinger, Simone M. and {Shapira-Frommer}, Ronnie and Gonzalez, Rene and Kirkwood, John M. and Wolchok, Jedd D. and Eggermont, Alexander and Li, Xiaoyun Nicole and Zhou, Wei and Zernhelt, Adriane M. and Lis, Joy and Ebbinghaus, Scot and Kang, S. Peter and Daud, Adil},
  year = {2015},
  keywords = {Pembrolizumab,Melanoma,★,pembrolizumab},
  pages = {908-918},
  file = {/Users/k/Zotero/storage/JEMX5LRL/Ribas et al. - 2015 - Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002) A randomise.pdf;/Users/k/Zotero/storage/XTHPB95P/Ribas et al. - 2015 - Supplementary - Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-.pdf},
  pmid = {26115796}
}

@article{Bhatia2014,
  title = {Melanoma: {{Immune}} Checkpoint Blockade Story Gets Better},
  issn = {1474547X},
  doi = {10.1016/S0140-6736(14)61140-5},
  abstract = {The 10-year survival for patients with metastatic melanoma is less than 10\%. 1 After decades of failed attempts to improve treatment outcomes in patients with this disease, 2 the recent successes with ipilimumab and the inhibitors of BRAF and MEK (vemurafenib, dabrafenib, and trametinib) have ushered in a new era in systemic therapy. 3\textemdash{}7 These breakthroughs have not only provided more treatment options for patients with melanoma, but have also spurred the investigation of a new generation of drugs for ...},
  journal = {The Lancet},
  author = {Bhatia, Shailender and Thompson, John A.},
  year = {2014},
  keywords = {Pembrolizumab,Melanoma,pembrolizumab},
  file = {/Users/k/Zotero/storage/6M87G4M6/Bhatia, Thompson - 2014 - Melanoma Immune checkpoint blockade story gets better.pdf},
  pmid = {25034863}
}

@article{Hamid2013,
  title = {Safety and Tumor Responses with Lambrolizumab (Anti-{{PD}}-1) in Melanoma.},
  volume = {369},
  issn = {1533-4406},
  doi = {10.1056/NEJMoa1305133},
  abstract = {BACKGROUND: The programmed death 1 (PD-1) receptor is a negative regulator of T-cell effector mechanisms that limits immune responses against cancer. We tested the anti-PD-1 antibody lambrolizumab (previously known as MK-3475) in patients with advanced melanoma.$\backslash$n$\backslash$nMETHODS: We administered lambrolizumab intravenously at a dose of 10 mg per kilogram of body weight every 2 or 3 weeks or 2 mg per kilogram every 3 weeks in patients with advanced melanoma, both those who had received prior treatment with the immune checkpoint inhibitor ipilimumab and those who had not. Tumor responses were assessed every 12 weeks.$\backslash$n$\backslash$nRESULTS: A total of 135 patients with advanced melanoma were treated. Common adverse events attributed to treatment were fatigue, rash, pruritus, and diarrhea; most of the adverse events were low grade. The confirmed response rate across all dose cohorts, evaluated by central radiologic review according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was 38\% (95\% confidence interval [CI], 25 to 44), with the highest confirmed response rate observed in the cohort that received 10 mg per kilogram every 2 weeks (52\%; 95\% CI, 38 to 66). The response rate did not differ significantly between patients who had received prior ipilimumab treatment and those who had not (confirmed response rate, 38\% [95\% CI, 23 to 55] and 37\% [95\% CI, 26 to 49], respectively). Responses were durable in the majority of patients (median follow-up, 11 months among patients who had a response); 81\% of the patients who had a response (42 of 52) were still receiving treatment at the time of analysis in March 2013. The overall median progression-free survival among the 135 patients was longer than 7 months.$\backslash$n$\backslash$nCONCLUSIONS: In patients with advanced melanoma, including those who had had disease progression while they had been receiving ipilimumab, treatment with lambrolizumab resulted in a high rate of sustained tumor regression, with mainly grade 1 or 2 toxic effects. (Funded by Merck Sharp and Dohme; ClinicalTrials.gov number, NCT01295827.).},
  number = {2},
  journal = {The New England journal of medicine},
  author = {Hamid, Omid and Robert, Caroline and Daud, Adil and Hodi, F Stephen and Hwu, Wen-Jen and Kefford, Richard and Wolchok, Jedd D and Hersey, Peter and Joseph, Richard W and Weber, Jeffrey S and Dronca, Roxana and Gangadhar, Tara C and Patnaik, Amita and Zarour, Hassane and Joshua, Anthony M and Gergich, Kevin and {Elassaiss-Schaap}, Jeroen and Algazi, Alain and Mateus, Christine and Boasberg, Peter and Tumeh, Paul C and Chmielowski, Bartosz and Ebbinghaus, Scot W and Li, Xiaoyun Nicole and Kang, S Peter and Ribas, Antoni},
  year = {2013},
  keywords = {Adult,Female,Humans,Middle Aged,Antineoplastic Agents,Pembrolizumab,Melanoma,Male,Antineoplastic Agents: administration \& dosage,Antineoplastic Agents: adverse effects,Dose-Response Relationship,Drug,80 and over,Aged,Antibodies,Antineoplastic Agents: pharmacokinetics,Brain Neoplasms,Brain Neoplasms: secondary,Drug Administration Schedule,Melanoma: drug therapy,Melanoma: secondary,Monoclonal,Monoclonal: administration \& dosage,Monoclonal: adverse effects,Monoclonal: pharmacokinetics,Programmed Cell Death 1 Receptor,Programmed Cell Death 1 Receptor: antagonists \& in,Skin Neoplasms,Skin Neoplasms: drug therapy,Skin Neoplasms: pathology,★,pembrolizumab},
  pages = {134-44},
  file = {/Users/k/Zotero/storage/6HERHCHJ/Hamid et al. - 2013 - Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma.pdf;/Users/k/Zotero/storage/F9SDE532/Hamid et al. - 2013 - Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma.pdf;/Users/k/Zotero/storage/N737ZZWD/Hamid et al. - 2013 - Supplementary - Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma.pdf},
  pmid = {23724846}
}

@article{Dummer2015,
  title = {A Randomized Controlled Comparison of Pembrolizumab and Chemotherapy in Patients with Ipilimumab-Refractory Melanoma},
  volume = {13},
  issn = {1479-5876},
  doi = {10.1186/1479-5876-13-S1-O5},
  number = {Suppl 1},
  journal = {Journal of Translational Medicine},
  author = {Dummer, Reinhard and Daud, Adil and Puzanov, Igor and Hamid, Omid and Schadendorf, Dirk and Robert, Caroline and Schachter, Jacob and Pavlick, Anna and Gonzalez, Rene and Hodi, F Stephen and Cranmer, Lee D and Blank, Christian and Day, Steven J O and a Ascierto, Paolo and Salama, April K S and Li, Nicole Xiaoyun and Zhou, Wei and Lis, Joy},
  year = {2015},
  keywords = {Pembrolizumab,Melanoma,pembrolizumab},
  pages = {O5},
  file = {/Users/k/Zotero/storage/76RB8RDG/Dummer et al. - 2015 - A randomized controlled comparison of pembrolizumab and chemotherapy in patients with ipilimumab-refractory melan.pdf;/Users/k/Zotero/storage/9Y6G3T58/Dummer et al. - 2015 - A randomized controlled comparison of pembrolizumab and chemotherapy in patients with ipilimumab-refractory melan.pdf},
  pmid = {25779181}
}

@article{Robert2015,
  title = {Pembrolizumab versus {{Ipilimumab}} in {{Advanced Melanoma}}.},
  volume = {372},
  issn = {1533-4406},
  doi = {10.1056/NEJMoa1503093},
  abstract = {BACKGROUND The immune checkpoint inhibitor ipilimumab is the standard-of-care treatment for patients with advanced melanoma. Pembrolizumab inhibits the programmed cell death 1 (PD-1) immune checkpoint and has antitumor activity in patients with advanced melanoma. METHODS In this randomized, controlled, phase 3 study, we assigned 834 patients with advanced melanoma in a 1:1:1 ratio to receive pembrolizumab (at a dose of 10 mg per kilogram of body weight) every 2 weeks or every 3 weeks or four doses of ipilimumab (at 3 mg per kilogram) every 3 weeks. Primary end points were progression-free and overall survival. RESULTS The estimated 6-month progression-free-survival rates were 47.3\% for pembrolizumab every 2 weeks, 46.4\% for pembrolizumab every 3 weeks, and 26.5\% for ipilimumab (hazard ratio for disease progression, 0.58; P$<$0.001 for both pembrolizumab regimens versus ipilimumab; 95\% confidence intervals [CIs], 0.46 to 0.72 and 0.47 to 0.72, respectively). Estimated 12-month survival rates were 74.1\%, 68.4\%, and 58.2\%, respectively (hazard ratio for death for pembrolizumab every 2 weeks, 0.63; 95\% CI, 0.47 to 0.83; P=0.0005; hazard ratio for pembrolizumab every 3 weeks, 0.69; 95\% CI, 0.52 to 0.90; P=0.0036). The response rate was improved with pembrolizumab administered every 2 weeks (33.7\%) and every 3 weeks (32.9\%), as compared with ipilimumab (11.9\%) (P$<$0.001 for both comparisons). Responses were ongoing in 89.4\%, 96.7\%, and 87.9\% of patients, respectively, after a median follow-up of 7.9 months. Efficacy was similar in the two pembrolizumab groups. Rates of treatment-related adverse events of grade 3 to 5 severity were lower in the pembrolizumab groups (13.3\% and 10.1\%) than in the ipilimumab group (19.9\%). CONCLUSIONS The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. (Funded by Merck Sharp \& Dohme; KEYNOTE-006 ClinicalTrials.gov number, NCT01866319.).},
  number = {26},
  journal = {The New England journal of medicine},
  author = {Robert, Caroline and Schachter, Jacob and Long, Georgina V and Arance, Ana and Grob, Jean Jacques and Mortier, Laurent and Daud, Adil and Carlino, Matteo S and McNeil, Catriona and Lotem, Michal and Larkin, James and Lorigan, Paul and Neyns, Bart and Blank, Christian U and Hamid, Omid and Mateus, Christine and {Shapira-Frommer}, Ronnie and Kosh, Michele and Zhou, Honghong and Ibrahim, Nageatte and Ebbinghaus, Scot and Ribas, Antoni and {KEYNOTE-006 investigators}},
  year = {2015},
  keywords = {Pembrolizumab,Melanoma,pembrolizumab},
  pages = {2521-32},
  file = {/Users/k/Zotero/storage/288R8A2V/Robert et al. - 2015 - Supplementary - Pembrolizumab versus Ipilimumab in Advanced Melanoma.pdf;/Users/k/Zotero/storage/9DS73IW9/Robert et al. - 2015 - Pembrolizumab versus Ipilimumab in Advanced Melanoma.pdf;/Users/k/Zotero/storage/NYCKX763/Robert et al. - 2015 - Pembrolizumab versus Ipilimumab in Advanced Melanoma.pdf},
  pmid = {25891173}
}

@article{Robert2014,
  title = {Anti-Programmed-Death-Receptor-1 Treatment with Pembrolizumab in Ipilimumab-Refractory Advanced Melanoma: {{A}} Randomised Dose-Comparison Cohort of a Phase 1 Trial},
  issn = {1474547X},
  doi = {10.1016/S0140-6736(14)60958-2},
  abstract = {Background: The anti-programmed-death-receptor-1 (PD-1) antibody pembrolizumab has shown potent antitumour activity at different doses and schedules in patients with melanoma. We compared the efficacy and safety of pembrolizumab at doses of 2 mg/kg and 10 mg/kg every 3 weeks in patients with ipilimumab-refractory advanced melanoma. Methods: In an open-label, international, multicentre expansion cohort of a phase 1 trial, patients (aged ???18 years) with advanced melanoma whose disease had progressed after at least two ipilimumab doses were randomly assigned with a computer-generated allocation schedule (1:1 final ratio) to intravenous pembrolizumab at 2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks until disease progression, intolerable toxicity, or consent withdrawal. Primary endpoint was overall response rate (ORR) assessed with the Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) by independent central review. Analysis was done on the full-analysis set (all treated patients with measurable disease at baseline). This study is registered with ClinicalTrials.gov, number NCT01295827. Findings 173 patients received pembrolizumab 2 mg/kg (n=89) or 10 mg/kg (n=84). Median follow-up duration was 8 months. ORR was 26\% at both doses - 21 of 81 patients in the 2 mg/kg group and 20 of 76 in the 10 mg/kg group (difference 0\%, 95\% CI -14 to 13; p=0??96). Treatment was well tolerated, with similar safety profiles in the 2 mg/kg and 10 mg/kg groups and no drug-related deaths. The most common drug-related adverse events of any grade in the 2 mg/kg and 10 mg/kg groups were fatigue (29 [33\%] vs 31 [37\%]), pruritus (23 [26\%] vs 16 [19\%]), and rash (16 [18\%] vs 15 [18\%]). Grade 3 fatigue, reported in five (3\%) patients in the 2 mg/kg pembrolizumab group, was the only drug-related grade 3 to 4 adverse event reported in more than one patient. Interpretation The results suggest that pembrolizumab at a dose of 2 mg/kg or 10 mg/kg every 3 weeks might be an effective treatment in patients for whom there are few effective treatment options.},
  journal = {The Lancet},
  author = {Robert, Caroline and Ribas, Antoni and Wolchok, Jedd D. and Hodi, F. Stephen and Hamid, Omid and Kefford, Richard and Weber, Jeffrey S. and Joshua, Anthony M. and Hwu, Wen Jen and Gangadhar, Tara C. and Patnaik, Amita and Dronca, Roxana and Zarour, Hassane and Joseph, Richard W. and Boasberg, Peter and Chmielowski, Bartosz and Mateus, Christine and Postow, Michael A. and Gergich, Kevin and {Elassaiss-Schaap}, Jeroen and Li, Xiaoyun Nicole and Iannone, Robert and Ebbinghaus, Scot W. and Kang, S. Peter and Daud, Adil},
  year = {2014},
  keywords = {PD1,Pembrolizumab,Melanoma,pembrolizumab},
  file = {/Users/k/Zotero/storage/8GS8F3F3/Robert et al. - 2014 - Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma A random.pdf;/Users/k/Zotero/storage/8UKH5JAQ/Robert et al. - 2014 - Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma A random.pdf},
  pmid = {25034862}
}

@article{Eisenstein2008,
  title = {Sensible Approaches for Reducing Clinical Trial Costs},
  volume = {5},
  issn = {1740-7745},
  doi = {10.1177/1740774507087551},
  abstract = {BACKGROUND: Over the past decade, annual funding for biomedical research has more than doubled while new molecular entity approvals have declined by one third. OBJECTIVE: To assess the value of practices commonly employed in the conduct of large-scale clinical trials, and to identify areas where costs could be reduced without compromising scientific validity. METHODS: In the qualitative phase of the study, an expert panel recommended potential modifications of mega-trial designs and operations in order to maximize their value (cost versus scientific benefit tradeoff). In the quantitative phase, a mega-trial economic model was used to assess the financial implications of these recommendations. Our initial chronic disease trial design included 20,000 patients randomized at 1000 sites. Each site was assigned 24 monitoring visits and a \$10,000 per patient site payment. The case report form (CRF) was 60 pages long, and trial duration was assumed to be 48 months. RESULTS: The total costs of the initial trial design were \$421 million (\$US 2007). Following the expert panel's recommendations, we varied study duration, CRF length, number of sites, electronic data capture (EDC), and site management components to determine their individual and combined effects upon total trial costs. The use of EDC and modified site management practices were associated with significant reductions in total trial costs. When reductions in all five trial components were combined in a streamlined pharmaceutical industry design, a 59\% reduction in total trial costs resulted. When we assumed an even more streamlined trial design than has typically been considered for regulatory submissions in the past, there was a 90\% reduction in total trial costs. CONCLUSION: Our results suggest that it is possible to reduce substantially the cost of large-scale clinical trials without compromising the scientific validity of their results. If implemented, our recommendations could free billions of dollars annually for additional clinical studies. Research in the setting of clinical trials should be conducted to refine these findings.},
  number = {1},
  journal = {Clinical Trials},
  author = {Eisenstein, E. L and Collins, R. and Cracknell, B. S and Podesta, O. and Reid, E. D and Sandercock, P. and Shakhov, Y. and Terrin, M. L and a. Sellers, M. and Califf, R. M and Granger, C. B and Diaz, R.},
  year = {2008},
  keywords = {Humans,Research Design,Chronic Disease,Chronic Disease: drug therapy,Clinical Trials as Topic,Clinical Trials as Topic: economics,Clinical Trials as Topic: methods,Computer Simulation,Econometric,Information Systems,Information Systems: organization \& administration,Models,Multicenter Studies as Topic,Multicenter Studies as Topic: economics,Multicenter Studies as Topic: methods},
  pages = {75-84},
  file = {/Users/k/Zotero/storage/QEV9UVJL/Eisenstein et al. - 2008 - Sensible approaches for reducing clinical trial costs.pdf},
  pmid = {18283084}
}

@article{KMok2016,
  title = {Are We Ready for Immune Checkpoint Inhibitors for Advanced Non-Small-Cell Lung Cancer?},
  volume = {387},
  issn = {01406736},
  doi = {10.1016/S0140-6736(15)01308-2},
  abstract = {http://dx.doi.org/10.1016/S0140-6736(15)01308-2 1 Are we ready to embrace the routine use of immune checkpoint inhibitors in patients with advanced stage non-small-cell lung cancer? In The Lancet, Roy Herbst and colleagues 1 report the results of KEYNOTE-010, a randomised phase 2/3 study in 202 academic medical centres in 24 countries that compared two doses of pembrolizumab (2 mg/kg and 10 mg/kg) with docetaxel (75 mg/m$^2$) every 3 weeks in 1034 patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer. This biomarker-enriched study had two primary endpoints of overall survival and progression-free survival both in the total population and in the subgroup of patients with tumour proportion score of 50\% or more, which is defi ned as the percentage of tumour cells expressing PD-L1 assessed by immunohistochemistry using antibody 22C3. In the total study population, there was signifi cant improvement in overall survival with pembrolizumab compared with docetaxel for both pembrolizumab 2 mg/kg (n=344; hazard ratio [HR] 0$\cdot$71, 95\% CI 0$\cdot$58\textendash{}0$\cdot$88; p=0$\cdot$0008) and pembrolizumab 10 mg/kg (n=346; 0$\cdot$61, 0$\cdot$49\textendash{}0$\cdot$75; p$<$0$\cdot$0001). Median progression-free survival was similar in all three groups (3$\cdot$9 months with pembrolizumab 2 mg/kg, 4$\cdot$0 months with pembrolizumab 10 mg/kg, and 4$\cdot$0 months with docetaxel) and diff erence between both doses of pembrolizumab versus docetaxel did not meet the pre-specifi ed threshold for statistical signifi cance (2 mg/kg 0$\cdot$88, 0$\cdot$74\textendash{}1$\cdot$05; p=0$\cdot$070; 10 mg/kg HR 0$\cdot$79, 95\% CI 0$\cdot$66\textendash{}0$\cdot$94; p=0$\cdot$004). In patients with at least 50\% of tumour cells expressing PD-L1, overall survival was signifi cantly longer with pembrolizumab than with docetaxel (for 2 mg/kg median 14$\cdot$9 months vs 8$\cdot$2 months, HR 0$\cdot$54, 95\% CI 0$\cdot$38\textendash{}0$\cdot$77, p=0$\cdot$0002; and for 10 mg/kg 17$\cdot$3 months vs 8$\cdot$2 months, 0$\cdot$50, 0$\cdot$36\textendash{}0$\cdot$70, p$<$0$\cdot$0001). Treatment-related adverse events were similar between the two doses of pembrolizumab but less common than with docetaxel. The results of KEYNOTE-010 support the recent approval of pembrolizumab for the management of advanced non-small-cell lung cancer. 2 However, these fi ndings need to be interpreted in light of two other randomised phase 3 studies of immune check-point inhibitors comparing second-line nivolumab with docetaxel, namely the CHECKMATE-017 and CHECKMATE-057 (table). 3,4 Amid the excitement of immuno-oncology, we must remain rational and address key questions related to the practical application of immune checkpoint inhibitors for advanced stage non-small-cell lung cancer. Namely, should immune checkpoint inhibitors be given as second-line or third-line therapy? Is the biomarker of PD-L1 expression according to tumour proportion score reliable and should all patients be tested before starting treatment? What is the optimum dose of pembrolizumab in advanced stage non-small-cell lung cancer? More importantly, given the hefty costs of these drugs, are they considered cost eff ective? We appreciate the investigators' intention to include patients whose disease had progressed after two lines of systemic therapy. 300 (29\%) of 1034 patients in the trial 1},
  journal = {The Lancet},
  author = {K Mok, Tony S and Loong, Herbert H},
  year = {2016},
  keywords = {NSCLC,PD1,Pembrolizumab,pembrolizumab},
  pages = {1488-90},
  file = {/Users/k/Zotero/storage/3DUPBWT4/K Mok, Loong - 2016 - Are we ready for immune checkpoint inhibitors for advanced non-small-cell lung cancer.pdf;/Users/k/Zotero/storage/HPHQPPHI/K Mok, Loong - 2016 - Are we ready for immune checkpoint inhibitors for advanced non-small-cell lung cancer.pdf},
  pmid = {26712085}
}

@article{Gillespie2014,
  title = {Estimating Minimally Important Differences for Two Vision-Specific Quality of Life Measures},
  volume = {55},
  issn = {15525783},
  doi = {10.1167/iovs.13-13683},
  abstract = {Guideline on Evaluation of Anticancer Medicinal Products in Man},
  number = {7},
  journal = {Investigative Ophthalmology and Visual Science},
  author = {Gillespie, Brenda W. and Musch, David C. and Niziol, Leslie M. and Janz, Nancy K.},
  year = {2014},
  keywords = {CIGTS,Glaucoma,MicrobialKeratitis,MID,NEI-VFQ,VAQ},
  pages = {4206-4212},
  file = {/Users/k/Zotero/storage/RAFUKJ5W/Gillespie et al. - 2014 - Estimating minimally important differences for two vision-specific quality of life measures.pdf;/Users/k/Zotero/storage/UU22ICGK/Gillespie et al. - 2014 - Estimating minimally important differences for two vision-specific quality of life measures.pdf},
  pmid = {24906863}
}

@article{Carpenter2016,
  title = {Stan: {{A Probabilistic Programming Language}}},
  volume = {76},
  abstract = {Stan is a probabilistic programming language for specifying statistical models. A Stan program imperatively defines a log probability function over parameters conditioned on specified data and constants. As of version 2.2.0, Stan provides full Bayesian inference for continuous-variable models through Markov chain Monte Carlo methods such as the No-U-Turn sampler, an adaptive form of Hamiltonian Monte Carlo sampling. Penalized maximum likelihood estimates are calculated using optimization methods such as the Broyden-Fletcher-Goldfarb-Shanno algorithm. Stan is also a platform for computing log densities and their gradients and Hessians, which can be used in alternative algorithms such as variational Bayes, expectation propa- gation, and marginal inference using approximate integration. To this end, Stan is set up so that the densities, gradients, and Hessians, along with intermediate quantities of the algorithm such as acceptance probabilities, are easily accessible. Stan can be called from the command line, through R using the RStan package, or through Python using the PyStan package. All three interfaces support sampling or optimization-based inference and analysis, and RStan and PyStan also provide access to log probabilities, gradients, Hessians, and data I/O.},
  number = {Ii},
  journal = {Journal of Statistical Software},
  author = {Carpenter, Bob and Gelman, Andrew and Hoffman, Matt and Lee, Daniel and Goodrich, Ben and Betancourt, Michael and Brubaker, Marcus A. and Li, Peter and Riddell, Allen},
  year = {2016},
  keywords = {Stan},
  pages = {1-32},
  file = {/Users/k/Zotero/storage/RV7VQKDQ/Gillespie et al. - 2014 - Estimating minimally important differences for two vision-specific quality of life measures(9).pdf;/Users/k/Zotero/storage/WKLTCCZ5/Carpenter et al. - 2016 - Stan A Probabilistic Programming Language.pdf}
}

@article{Chatterjee2016,
  title = {Systematic Evaluation of Pembrolizumab Dosing in Patients with Advanced Non-Small Cell Lung Cancer.},
  issn = {1569-8041},
  doi = {10.1093/annonc/mdw174},
  abstract = {BACKGROUND: In the phase I KEYNOTE-001 study, pembrolizumab demonstrated durable antitumor activity in patients with advanced non-small cell lung cancer (NSCLC). We sought to characterize the relationship between pembrolizumab dose, exposure, and response to define an effective dose for these patients. METHODS: Patients received pembrolizumab 2 mg/kg every 3 weeks (Q3W) (n=55), 10 mg/kg Q3W (n=238), or 10 mg/kg Q2W (n=156). Response (RECIST v1.1) was assessed every 9 weeks. The relationship between the estimated pembrolizumab area under the concentration-time curve at steady-state over 6 weeks (AUCss-6weeks) and the longitudinal change in tumor size (sum of longest diameters) was analyzed by regression and nonlinear mixed effects modeling. This model was simultaneously fit to all tumor size data, then used to simulate response rates, normalizing the trial data across dose for prognostic covariates (tumor PD-L1 expression and EGFR mutation status). The exposure-safety relationship was assessed by logistic regression of pembrolizumab AUCss-6weeks versus occurrence of adverse events of interest based on their immune etiology. RESULTS: Overall response rates were 15\% (95\% confidence interval [CI] 7\%-28\%) at 2 Q3W, 25\% (18\%-33\%) at 10 Q3W, and 21\% (95\% CI 14\% to 30\%) at 10 Q2W. Regression analyses of percentage change from baseline in tumor size versus AUCss-6week indicated a flat relationship (regression slope P$>$0.05). Simulations showed the exposure-response relationship to be similarly flat, thus indicating that the lowest evaluated dose of 2 mg/kg Q3W to likely be at or near the efficacy plateau. Exposure-safety analysis showed the adverse event incidence to be similar among the clinically tested doses. CONCLUSIONS: No significant exposure dependency on efficacy or safety was identified for pembrolizumab across doses of 2 mg/kg to 10 mg/kg. These results support the use of a 2-mg/kg Q3W dosage in patients with previously treated, advanced NSCLC.ClinicalTrials.gov registry: NCT01295827.},
  journal = {Annals of oncology : official journal of the European Society for Medical Oncology / ESMO},
  author = {Chatterjee, M and Turner, D C and Felip, E and Lena, H and Cappuzzo, F and Horn, L and Garon, E B and Hui, R and Arkenau, H-T and Gubens, M A and Hellmann, M D and Dong, D and Li, C and Mayawala, K and Freshwater, T and Ahamadi, M and Stone, J and Lubiniecki, G M and Zhang, J and Im, E and De Alwis, D P and Kondic, A G and Fl\o{}tten, \O{}},
  year = {2016},
  keywords = {Non-small-cell lung cancer,NSCLC,PD1,Pembrolizumab,Immunotherapy,exposure,pd-l1,response,tumor size,non-small-cell lung cancer,pembrolizumab,immunotherapy},
  file = {/Users/k/Zotero/storage/ZU7PGFTF/Chatterjee et al. - 2016 - Systematic evaluation of pembrolizumab dosing in patients with advanced non-small cell lung cancer.pdf},
  pmid = {27117531}
}

@article{Bowen2016,
  title = {Accumulated Workloads and the Acute:Chronic Workload Ratio Relate to Injury Risk in Elite Youth Football Players},
  issn = {0306-3674},
  doi = {10.1136/bjsports-2015-095820},
  journal = {British Journal of Sports Medicine},
  author = {Bowen, Laura and Gross, Aleksander Stefan and Gimpel, Mo and Li, Fran{\c c}ois-Xavier},
  year = {2016},
  file = {/Users/k/Zotero/storage/A7XV8TWZ/Bowen et al. - 2016 - Accumulated workloads and the acutechronic workload ratio relate to injury risk in elite youth football players.pdf;/Users/k/Zotero/storage/QK2SSAXD/Bowen et al. - 2016 - Accumulated workloads and the acutechronic workload ratio relate to injury risk in elite youth football players.pdf}
}

@article{Baccarani2013,
  title = {Review {{Article European LeukemiaNet}} Recommendations for the Management of Chronic Myeloid Leukemia : 2013},
  volume = {122},
  issn = {1528-0020},
  doi = {10.1182/blood-2013-05-501569.The},
  abstract = {Advances in chronic myeloid leukemia treatment, particularly regarding tyrosine kinase inhibitors, mandate regular updating of concepts and management. A European LeukemiaNet expert panel reviewed prior and new studies to update recommendations made in 2009. We recommend as initial treatment imatinib, nilotinib, or dasatinib. Response is assessed with standardized real quantitative polymerase chain reaction and/or cytogenetics at 3, 6, and 12 months. BCR-ABL1 transcript levels $\leq$10\% at 3 months, $<$1\% at 6 months, and $\leq$0.1\% from 12 months onward define optimal response, whereas $>$10\% at 6 months and $>$1\% from 12 months onward define failure, mandating a change in treatment. Similarly, partial cytogenetic response (PCyR) at 3 months and complete cytogenetic response (CCyR) from 6 months onward define optimal response, whereas no CyR (Philadelphia chromosome-positive [Ph+] $>$95\%) at 3 months, less than PCyR at 6 months, and less than CCyR from 12 months onward define failure. Between optimal and failure, there is an intermediate warning zone requiring more frequent monitoring. Similar definitions are provided for response to second-line therapy. Specific recommendations are made for patients in the accelerated and blastic phases, and for allogeneic stem cell transplantation. Optimal responders should continue therapy indefinitely, with careful surveillance, or they can be enrolled in controlled studies of treatment discontinuation once a deeper molecular response is achieved.},
  number = {6},
  journal = {Blood},
  author = {Baccarani, Michele and Deininger, Michael W and Rosti, Gianantonio and Hochhaus, Andreas and Soverini, Simona and Apperley, Jane F and Cervantes, Francisco and Clark, Richard E and Cortes, Jorge E and {Hjorth-Hansen}, Henrik and Hughes, Timothy P and Kantarjian, Hagop M and Kim, Dong-Wook and a Larson, Richard and Lipton, Jeffrey H and Martinelli, Giovanni and Mayer, Jiri and Martin, C M and Steegmann, Juan-Luis and Goldman, John M and Guilhot, Fran{\c c}ois and {Hjorth-Hansen}, Henrik and Hughes, Timothy P and Kantarjian, Hagop M and Kim, Dong-Wook and a Larson, Richard and Lipton, Jeffrey H and Mahon, Fran{\c c}ois-Xavier and Martinelli, Giovanni and Mayer, Jiri and M\"uller, Martin C and Niederwieser, Dietger and Pane, Fabrizio and Radich, Jerald P and Rousselot, Philippe and Saglio, Giuseppe and Sau\ss{}ele, Susanne and Schiffer, Charles and Silver, Richard and Simonsson, Bengt and Steegmann, Juan-Luis and Goldman, John M and Hehlmann, R\"udiger},
  year = {2013},
  keywords = {Humans,Treatment Outcome,CML,Fusion Proteins,Leukemia,Antineoplastic Agents,Antineoplastic Agents: therapeutic use,bcr-abl,BCR-ABL Positive,BCR-ABL Positive:,bcr-abl: metabolism,Benzamides,Benzamides: therapeutic use,Chronic,Europe,Myelogenous,Piperazines,Piperazines: therapeutic use,Prognosis,Pyrimidines,Pyrimidines: therapeutic use,Randomized Controlled Trials as Topic,Stem Cell Transplantation,Thiazoles,Thiazoles: therapeutic use},
  pages = {872-884},
  file = {/Users/k/Zotero/storage/3Q8XTIJX/Baccarani et al. - 2013 - Review Article European LeukemiaNet recommendations for the management of chronic myeloid leukemia 2013.pdf},
  pmid = {23803709}
}

@article{Hughes2014,
  title = {Early Molecular Response Predicts Outcomes in Patients with Chronic Myeloid Leukemia in Chronic Phase Treated with Frontline Nilotinib or Imatinib},
  volume = {123},
  issn = {15280020},
  doi = {10.1182/blood-2013-06-510396},
  abstract = {We explored the impact of early molecular response (EMR; BCR-ABL $\leq$10\% on the international scale [BCR-ABL(IS)] at 3 or 6 months) on outcomes in patients with newly diagnosed chronic myeloid leukemia in chronic phase treated with nilotinib or imatinib based on 4 years of follow up in Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients. Patients (n = 846) received nilotinib 300 mg twice daily, nilotinib 400 mg twice daily, or imatinib 400 mg once daily. At 3 months, more patients had EMR failure (ie, BCR-ABL(IS) $>$10\%) on imatinib (33\%) than on nilotinib (9\%-11\%); similarly at 6 months, 16\% of patients in the imatinib arm vs 3\% and 7\% in the nilotinib arms had EMR failure. In all arms, EMR failure was associated with lower rates of molecular response, an increased risk of progression, and lower overall survival compared with EMR achievement. We also analyzed patient and treatment characteristics associated with EMR and found distinct patterns in the nilotinib arms vs the imatinib arm. High Sokal risk score was associated with a high rate of EMR failure on imatinib, but not on nilotinib. In contrast, reduced dose intensity and dose interruptions were strongly associated with EMR failure in nilotinib-treated, but not imatinib-treated, patients. This study is registered at www.clinicaltrials.gov as \#NCT00471497.},
  number = {9},
  journal = {Blood},
  author = {Hughes, Timothy P. and Saglio, Giuseppe and Kantarjian, Hagop M. and Guilhot, Fran??ois and Niederwieser, Dietger and Rosti, Gianantonio and Nakaseko, Chiaki and De Souza, Carmino Antonio and Kalaycio, Matt E. and Meier, Stephan and Fan, Xiaolin and Menssen, Hans D. and Larson, Richard A. and Hochhaus, Andreas},
  year = {2014},
  keywords = {CML},
  pages = {1353-1360},
  file = {/Users/k/Zotero/storage/PP35ADXV/Hughes et al. - 2014 - Early molecular response predicts outcomes in patients with chronic myeloid leukemia in chronic phase treated wit.pdf},
  pmid = {24335106}
}

@article{Hochhaus2012,
  title = {Dasatinib versus Imatinib in Newly Diagnosed Chronic Myeloid Leukemia in Chronic-Phase ({{CML}}-{{CP}}):{{DASISION}}  3-Year Follow-Up},
  volume = {30},
  number = {15\_suppl-May 20},
  journal = {J Clin Oncol (2012 ASCO Annual Meeting Proceedings)},
  author = {Hochhaus, A and Shah, N P and Cortes, J E and Baccarani, M and {Bradley-Garelik}, M B and Dejardin, D and Kantarjian, H M},
  year = {2012},
  keywords = {Humans,Treatment Outcome,Age of Onset,Algorithms,Antineoplastic Agents/adverse effects/therapeutic,bcr-abl/genetics,Chronic-Phase/diagnosis/*drug t,CML,Cytogenetic Analysis,DNA Mutational Analysis,Follow-Up Studies,Fusion Proteins,Leukemia,Middle Aged,Myeloid,Neoadjuvant Therapy,Piperazines/adverse effects/*therapeutic use,Pyrimidines/adverse effects/*therapeutic use,Thiazoles/adverse effects/*therapeutic use,Time Factors,Fusion Proteins; bcr-abl/genetics,Leukemia; Myeloid; Chronic-Phase/diagnosis/*drug t},
  pages = {6504},
  file = {/Users/k/Zotero/storage/5KPIJWHP/Hochhaus et al. - 2012 - Dasatinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic-phase (CML-CP)DASISION 3-year.pdf}
}

@article{Kim2014,
  title = {Efficacy and Safety of Radotinib in Chronic Phase Chronic Myeloid Leukemia Patients with Resistance or Intolerance to {{BCR}}-{{ABL1}} Tyrosine Kinase Inhibitors.},
  volume = {99},
  issn = {1592-8721},
  doi = {10.3324/haematol.2013.096776},
  abstract = {Radotinib (IY5511HCL), a novel and selective BCR-ABL1 tyrosine kinase inhibitor, has shown preclinical and phase 1 activity and safety in chronic myeloid leukemia. This phase 2 study investigated the efficacy and safety of radotinib in Philadelphia chromosome-positive chronic phase chronic myeloid leukemia patients with resistance and/or intolerance to BCR-ABL1 tyrosine kinase inhibitors. Patients received radotinib 400 mg twice daily for 12 cycles based on results from the phase 1 trial. The primary endpoint was rate of major cytogenetic response by 12 months. A total of 77 patients were enrolled. Major cytogenetic response was achieved in 50 (65\%; cumulative, 75\%) patients, including 36 (47\%) patients with complete cytogenetic response by 12 months. Median time to major cytogenetic response and complete cytogenetic response were 85 days and 256 days, respectively. Major cytogenetic response and complete cytogenetic response rates were similar between imatinib-resistant and imatinib-intolerant patients, but were higher in patients without BCR-ABL1 mutations. Overall and progression-free survival rates at 12 months were 96.1\% and 86.3\%, respectively. All newly-occurring or worsening grade 3/4 hematologic abnormalities included thrombocytopenia (24.7\%) and anemia (5.2\%); grade 3/4 drug-related nonhematologic adverse events included fatigue (3.9\%), asthenia (3.9\%), and nausea (2.6\%). The most common biochemistry abnormality was hyperbilirubinemia (grade 3/4, 23.4\%), and 12 of 18 cases were managed with dose modification. Study findings suggest radotinib is effective and well tolerated in chronic phase-chronic myeloid leukemia patients with resistance and/or intolerance to BCR-ABL1 tyrosine kinase inhibitors and may represent a promising alternative for these patients. (NCT01602952; ClinicalTrials.gov).},
  number = {7},
  journal = {Haematologica},
  author = {Kim, Sung-Hyun and Menon, Hari and Jootar, Saengsuree and Saikia, Tapan and Kwak, Jae-Yong and Sohn, Sang-Kyun and Park, Joon Seong and Jeong, Seong Hyun and Kim, Hyeoung Joon and Kim, Yeo-Kyeoung and Oh, Suk Joong and Kim, Hawk and Zang, Dae Young and Chung, Joo Seop and Shin, Ho Jin and Do, Young Rok and Kim, Jeong-A and Kim, Dae-Young and Choi, Chul Won and Park, Sahee and Park, Hye Lin and Lee, Gong Yeal and Cho, Dae Jin and Shin, Jae Soo and Kim, Dong-Wook},
  year = {2014},
  keywords = {CML},
  pages = {1191-6},
  file = {/Users/k/Zotero/storage/45EVF22S/Kim et al. - 2014 - Efficacy and safety of radotinib in chronic phase chronic myeloid leukemia patients with resistance or intolerance t.pdf},
  pmid = {24705186}
}

@article{Tepper2017,
  title = {Safety and Efficacy of Erenumab for Preventive Treatment of Chronic Migraine: A Randomised, Double-Blind, Placebo-Controlled Phase 2 Trial},
  volume = {16},
  issn = {14744422},
  doi = {10.1016/S1474-4422(17)30083-2},
  abstract = {Background The calcitonin gene-related peptide (CGRP) pathway is important in migraine pathophysiology. We assessed the efficacy and safety of erenumab, a fully human monoclonal antibody against the CGRP receptor, in patients with chronic migraine.},
  journal = {The Lancet Neurology},
  author = {Tepper, Stewart and Ashina, Messoud and Reuter, Uwe and Brandes, Jan L and Dole{\v z}il, David and Silberstein, Stephen and Winner, Paul and Leonardi, Dean and Mikol, Daniel and Lenz, Robert},
  year = {2017},
  keywords = {Headache},
  pages = {425-34},
  file = {/Users/k/Zotero/storage/LEDMU3WG/Tepper et al. - 2017 - Safety and efficacy of erenumab for preventive treatment of chronic migraine a randomised, double-blind, placebo-.pdf},
  pmid = {28460892}
}

@article{Bigal2015,
  title = {Safety, Tolerability, and Efficacy of {{TEV}}-48125 for Preventive Treatment of Chronic Migraine: {{A}} Multicentre, Randomised, Double-Blind, Placebo-Controlled, Phase 2b Study},
  volume = {14},
  issn = {14744465},
  doi = {10.1016/S1474-4422(15)00245-8},
  abstract = {Background: Benefits of calcitonin-gene related peptide (CGRP) inhibition have not been established in chronic migraine. Here we assess the safety, tolerability, and efficacy of two doses of TEV-48125, a monoclonal anti-CGRP antibody, in the preventive treatment of chronic migraine. Methods: In this multicentre, randomised, double-blind, double-dummy, placebo-controlled, parallel-group phase 2b study, we enrolled men and women (aged 18-65 years) from 62 sites in the USA who had chronic migraine. Using a randomisation list generated by a central computerised system and an interactive web response system, we randomly assigned patients (1:1:1, stratified by sex and use of concomitant preventive drugs) to three 28-day treatment cycles of subcutaneous TEV-48125 675/225 mg (675 mg in the first treatment cycle and 225 mg in the second and third treatment cycles), TEV-48125 900 mg (900 mg in all three treatment cycles), or placebo. Investigators, patients, and the funder were blinded to treatment allocation. Daily headache information was captured using an electronic diary. Primary endpoints were change from baseline in the number of headache-hours during the third treatment cycle (weeks 9-12) and safety and tolerability during the study. Secondary endpoint was change in the number of moderate or severe headache-days in weeks 9-12 relative to baseline. Efficacy endpoints were analysed for the intention-to-treat population. Safety and tolerability were analysed using descriptive statistics. This trial is registered with ClinicalTrials.gov, number, NCT02021773. Findings: Between Jan 8, 2014, and Aug 27, 2014, we enrolled 264 participants: 89 were randomly assigned to receive placebo, 88 to receive 675/225 mg TEV-48125, and 87 to receive 900 mg TEV-48125. The mean change from baseline in number of headache-hours during weeks 9-12 was -59.84 h (SD 80.38) in the 675/225 mg group and -67.51 h (79.37) in the 900 mg group, compared with -37.10 h (79.44) in the placebo group. The least square mean difference in the reduction of headache-hours between the placebo and 675/225 mg dose groups was -22.74 h (95\% CI -44.28 to -1.21; p=0.0386), whereas the difference between placebo and 900 mg dose groups was -30.41 h (-51.88 to -8.95; p=0.0057). Adverse events were reported by 36 (40\%) patients in the placebo group, 47 (53\%) patients in the 675/225 mg dose group, and 41 (47\%) patients in the 900 mg dose group, whereas treatment-related adverse events were recorded in 15 (17\%) patients, 25 (29\%) patients, and 28 (32\%) patients, respectively. The most common adverse events were mild injection-site pain and pruritus. Four (1\%) patients had serious non-treatment-related adverse events (one patient in the placebo group, one patient in the 675/225 mg group, and two patients in the 900 mg group); no treatment-related adverse events were serious and there were no relevant changes in blood pressure or other vital signs. Interpretation: TEV-48125 given by subcutaneous injection every 28 days seems to be tolerable and effective, thus supporting the further development of TEV-48125 for the preventive treatment of chronic migraine in a phase 3 trial. Funding: Teva Pharmaceuticals.},
  number = {11},
  journal = {The Lancet Neurology},
  author = {Bigal, Marcelo E. and Edvinsson, Lars and Rapoport, Alan M. and Lipton, Richard B. and Spierings, Egilius L H and Diener, Hans Christoph and Burstein, Rami and Loupe, Pippa S. and Ma, Yuju and Yang, Ronghua and Silberstein, Stephen D.},
  year = {2015},
  keywords = {Headache},
  pages = {1091-1100},
  file = {/Users/k/Zotero/storage/GEK9NBH5/Bigal et al. - 2015 - Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine A multicentre, random.pdf},
  pmid = {26432181}
}

@article{Tfelt-Hansen2012,
  title = {Guidelines for Controlled Trials of Drugs in Migraine: {{Second}} Edition},
  volume = {32},
  issn = {03331024},
  doi = {10.1046/j.1468-2982.2000.00117.x},
  number = {1},
  journal = {Cephalalgia},
  author = {{Tfelt-Hansen}, P. and Block, G. and Dahl\"of, C. and Diener, H. C. and Ferrari, Md and Goadsby, Pj and Guidetti, V. and Jones, B. and Lipton, Rb and Massiou, H. and Meinert, C. and Sandrini, G. and Steiner, T. and Winter, Pbo},
  year = {2012},
  keywords = {Headache},
  file = {/Users/k/Zotero/storage/U262T39J/Tfelt-Hansen et al. - 2012 - Guidelines for controlled trials of drugs in migraine Second edition.pdf},
  pmid = {11167908}
}

@article{Silberstein2007,
  title = {Efficacy and Safety of Topiramate for the Treatment of Chronic Migraine: {{A}} Randomized, Double-Blind, Placebo-Controlled Trial},
  volume = {47},
  issn = {00178748},
  doi = {10.1111/j.1526-4610.2006.00684.x},
  abstract = {OBJECTIVE$\backslash$n$\backslash$nTo evaluate the efficacy and safety of topiramate (100 mg/day) compared with placebo for the treatment of chronic migraine.$\backslash$n$\backslash$n$\backslash$nMETHODS$\backslash$n$\backslash$nThis was a randomized, placebo-controlled, parallel-group, multicenter study consisting of 16 weeks of double-blind treatment. Subjects aged 18 to 65 years with 15 or more headache days per month, at least half of which were migraine/migrainous headaches, were randomized 1:1 to either topiramate 100 mg/day or placebo. An initial dose of topiramate 25 mg/day (or placebo) was titrated upward in weekly increments of 25 mg/day to a maximum of 100 mg/day (or to the maximum tolerated dose). Concomitant preventive migraine treatment was not allowed, and acute headache medication use was not to exceed 4 days per week during the double-blind maintenance period. The primary efficacy endpoint was the change from baseline in the mean monthly number of migraine/migrainous days; the change in the mean monthly number of migraine days also was analyzed. A fixed sequence approach (ie, gatekeeper approach) using analysis of covariance was used to analyze the efficacy endpoints. Assessments of safety and tolerability included physical and neurologic examinations, clinical laboratory parameters, and spontaneous reports of clinical adverse events.$\backslash$n$\backslash$n$\backslash$nRESULTS$\backslash$n$\backslash$nThe intent-to-treat population included 306 (topiramate, n = 153; placebo, n = 153) of 328 randomized subjects who provided at least 1 efficacy assessment; 55.8\% of the topiramate group and 55.2\% on placebo were trial completers. The mean final topiramate maintenance dose was 86.0 mg/day. The mean duration of therapy was 91.7 days for the topiramate group and 90.6 days for the placebo group. Topiramate treatment resulted in a statistically significant mean reduction of migraine/migrainous headache days (topiramate -6.4 vs placebo -4.7, P= .010) and migraine headache days relative to baseline (topiramate -5.6 vs placebo -4.1, P= .032). Treatment-emergent adverse events occurred in 132 (82.5\%) and 113 (70.2\%) of topiramate-treated and placebo-treated subjects, respectively, and were generally of mild or moderate severity. Most commonly reported adverse events in the topiramate group were paresthesia (n = 46, 28.8\%), upper respiratory tract infection (n = 22, 13.8\%), and fatigue (n = 19, 11.9\%). The most common adverse events in the placebo group were upper respiratory tract infection (n = 20, 12.4\%), fatigue (n = 16, 9.9\%), and nausea (n = 13, 8.1\%). Discontinuations due to adverse events occurred in 18 (10.9\%) topiramate subjects and 10 (6.1\%) placebo subjects. There were no serious adverse events or deaths.$\backslash$n$\backslash$n$\backslash$nCONCLUSIONS$\backslash$n$\backslash$nTopiramate treatment at daily doses of approximately 100 mg resulted in statistically significant improvements compared with placebo in mean monthly migraine/migrainous and migraine headache days. Topiramate is safe and generally well tolerated in this group of subjects with chronic migraine, a burdensome condition with important unmet treatment needs. Safety and tolerability of topiramate were consistent with experience in previous clinical trials involving the drug.},
  number = {2},
  journal = {Headache},
  author = {Silberstein, Stephen D. and Lipton, Richard B. and Dodick, David W. and Freitag, Frederick G. and Ramadan, Nabih and Mathew, Ninan and Brandes, Jan L. and Bigal, Marcelo and Saper, Joel and Ascher, Steven and Jordan, Donna M. and Greenberg, Steven J. and Hulihan, Joseph},
  year = {2007},
  keywords = {Clinical trial,Headache,Chronic daily headache,Migraine,Preventive treatment,Topiramate,Transformed migraine},
  pages = {170-180},
  file = {/Users/k/Zotero/storage/RQCKWCH6/Silberstein et al. - 2007 - Efficacy and safety of topiramate for the treatment of chronic migraine A randomized, double-blind, placebo-.pdf},
  pmid = {17300356}
}

@article{Kakkis2015,
  title = {Recommendations for the Development of Rare Disease Drugs Using the Accelerated Approval Pathway and for Qualifying Biomarkers as Primary Endpoints},
  volume = {10},
  issn = {1750-1172},
  doi = {10.1186/s13023-014-0195-4},
  abstract = {For rare serious and life-threatening disorders, there is a tremendous challenge of transforming scientific discoveries into new drug treatments. This challenge has been recognized by all stakeholders who endorse the need for flexibility in the regulatory review process for novel therapeutics to treat rare diseases. In the United States, the best expression of this flexibility was the creation of the Accelerated Approval (AA) pathway. The AA pathway is critically important for the development of treatments for diseases with high unmet medical need and has been used extensively for drugs used to treat cancer and infectious diseases like HIV.},
  number = {1},
  journal = {Orphanet Journal of Rare Diseases},
  author = {Kakkis, Emil D and O'Donovan, Mary and Cox, Gerald and Hayes, Mark and Goodsaid, Federico and Tandon, PK and Furlong, Pat and Boynton, Susan and Bozic, Mladen and Orfali, May and Thornton, Mark},
  year = {2015},
  keywords = {Biomarkers,RareDiseases,biomarkers},
  pages = {16},
  file = {/Users/k/Zotero/storage/CDTAPN3F/Kakkis et al. - 2015 - Recommendations for the development of rare disease drugs using the accelerated approval pathway and for qualifyi.pdf},
  pmid = {25757705}
}

@article{Molenberghs2004,
  title = {Analyzing Incomplete Longitudinal Clinical Trial Data},
  volume = {5},
  issn = {1465-4644},
  doi = {10.1093/biostatistics/5.3.445},
  abstract = {Using standard missing data taxonomy, due to Rubin and co-workers, and simple algebraic derivations, it is argued that some simple but commonly used methods to handle incomplete longitudinal clinical trial data, such as complete case analyses and methods based on last observation carried forward, require restrictive assumptions and stand on a weaker theoretical foundation than likelihood-based methods developed under the missing at random (MAR) framework. Given the availability of flexible software for analyzing longitudinal sequences of unequal length, implementation of likelihood-based MAR analyses is not limited by computational considerations. While such analyses are valid under the comparatively weak assumption of MAR, the possibility of data missing not at random (MNAR) is difficult to rule out. It is argued, however, that MNAR analyses are, themselves, surrounded with problems and therefore, rather than ignoring MNAR analyses altogether or blindly shifting to them, their optimal place is within sensitivity analysis. The concepts developed here are illustrated using data from three clinical trials, where it is shown that the analysis method may have an impact on the conclusions of the study.},
  number = {3},
  journal = {Biostatistics},
  author = {Molenberghs, G. and Thijs, Herbert and Jansen, Ivy and Beunckens, Caroline},
  year = {2004},
  pages = {445-464},
  file = {/Users/k/Zotero/storage/GBRN3XU2/Molenberghs et al. - 2004 - Analyzing incomplete longitudinal clinical trial data.pdf}
}

@article{Friedman2014,
  title = {The {{Idiopathic Intracranial Hypertension Treatment Trial}}: {{Design Considerations}} and {{Methods}}},
  volume = {34},
  issn = {1070-8022},
  doi = {10.1097/WNO.0000000000000114},
  number = {2},
  journal = {Journal of Neuro-Ophthalmology},
  author = {Friedman, Deborah I. and McDermott, Michael P. and Kieburtz, Karl and Kupersmith, Mark and Stoutenburg, Ann and Keltner, John L. and Feldon, Steven E. and Schron, Eleanor and Corbett, James J. and Wall, Michael},
  year = {2014},
  keywords = {IIH},
  pages = {107-117},
  file = {/Users/k/Zotero/storage/N7F3EZMV/Friedman et al. - 2014 - The Idiopathic Intracranial Hypertension Treatment Trial Design Considerations and Methods.pdf}
}

@article{Wall2014b,
  title = {The {{Idiopathic Intracranial Hypertension Treatment Trial}}},
  volume = {71},
  issn = {2168-6149},
  doi = {10.1001/jamaneurol.2014.133},
  number = {6},
  journal = {JAMA Neurology},
  author = {Wall, Michael and Kupersmith, Mark J. and Kieburtz, Karl D. and Corbett, James J. and Feldon, Steven E. and Friedman, Deborah I. and Katz, David M. and Keltner, John L. and Schron, Eleanor B. and McDermott, Michael P.},
  year = {2014},
  keywords = {IIH},
  pages = {693},
  file = {/Users/k/Zotero/storage/ENCYMW48/Wall et al. - 2014 - The Idiopathic Intracranial Hypertension Treatment Trial.pdf}
}

@article{Salen1994,
  title = {The Disability Rating Index: {{An}} Instrument for the Assessment of Disability in Clinical Settings},
  volume = {47},
  issn = {08954356},
  doi = {10.1016/0895-4356(94)90086-8},
  abstract = {The purpose of this study was to evaluate an instrument for assessment of physical disability, mainly intended for clinical settings, the Disability Rating Index (DRI). Healthy persons (n = 1092), both white and blue collar workers, and patients (n = 366) with different levels of physical capacity, were assessed. Most of the patients (n = 303) underwent rehabilitation programmes for neck/shoulder/low-back pain but some (n = 47) were arthritis patients waiting for hip or knee replacement surgery, or wheelchair patients with multiple sclerosis (n = 16). The reliability was investigated by test-retest studies, intra- and inter-rater and internal consistency studies. Five construct validity tests were carried out: a discrimination study; a converging validity test; a test for sensitivity to small alterations in health status; and two correlational validity tests. Correlation of the self-reported DRI to the actual performance in similar activities was carried out. Responsiveness was tested by correlation of the DRI before/after replacement surgery for arthritis. The test-retest correlations were 0.83-0.95 in the studies, including correlation of different versions. The intra- and inter-rater reproducibility was 0.98 and 0.99 respectively. The Kruskal-Wallis test in the discrimination study yielded p $<$ 0.0001. More than 90\% of the respondents completed the questionnaire correctly. Correlation of the DRI to the Functional Status Questionnaire was 0.46. The responsiveness was excellent, p = 0.0001. The DRI proved to be a robust, practical clinical and research instrument with good responsiveness and acceptability for assessment of disability caused by impairment of common motor functions. ?? 1994.},
  number = {12},
  journal = {Journal of Clinical Epidemiology},
  author = {Salen, Bo A. and Erik, Erik V. and Nordemar, Rolf},
  year = {1994},
  keywords = {Disability evaluation,DRI,Evaluation study,Outcome assessment,Physical disability},
  pages = {1423-1435},
  file = {/Users/k/Zotero/storage/3GS8BTI9/Salen, Erik, Nordemar - 1994 - The disability rating index An instrument for the assessment of disability in clinical settings.pdf},
  pmid = {7730851}
}

@article{MentalHealthCommissionofCanada2009,
  title = {{{SF}}-12 {{Health Survey Patient}} Name : {{Date}} : {{PCS}} : {{MCS}} :},
  issn = {0713-3936},
  doi = {10.7870/cjcmh-2013-001},
  abstract = {This is the first mental health strategy for Canada. Its release marks a significant mile- stone in the journey to bring mental health `out of the shadows' and to recognize, in both words and deeds, the truth of the saying that there can be no health without mental health. Although there are several population groups and policy areas for which the federal gov- ernment has important mental health responsibilities, the organization and delivery of health care, social services and education in Canada largely fall to provincial and territo- rial governments. Despite the fact that pan-Canadian initiatives could help all jurisdictions to improve mental health outcomes, planning documents that address these matters from the perspective of the country as a whole are rare. Jurisdictional challenges have been compounded by the stigma that has kept discussion of mental health issues out of the public arena for far too long. Changing Directions, Changing Lives is the culmination of many years of hard work and advocacy by people across the country. A key driver behind its development has been the testimony of thousands of people living with mental health problems and illnesses. In increasing numbers they have found the courage to speak publicly about their personal experiences and the many obstacles they face in obtaining the help and support they need from an underfunded and fragmented mental health system. Family members have echoed this assessment while pointing to the many challenges that they also confront. Service providers (within the mental health system as well as outside of it), researchers, and policy experts have added their voice to the chorus calling for much- needed change. They have all had a voice in the development of this Strategy.},
  journal = {Mental Health Commission of Canada},
  author = {{Mental Health Commission of Canada}},
  year = {2009},
  keywords = {SF-12},
  pages = {24},
  file = {/Users/k/Zotero/storage/7ZM42UHH/Mental Health Commission of Canada - 2009 - SF-12 Health Survey Patient name Date PCS MCS.pdf}
}

@article{Ware1998,
  title = {How to Score the {{SF}}-12 Physical and Mental Health Summary Scales},
  number = {April},
  journal = {Lincoln, RI: Quality Metric.},
  author = {Ware, J. E. and Kosinski, M. and Keller, S. D.},
  year = {1998},
  keywords = {SF-12},
  file = {/Users/k/Zotero/storage/X99UXX8Z/Ware, Kosinski, Keller - 1998 - How to score the SF-12 physical and mental health summary scales.pdf}
}

@article{Jenkinson1997,
  title = {A Shorter Form Health Survey: Can the {{SF}}-12 Replicate Results from the {{SF}}-36 in Longitudinal Studies?},
  volume = {19},
  issn = {1741-3842},
  doi = {10.1093/oxfordjournals.pubmed.a024606},
  abstract = {BACKGROUND: The SF-36 is a generic health status measure which has gained popularity as a measure of outcome in a wide variety of patient groups and social surveys. However, there is a need for even shorter measures, which reduce respondent burden. The developers of the SF-36 have consequently suggested that a 12-item sub-set of the items may accurately reproduce the two summary component scores which can be derived from the SF-36 [the Physical Component Summary Score (PCS) and Mental Health Component Summary Score (MCS)]. In this paper, we adopt scoring algorithms for the UK SF-36 and SF-12 summary scores to evaluate the picture of change gained in various treatment groups.$\backslash$n$\backslash$nMETHODS: The SF-36 was administered in three treatment groups (ACE inhibitors for congestive heart failure, continuous positive airways therapy for sleep apnoea, and open vs laparoscopic surgery for inguinal hernia).$\backslash$n$\backslash$nRESULTS: PCS and MCS scores calculated from the SF-36 or a sub-set of 12 items (the 'SF-12') were virtually identical, and indicated the same magnitude of ill-health and degree of change over time.$\backslash$n$\backslash$nCONCLUSION: The results suggest that where two summary scores of health status are adequate than the SF-12 may be the instrument of choice.},
  number = {2},
  journal = {Journal of Public Health},
  author = {Jenkinson, C. and Layte, R. and Jenkinson, D. and Lawrence, K. and Petersen, S. and Paice, C. and Stradling, J.},
  year = {1997},
  keywords = {SF-12},
  pages = {179-186},
  file = {/Users/k/Zotero/storage/PFX8YSRE/Jenkinson et al. - 1997 - A shorter form health survey can the SF-12 replicate results from the SF-36 in longitudinal studies.pdf},
  pmid = {9243433}
}

@article{Ware1996,
  title = {A 12-{{Item Short}}-{{Form Health Survey}}: Construction of Scales and Preliminary Tests of Reliability and Validity.},
  volume = {34},
  issn = {0025-7079},
  doi = {10.2307/3766749},
  abstract = {Regression methods were used to select and score 12 items from the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) to reproduce the Physical Component Summary and Mental Component Summary scales in the general US population (n=2,333). The resulting 12-item short-form (SF-12) achieved multiple R squares of 0.911 and 0.918 in predictions of the SF-36 Physical Component Summary and SF-36 Mental Component Summary scores, respectively. Scoring algorithms from the general population used to score 12-item versions of the two components (Physical Components Summary and Mental Component Summary) achieved R squares of 0.905 with the SF-36 Physical Component Summary and 0.938 with SF-36 Mental Component Summary when cross-validated in the Medical Outcomes Study. Test-retest (2-week)correlations of 0.89 and 0.76 were observed for the 12-item Physical Component Summary and the 12-item Mental Component Summary, respectively, in the general US population (n=232). Twenty cross-sectional and longitudinal tests of empirical validity previously published for the 36-item short-form scales and summary measures were replicated for the 12-item Physical Component Summary and the 12-item Mental Component Summary, including comparisons between patient groups known to differ or to change in terms of the presence and seriousness of physical and mental conditions, acute symptoms, age and aging, self-reported 1-year changes in health, and recovery for depression. In 14 validity tests involving physical criteria, relative validity estimates for the 12-item Physical Component Summary ranged from 0.43 to 0.93 (median=0.67) in comparison with the best 36-item short-form scale. Relative validity estimates for the 12-item Mental Component Summary in 6 tests involving mental criteria ranged from 0.60 to 107 (median=0.97) in relation to the best 36-item short-form scale. Average scores for the 2 summary measures, and those for most scales in the 8-scale profile based on the 12-item short-form, closely mirrored those for the 36-item short-form, although standard errors were nearly always larger for the 12-item short-form.},
  number = {3},
  journal = {Medical Care},
  author = {Ware, John Jr and Kosinski, Mark MA and Keller, SD Susan D},
  year = {1996},
  keywords = {SF-12},
  pages = {220-233},
  file = {/Users/k/Zotero/storage/QWGHVUUF/Ware, Kosinski, Keller - 1996 - A 12-Item Short-Form Health Survey construction of scales and preliminary tests of reliability and valid.pdf},
  pmid = {8628042}
}

@article{Hung2015,
  title = {Validation of the {{EQ}}-{{5D}} in {{Patients}} with {{Traumatic Limb Injury}}},
  volume = {25},
  issn = {10530487},
  doi = {10.1007/s10926-014-9547-0},
  abstract = {Purpose The measurement properties of the EQ-5D have not been explored for patients with traumatic limb injuries. The purpose of this study was to examine the construct validity, predictive validity, and responsiveness of the EQ-5D in patients with traumatic limb injuries. Methods A consecutive cohort of 1,167 patients was assessed with the EQ-5D and the World Health Organization Quality of Life instrument (WHOQOL-BREF) at baseline while the patients were hospitalized because of the injury, and the patients were followed up at 3 months (1,003 patients), 6 months (1,010 patients), and 12 months (987 patients) after injury via telephone interview. Results The utility and visual analogue scale (VAS) scores of the EQ-5D had moderate to high association with the physical and psychological domains and the two general questions (overall QOL and overall health) of the WHOQOL-BREF at all time points except baseline (Pearson's correlation coefficient $>$0.3), but the EQ-5D profiles were weakly associated with the social and environment domains of the WHOQOL-BREF (absolute value of Spearman's correlation coefficient $<$0.3). These results indicate that the EQ-5D has satisfactory construct validity. The utility and VAS scores of the EQ-5D at 3 and 6 months after injury can predict (with moderate to large relationships) the four domains and two general questions of the WHOQOL-BREF administered at 12 months after injury. The responsiveness of the utility and VAS of the EQ-5D were high (effect sizes $>$0.9) at 0-3, 0-6, and 0-12 months after injury. Conclusions The EQ-5D has sufficient construct validity, predictive validity, and responsiveness, and also provides evidence for using the utility of the EQ-5D for cost-utility analyses of patients with traumatic limb injuries in the future.},
  number = {2},
  journal = {Journal of Occupational Rehabilitation},
  author = {Hung, Mei Chuan and Lu, Wen Shian and Chen, Sheng Shiung and Hou, Wen Hsuan and Hsieh, Ching Lin and Wang, Jung Der},
  year = {2015},
  keywords = {Construct validity,EQ-5D,EQ5D,Predictive validity,Responsiveness,Traumatic limb injury},
  pages = {387-393},
  file = {/Users/k/Zotero/storage/CZYSITIA/Hung et al. - 2015 - Validation of the EQ-5D in Patients with Traumatic Limb Injury.pdf},
  pmid = {25261389}
}

@techreport{Devlin2009,
  address = {London},
  title = {Using the {{EQ}}-{{5D}} as a Performance Measurement Tool in the {{NHS}}},
  institution = {{City University London}},
  author = {Devlin, Nancy J. and Parkin, David and Browne, John},
  year = {2009},
  keywords = {EQ5D},
  file = {/Users/k/Zotero/storage/B8VPUVNS/Devlin, Parkin, Browne - 2009 - Using the EQ-5D as a performance measurement tool in the NHS.pdf}
}

@article{Fisher2012,
  title = {Seizure Diaries for Clinical Research and Practice: Limitations and Future Prospects.},
  volume = {24},
  issn = {15255069},
  doi = {10.1016/j.yebeh.2012.04.128},
  abstract = {An NINDS-sponsored conference in April of 2011 reviewed issues in epilepsy clinical trials. One goal was to clarify new electronic methods for recording seizure information and other data in clinical trials. This selective literature review and compilation of expert opinion considers advantages and limitations of traditional paper-based seizure diaries in comparison to electronic diaries. Seizure diaries are a type of patient-reported outcome. All seizure diaries depend first on accurate recognition and recording of seizures, which is a problem since about half of seizures recorded during video-EEG monitoring are not known to the patient. Reliability of recording is another key issue. Diaries may not be at hand after a seizure, lost or not brought to clinic visits. On-line electronic diaries have several potential advantages over paper diaries. Smartphones are increasingly accessible as data entry gateways. Data are not easily lost and are accessible from clinic. Entries can be time-stamped and provide immediate feedback, validation or reminders. Data can also can be graphed and pasted into an EMR. Disadvantages include need for digital sophistication, higher cost, increased setup time, and requiring attention to potential privacy issues. The Epilepsy Diary by epilepsy.com and Irody, Inc. has over 13,000 registrants and SeizureTracker over 10,000, and both are used for clinical and research purposes. Some studies have documented patient preference and increased compliance for electronic versus paper diaries. Seizure diaries can be challenging in the pediatric population. Children often have multiple seizure types and limited reporting of subjective symptoms. Multiple caregivers during the day require more training to produce reliable and consistent data. Diary-based observational studies have the advantages of low cost, allowing locus-of-control by the patient and testing in a "real-world" environment. Diary-based studies can also be useful as descriptive "snapshots" of a population. However, the type of information available is very different from that obtained by prospective controlled studies. The act of self-recording observations may itself influence the observation, for example, by causing the subject to attend more vigilantly to seizures after changing medication. Pivotal anti-seizure drug or device trials still mostly rely on paper-based seizure diaries. Industry is aware of the potential advantages of electronic diaries, particularly, the promise of real-time transmission of data, time-stamping of entries, reminders to subjects, and potentially automatic interfaces to other devices. However, until diaries are validated as research tools and the regulatory environment becomes clearer, adoption of new types of diaries as markers for a primary study outcome will be cautious. Recommendations from the conference included: further studies of validity of epilepsy diaries and how they can be used to improve adherence; use and further development of core data sets, such as the one recently developed by NINDS; encouraging links of diaries to electronic sensors; development of diary privacy and legal policies; examination of special pediatric diary issues; development of principles for observational research from diaries; and work with the FDA to make electronic diaries more useful in industry-sponsored clinical trials. Copyright \textcopyright{} 2012 Elsevier Inc. All rights reserved.},
  number = {3},
  journal = {Epilepsy \& behavior : E\&B},
  author = {Fisher, Robert S. and Blum, David E. and DiVentura, Bree and Vannest, Jennifer and Hixson, John D. and Moss, Robert and Herman, Susan T. and Fureman, Brandy E. and French, Jacqueline A.},
  year = {2012},
  keywords = {Clinical trials,Diaries,Epilepsy,Internet,Patient-reported outcomes,Seizure},
  pages = {304-310},
  file = {/Users/k/Zotero/storage/H4EPRCRE/Fisher et al. - 2012 - Seizure diaries for clinical research and practice limitations and future prospects.pdf},
  pmid = {22652423}
}

@article{Devlin2010,
  title = {{{PATIENT}}-{{REPORTED OUTCOME MEASURES IN THE NHS}}: {{NEW METHODS FOR ANALYSING AND REPORTING EQ}}-{{5D DATA}}},
  volume = {19},
  issn = {1099-1050},
  doi = {10.1002/hec},
  number = {June},
  journal = {Health Economics},
  author = {Devlin, Nancy J. and Parkin, David and Browne, John},
  year = {2010},
  keywords = {EQ-5D,EQ5D,health outcomes,performance indicators,PROMs},
  pages = {886-905},
  file = {/Users/k/Zotero/storage/XGEZTSYM/Devlin, Parkin, Browne - 2010 - PATIENT-REPORTED OUTCOME MEASURES IN THE NHS NEW METHODS FOR ANALYSING AND REPORTING EQ-5D DATA.pdf},
  pmid = {19816948}
}

@article{Thurman2011,
  archivePrefix = {arXiv},
  eprinttype = {arxiv},
  eprint = {1011.1669v3},
  title = {Standards for Epidemiologic Studies and Surveillance of Epilepsy},
  volume = {52},
  issn = {00139580},
  doi = {10.1111/j.1528-1167.2011.03121.x},
  abstract = {Worldwide, about 65 million people are estimated to have epilepsy. Epidemiologic studies are necessary to define the full public health burden of epilepsy; to set public health and health care priorities; to provide information needed for prevention, early detection, and treatment; to identify education and service needs; and to promote effective health care and support programs for people with epilepsy. However, different definitions and epidemiologic methods complicate the tasks of these studies and their interpretations and comparisons. The purpose of this document is to promote consistency in definitions and methods in an effort to enhance future population-based epidemiologic studies, facilitate comparison between populations, and encourage the collection of data useful for the promotion of public health. We discuss: (1) conceptual and operational definitions of epilepsy, (2) data resources and recommended data elements, and (3) methods and analyses appropriate for epidemiologic studies or the surveillance of epilepsy. Variations in these are considered, taking into account differing resource availability and needs among countries and differing purposes among studies.},
  number = {SUPPL. 7},
  journal = {Epilepsia},
  author = {Thurman, David J. and Beghi, Ettore and Begley, Charles E. and Berg, Anne T. and Buchhalter, Jeffrey R. and Ding, Ding and Hesdorffer, Dale C. and Hauser, W. Allen and Kazis, Lewis and Kobau, Rosemarie and Kroner, Barbara and Labiner, David and Liow, Kore and Logroscino, Giancarlo and Medina, Marco T. and Newton, Charles R. and Parko, Karen and Paschal, Angelia and Preux, Pierre Marie and Sander, Josemir W. and Selassie, Anbesaw and Theodore, William and Tomson, Torbj\"orn and Wiebe, Samuel},
  year = {2011},
  keywords = {Epilepsy,Epidemiology,Surveillance},
  pages = {2-26},
  file = {/Users/k/Zotero/storage/VTIJLZGI/Thurman et al. - 2011 - Standards for epidemiologic studies and surveillance of epilepsy.pdf},
  pmid = {21899536}
}

@article{Loring2011,
  title = {Common Data Elements in Epilepsy Research: {{Development}} and Implementation of the {{NINDS}} Epilepsy {{CDE}} Project},
  volume = {52},
  issn = {00139580},
  doi = {10.1111/j.1528-1167.2011.03018.x},
  abstract = {The Common Data Element (CDE) Project was initiated in 2006 by the National Institute of Neurological Disorders and Stroke (NINDS) to develop standards for performing funded neuroscience-related clinical research. CDEs are intended to standardize aspects of data collection; decrease study start-up time; and provide more complete, comprehensive, and equivalent data across studies within a particular disease area. Therefore, CDEs will simplify data sharing and data aggregation across NINDS-funded clinical research, and where appropriate, facilitate the development of evidenced-based guidelines and recommendations. Epilepsy-specific CDEs were established in nine content areas: (1) Antiepileptic Drugs (AEDs) and Other Antiepileptic Therapies (AETs), (2) Comorbidities, (3) Electrophysiology, (4) Imaging, (5) Neurological Exam, (6) Neuropsychology, (7) Quality of Life, (8) Seizures and Syndromes, and (9) Surgery and Pathology. CDEs were developed as a dynamic resource that will accommodate recommendations based on investigator use, new technologies, and research findings documenting emerging critical disease characteristics. The epilepsy-specific CDE initiative can be viewed as part of the larger international movement toward "harmonization" of clinical disease characterization and outcome assessment designed to promote communication and research efforts in epilepsy. It will also provide valuable guidance for CDE improvement during further development, refinement, and implementation. This article describes the NINDS CDE Initiative, the process used in developing Epilepsy CDEs, and the benefits of CDEs for the clinical investigator and NINDS.},
  number = {6},
  journal = {Epilepsia},
  author = {Loring, David W. and Lowenstein, Daniel H. and Barbaro, Nicholas M. and Fureman, Brandy E. and Odenkirchen, Joanne and Jacobs, Margaret P. and Austin, Joan K. and Dlugos, Dennis J. and French, Jacqueline A. and Gaillard, William Davis and Hermann, Bruce P. and Hesdorffer, Dale C. and Roper, Steven N. and Van Cott, Anne C. and Grinnon, Stacie and Stout, Alexandra},
  year = {2011},
  keywords = {Epilepsy,National Institute of Neurological Disorders and S,Research},
  pages = {1186-1191},
  file = {/Users/k/Zotero/storage/DLCRBIRK/Loring et al. - 2011 - Common data elements in epilepsy research Development and implementation of the NINDS epilepsy CDE project.pdf},
  pmid = {21426327}
}

@article{Groenewegen2014,
  title = {Measures for Improving Treatment Outcomes for Patients with Epilepsy - {{Results}} from a Large Multinational Patient-Physician Survey},
  volume = {34},
  issn = {15255069},
  doi = {10.1016/j.yebeh.2014.02.033},
  abstract = {In this large-scale, multinational, descriptive survey, we sought to identify measures for improving treatment outcomes for individuals with epilepsy. As a framework, questions relating specifically to each of the five steps of the 'patient-physician journey', namely, patient identification (omitted in this survey), diagnosis, choice of drug, disease and drug information, and patient monitoring were asked. Overall, 337 physicians and 1150 patients across France, Germany, and the United States returned questionnaires. Results indicated that 16\% of the patients were initially misdiagnosed. Treatment choice was driven by efficacy, safety, experience with a drug (physician only), and convenience (patient only). Physicians were identified as the primary source of information for patients, and, as expected, better informed patients were found to adhere better to their therapy than those who were less well informed. Approximately 50\% of the patients had not seen their specialist in the last year, which indicates poor follow-up; furthermore, important topics such as seizures, treatment, and its side effects were not discussed at every visit. Specialists, but not primary care practitioners (PCPs), consistently reported discussing all topics more frequently than their patients, suggesting that specialists may overestimate the clarity of their questions. There was also substantial disparity in the reasons cited for nonadherence - patients overwhelmingly cited forgetfulness, while both PCPs and specialists cited complacency, forgetfulness, and tolerability. We also noted a disparity between physicians and their patients, as well as between PCPs and specialists, in their views on the impact of epilepsy on patients' lives. Our results indicate multiple opportunities to intervene at all stages of the patient-physician journey to improve treatment outcomes. We provide practical suggestions to achieve the most from these opportunities. ?? 2014 The Authors.},
  journal = {Epilepsy and Behavior},
  author = {Groenewegen, Andr?? and Tofighy, Azita and Ryvlin, Philippe and Steinhoff, Bernhard J. and Dedeken, Peter},
  year = {2014},
  keywords = {Epilepsy,Diagnosis,Follow-up,Patient-physician,Survey,Treatment},
  pages = {58-67},
  file = {/Users/k/Zotero/storage/V8BZACIB/Groenewegen et al. - 2014 - Measures for improving treatment outcomes for patients with epilepsy - Results from a large multinational pa.pdf},
  pmid = {2014230559}
}

@article{White2011a,
  title = {Strategies for Handling Missing Data in Randomised Trials},
  volume = {12},
  issn = {1745-6215},
  number = {October},
  journal = {Trials},
  author = {White, Ian},
  year = {2011},
  keywords = {MissingData},
  pages = {A59},
  file = {/Users/k/Zotero/storage/RJ5CQ6YQ/White - 2011 - Strategies for handling missing data in randomised trials(2).pdf;/Users/k/Zotero/storage/W3WD8SB8/White - 2011 - Strategies for handling missing data in randomised trials.pdf}
}

@misc{JacqminGadda,
  title = {Introduction to Mixed Model and Missing Data Issues in Longitudinal Studies},
  publisher = {{INSERM Workshop U897}},
  author = {{Jacqmin-Gadda}, Helene},
  keywords = {MissingData},
  file = {/Users/k/Zotero/storage/42KAFR3A/Jacqmin-Gadda - Unknown - Introduction to mixed model and missing data issues in longitudinal studies.pdf},
  note = {Place: Bordeaux}
}

@article{White2011,
  title = {Strategy for Intention to Treat Analysis in Randomised Trials with Missing Outcome {{Data Strategy}} for Intention to Treat Analysis in Randomised},
  volume = {342},
  doi = {10.1136/bmj.d40},
  number = {d40},
  journal = {British Medical Journal},
  author = {White, Ian and Horton, Nicholas and Carpenter, James and Pocock, Stuart},
  year = {2011},
  keywords = {MissingData},
  file = {/Users/k/Zotero/storage/Z44EBEZ9/White et al. - 2011 - Strategy for intention to treat analysis in randomised trials with missing outcome Data Strategy for intention to.pdf}
}

@article{Thall2017,
  title = {Parametric Dose Standardization for Optimizing Two-Agent Combinations in a Phase {{I}}-{{II}} Trial with Ordinal Outcomes},
  volume = {66},
  issn = {14679876},
  doi = {10.1111/rssc.12162},
  number = {1},
  journal = {Journal of the Royal Statistical Society. Series C: Applied Statistics},
  author = {Thall, Peter F. and Nguyen, Hoang Q. and Zinner, Ralph G.},
  year = {2017},
  keywords = {Bayesian design,Adaptive design,Combination trial,Ordinal variables,Phase I-II clinical trial,Utility},
  pages = {201-224},
  file = {/Users/k/Zotero/storage/MSYZPT89/Thall, Nguyen, Zinner - 2017 - Parametric dose standardization for optimizing two-agent combinations in a phase I-II trial with ordinal.pdf}
}

@article{Jin2014,
  title = {Using {{Data Augmentation}} to {{Facilitate Conduct}} of {{Phase I}}-{{II Clinical Trials}} with {{Delayed Outcomes}}.},
  volume = {109},
  issn = {0162-1459},
  doi = {10.1080/01621459.2014.881740},
  abstract = {A practical impediment in adaptive clinical trials is that outcomes must be observed soon enough to apply decision rules to choose treatments for new patients. For example, if outcomes take up to six weeks to evaluate and the accrual rate is one patient per week, on average three new patients will be accrued while waiting to evaluate the outcomes of the previous three patients. The question is how to treat the new patients. This logistical problem persists throughout the trial. Various ad hoc practical solutions are used, none entirely satisfactory. We focus on this problem in phase I-II clinical trials that use binary toxicity and efficacy, defined in terms of event times, to choose doses adaptively for successive cohorts. We propose a general approach to this problem that treats late-onset outcomes as missing data, uses data augmentation to impute missing outcomes from posterior predictive distributions computed from partial follow-up times and complete outcome data, and applies the design's decision rules using the completed data. We illustrate the method with two cancer trials conducted using a phase I-II design based on efficacy-toxicity trade-offs, including a computer stimulation study.},
  number = {506},
  journal = {Journal of the American Statistical Association},
  author = {Jin, Ick Hoon and Liu, Suyu and Thall, Peter F and Yuan, Ying},
  year = {2014},
  keywords = {DoseFinding,dose-finding,missing data,bayesian adaptive clinical design,data augmentation algorithm,design,phase i-ii clinical trial,piecewise exponential model},
  pages = {525-536},
  file = {/Users/k/Zotero/storage/BMJRJ8MP/Jin et al. - 2014 - Using Data Augmentation to Facilitate Conduct of Phase I-II Clinical Trials with Delayed Outcomes.pdf},
  pmid = {25382884}
}

@book{Yuan2016,
  address = {C},
  edition = {1st},
  title = {Bayesian {{Designs}} for {{Phase I}}\textendash{{II Clinical Trials}}},
  isbn = {978-1-4987-0955-2},
  publisher = {{CRC Press}},
  author = {Yuan, Ying and Nguyen, Hoang Q. and Thall, Peter F.},
  year = {2016},
  keywords = {DoseFinding}
}

@article{Gelman,
  title = {The Garden of Forking Paths},
  author = {Gelman, Andrew and Loken, Eric},
  year = {2013},
  file = {/Users/k/Zotero/storage/3QZNM8SD/Gelman, Loken - 2013 - The garden of forking paths.pdf}
}

@article{Hergt2016,
  title = {Use of a 2-Tier Histologic Grading System for Canine Cutaneous Mast Cell Tumors on Cytology Specimens},
  volume = {45},
  issn = {1939165X},
  doi = {10.1111/vcp.12387},
  abstract = {BACKGROUND Mast cell tumors (MCT) represent the most common malignant skin tumor in the dog. Diagnosis of an MCT can be achieved through cytologic examination of a fine-needle aspirate. However, the grade of the tumor is an important prognostic marker and currently requires histologic assessment. Recently a 2-tier histologic grading system based on nuclear features including number of mitoses, multinucleated cells, bizarre nuclei, and karyomegaly was proposed. OBJECTIVES The aim of this study was to assess if the cytomorphologic criteria proposed in the 2-tier histologic grading system are applicable to cytology specimens. METHODS A total of 141 MCT specimens reported as grade I, II, or III according to the Patnaik system with both histologic specimens and fine-needle aspirates available were histologically and cytologically reevaluated in a retrospective study. RESULTS According to the 2-tier grading system, 38 cases were diagnosed histologically as high-grade and 103 as low-grade MCT. Cytologic grading resulted in 36 high-grade and 105 low-grade tumors. Agreement between histologic and cytologic grading based on the 2-tier grading system was achieved in 133 cases (sensitivity 86.8\%, specificity 97.1\%, kappa value 0.853), but 5 high-grade tumors on histology were classified as low-grade on cytology. CONCLUSION Cytologic grading of MCT in the dog is helpful for initial assessment. However, the reliability of cytology using the 2-tier grading system is considered inadequate at this point. Prospective studies including clinical outcome should be pursued to further determine diagnostic accuracy of cytologic mast cell grading.},
  number = {3},
  journal = {Veterinary Clinical Pathology},
  author = {Hergt, Franziska and {von Bomhard}, Wolf and Kent, Michael S. and Hirschberger, Johannes},
  year = {2016},
  keywords = {Canine mast cell,Cytomorphologic criteria,dog,fine-needle aspirates,nuclear abnormalities},
  pages = {477-483},
  file = {/Users/k/Zotero/storage/U73GAY2K/Hergt et al. - 2016 - Use of a 2-tier histologic grading system for canine cutaneous mast cell tumors on cytology specimens.pdf},
  pmid = {27483044}
}

@article{Scarpa2016,
  title = {Cytological Grading of Canine Cutaneous Mast Cell Tumours},
  volume = {14},
  issn = {14765829},
  doi = {10.1111/vco.12090},
  abstract = {A cytological grading for mast cell tumours (MCTs) would be highly desirable, allowing to select the most appropriate therapeutic intervention prior to surgery. This study evaluates the applicability on fine-needle aspirations (FNAs) of the novel Kiupel grading system, based on number of mitoses, multinucleated cells, bizarre nuclei and presence of karyomegaly. Fifty consecutive cases with pre-operative cytological diagnosis were included. In cytological specimens, approximately 1000 cells were evaluated, and the histological grade was assessed on the corresponding resected specimens. On cytology, the above parameters were significantly different between histologically low-grade and high-grade tumours (P\,$<$\,0.001). The cytograding correctly predicted the histological grade in 47 cases (accuracy, 94\%; sensitivity, 84.6\%; specificity, 97.3\%). Two high-grade MCTs (4\%) were not detected on cytology. The cytograding can provide helpful insights to assist clinical decisions in most cases. However, the risk of underestimation in a minority of patients represents a limit to the overall utility of the technique.},
  number = {3},
  journal = {Veterinary and Comparative Oncology},
  author = {Scarpa, Filippo and Sabattini, Silvia and Bettini, Giuliano},
  year = {2016},
  keywords = {Canine mast cell,canine,cytology,grading,mast cell tumour},
  pages = {245-251},
  file = {/Users/k/Zotero/storage/BT9BFW7U/Scarpa, Sabattini, Bettini - 2016 - Cytological grading of canine cutaneous mast cell tumours.pdf},
  pmid = {24717019}
}

@article{Camus2016,
  title = {Cytologic {{Criteria}} for {{Mast Cell Tumor Grading}} in {{Dogs With Evaluation}} of {{Clinical Outcome}}},
  volume = {53},
  issn = {0300-9858},
  doi = {10.1177/0300985816638721},
  abstract = {A 2-tiered histologic grading scheme for canine cutaneous mast cell tumors (MCTs) is based on morphologic characteristics of neoplastic cells, including karyomegaly, multinucleation, nuclear pleomorphism, and mitotic figures. Aspirates from MCTs may provide the same information more quickly, inexpensively, and less invasively. This study used these criteria to develop a cytologic grading scheme for canine MCTs to predict outcome. Three anatomic pathologists graded histologic samples from 152 canine MCTs. Three clinical pathologists evaluated aspirates from these masses using similar criteria. A cytologic grading scheme was created based on correlation with histologic grade and evaluated with a kappa statistic. Survival was evaluated with Kaplan-Meier survival curves. Cox proportional hazards regression was used to estimate hazard ratios for tumor grades and individual grading components. Simple logistic regression tested for relationships between risk factors and mortality. The cytologic grading scheme that best correlated with histology (kappa = 0.725 $\pm$ 0.085) classified a tumor as high grade if it was poorly granulated or had at least 2 of 4 findings: mitotic figures, binucleated or multinucleated cells, nuclear pleomorphism, or $>$50\% anisokaryosis. The cytologic grading scheme had 88\% sensitivity and 94\% specificity relative to histologic grading. Dogs with histologic and cytologic high grade MCTs were 39 times and 25 times more likely to die within the 2-year follow-up period, respectively, than dogs with low grade MCTs. High tumor grade was associated with increased probability of additional tumors or tumor regrowth. This study concluded that cytologic grade is a useful predictor for treatment planning and prognostication.},
  number = {6},
  journal = {Veterinary Pathology},
  author = {Camus, M. S. and Priest, H. L. and Koehler, J. W. and Driskell, E. A. and Rakich, P. M. and Ilha, M. R. and Krimer, P. M.},
  year = {2016},
  keywords = {Canine mast cell,dog,cytology,grading,13,21,accounting for up to,are common cutaneous neoplasms,dogs,histology,in,mast cell tumor,mast cell tumors,mcts,neoplasia,of all canine skin,skin,tumors},
  pages = {1-7},
  file = {/Users/k/Zotero/storage/LFDZW2A2/Camus et al. - 2016 - Cytologic Criteria for Mast Cell Tumor Grading in Dogs With Evaluation of Clinical Outcome.pdf},
  pmid = {27034386}
}

@article{Kato2017,
  title = {Hyper-Progressors after {{Immunotherapy}}: {{Analysis}} of {{Genomic Alterations Associated}} with {{Accelerated Growth Rate}}},
  issn = {1078-0432},
  doi = {10.1158/1078-0432.CCR-16-3133},
  journal = {Clinical Cancer Research},
  author = {Kato, Shumei and Goodman, Aaron Michael and Walavalkar, Vighnesh and Barkauskas, Donald A. and Sharabi, Andrew and Kurzrock, Razelle},
  year = {2017},
  keywords = {HyperProgression},
  pages = {clincanres.3133.2016},
  file = {/Users/k/Zotero/storage/6N6ZMB2K/Kato et al. - 2017 - Hyper-progressors after Immunotherapy Analysis of Genomic Alterations Associated with Accelerated Growth Rate.pdf},
  pmid = {28351930}
}

@article{Champiat2016,
  title = {Hyperprogressive {{Disease Is}} a {{New Pattern}} of {{Progression}} in {{Cancer Patients Treated}} By},
  doi = {10.1158/1078-0432.CCR-16-1741},
  author = {Dercle, Laurent and Ammari, Samy and Massard, Christophe and Soria, Jean-charles and Fert, Charles},
  year = {2016},
  keywords = {HyperProgression},
  pages = {1-10},
  file = {/Users/k/Zotero/storage/YX4ULJGA/Dercle et al. - 2016 - Hyperprogressive Disease Is a New Pattern of Progression in Cancer Patients Treated by.pdf}
}

@article{Sharon2017,
  title = {Can an Immune Checkpoint Inhibitor (Sometimes) Make Things Worse?},
  issn = {1078-0432},
  doi = {10.1158/1078-0432.CCR-16-2926},
  abstract = {Champiat and colleagues have identified in their trial participants a group of patients that appear to have accelerated tumor progression when treated with PD1/PDL1 inhibitors. While their work is provocative, there are several limitations present in their analysis. Investigators should work quickly to verify and better characterize these results.},
  journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
  author = {Sharon, Elad},
  year = {2017},
  keywords = {HyperProgression},
  pages = {10-13},
  file = {/Users/k/Zotero/storage/P2566H7A/Sharon - 2017 - Can an immune checkpoint inhibitor (sometimes) make things worse.pdf},
  pmid = {28258060}
}

@article{Kersten2014,
  title = {Is the Pain Visual Analogue Scale Linear and Responsive to Change? {{An}} Exploration Using Rasch Analysis},
  volume = {9},
  issn = {19326203},
  doi = {10.1371/journal.pone.0099485},
  abstract = {OBJECTIVES: Pain visual analogue scales (VAS) are commonly used in clinical trials and are often treated as an interval level scale without evidence that this is appropriate. This paper examines the internal construct validity and responsiveness of the pain VAS using Rasch analysis. METHODS: Patients (n = 221, mean age 67, 58\% female) with chronic stable joint pain (hip 40\% or knee 60\%) of mechanical origin waiting for joint replacement were included. Pain was scored on seven daily VASs. Rasch analysis was used to examine fit to the Rasch model. Responsiveness (Standardized Response Means, SRM) was examined on the raw ordinal data and the interval data generated from the Rasch analysis. RESULTS: Baseline pain VAS scores fitted the Rasch model, although 15 aberrant cases impacted on unidimensionality. There was some local dependency between items but this did not significantly affect the person estimates of pain. Daily pain (item difficulty) was stable, suggesting that single measures can be used. Overall, the SRMs derived from ordinal data overestimated the true responsiveness by 59\%. Changes over time at the lower and higher end of the scale were represented by large jumps in interval equivalent data points; in the middle of the scale the reverse was seen. CONCLUSIONS: The pain VAS is a valid tool for measuring pain at one point in time. However, the pain VAS does not behave linearly and SRMs vary along the trait of pain. Consequently, Minimum Clinically Important Differences using raw data, or change scores in general, are invalid as these will either under- or overestimate true change; raw pain VAS data should not be used as a primary outcome measure or to inform parametric-based Randomised Controlled Trial power calculations in research studies; and Rasch analysis should be used to convert ordinal data to interval data prior to data interpretation.},
  number = {6},
  journal = {PLoS ONE},
  author = {Kersten, Paula and White, Peter J. and Tennant, Alan},
  year = {2014},
  file = {/Users/k/Zotero/storage/NGUFDK9V/Kersten, White, Tennant - 2014 - Is the pain visual analogue scale linear and responsive to change An exploration using rasch analysis.pdf},
  pmid = {24921952}
}

@article{Foster,
  title = {Steroids \& {{Immunity}} from {{Injury Through}} to {{Rehabilitation}} - the {{SIR Study}}},
  author = {Foster, Mark},
  file = {/Users/k/Zotero/storage/6KKKP3KT/Foster - Unknown - Steroids & Immunity from Injury Through to Rehabilitation - the SIR Study.pdf}
}

@article{Morris2014,
  title = {A Web-Based Tool for Eliciting Probability Distributions from Experts},
  volume = {52},
  issn = {13648152},
  doi = {10.1016/j.envsoft.2013.10.010},
  abstract = {We present a web-based probability distribution elicitation tool: The MATCH Uncertainty Elicitation Tool. The Tool is designed to help elicit probability distributions about uncertain model parameters from experts, in situations where suitable data is either unavailable or sparse. The Tool is free to use, and offers five different techniques for eliciting univariate probability distributions. A key feature of the Tool is that users can log in from different sites and view and interact with the same graphical displays, so that expert elicitation sessions can be conducted remotely (in conjunction with tele- or videoconferencing). This will make probability elicitation easier in situations where it is difficult to interview experts in person. Even when conducting elicitation remotely, interviewers will be able to follow good elicitation practice, advise the experts, and provide instantaneous feedback and assistance. \textcopyright{} 2013 The Authors.},
  journal = {Environmental Modelling and Software},
  author = {Morris, David E. and Oakley, Jeremy E. and Crowe, John A.},
  year = {2014},
  keywords = {Bayesian prior distribution,Expert judgement,Subjective probability,Web-based elicitation},
  pages = {1-4},
  file = {/Users/k/Zotero/storage/4K33VNM7/Morris, Oakley, Crowe - 2014 - A web-based tool for eliciting probability distributions from experts.pdf}
}

@article{Shepheard2017,
  title = {A Prognostic , Disease Progression , and Pharmacodynamic},
  volume = {0},
  author = {Shepheard, Stephanie R and Wuu, Joanne and Cardoso, Michell and Wiklendt, Luke and Dinning, Phil G and Chataway, Tim and Schultz, David and Benatar, Michael},
  year = {2017},
  keywords = {ALS},
  pages = {1-8},
  file = {/Users/k/Zotero/storage/NTP2HDF7/Shepheard et al. - 2017 - A prognostic , disease progression , and pharmacodynamic.pdf}
}

@article{Yeh2012,
  title = {One Year Study on the Integrative Intervention of Acupressure and Interactive Multimedia for Visual Health in School Children},
  volume = {20},
  issn = {09652299},
  doi = {10.1016/j.ctim.2012.09.001},
  abstract = {Objective: This study used a larger sample size, added a long-term observation of the effect of intervention, and provided an integrated intervention of acupressure and interactive multimedia of visual health instruction for school children. The short- and long-term effects of the interventions were then evaluated by visual health knowledge, visual acuity, and refractive error. Design: A repeated pretest-posttest controlled trial was used with two experimental groups and one control group. Setting: Four elementary schools in northern Taiwan. Participants: 287 School children with visual impairment in fourth grade were recruited. Method: One experimental group received the integrative intervention of acupressure and interactive multimedia of visual health instruction (ACIMU), and another received auricular acupressure (AC) alone; whereas a control group received no intervention. Two 10-week interventions were separately given in the fall and spring semesters. The short- and long-term effects of the interventions were then evaluated by visual health knowledge, visual acuity, and refractive error. Results: During the school year the visual health knowledge was significantly higher in the ACIMU group than the control group (p$<$0.001). A significant difference in the changing visual acuity was in the three groups (p$<$0.001), with the improvement in the ACIMU group. No difference in the refractive error was found between any two groups (p$>$0.05). Conclusions: This study demonstrated that a long-term period of acupressure is required to improve school children's visual health. School children receiving the intervention of acupressure combined with interactive multimedia had better improvement of visual health and related knowledge than others. Further study is suggested in which visual health and preventative needs can be established for early childhood. ?? 2012 Elsevier Ltd.},
  number = {6},
  journal = {Complementary Therapies in Medicine},
  author = {Yeh, Mei Ling and Chen, Hsing Hsia and Chung, Yu Chu},
  year = {2012},
  keywords = {Auricular acupressure,Controlled trial,Interactive multimedia,Knowledge,Myopia,Refractive error,School children,Visual acuity,VisualAcuity},
  pages = {385-392},
  file = {/Users/k/Zotero/storage/VIGNQV8C/Yeh, Chen, Chung - 2012 - One year study on the integrative intervention of acupressure and interactive multimedia for visual health in.pdf},
  pmid = {23131368}
}

@article{Lam2014,
  title = {Trial End Points and Natural History in Patients with {{G11778A Leber}} Hereditary Optic Neuropathy : Preparation for Gene Therapy Clinical Trial.},
  volume = {132},
  issn = {2168-6173},
  doi = {10.1001/jamaophthalmol.2013.7971},
  abstract = {IMPORTANCE Establishing the natural history of G11778A Leber hereditary optic neuropathy (LHON) is important to determine the optimal end points to assess the safety and efficacy of a planned gene therapy trial. OBJECTIVE To use the results of the present natural history study of patients with G11778A LHON to plan a gene therapy clinical trial that will use allotopic expression by delivering a normal nuclear-encoded ND4 gene into the nuclei of retinal ganglion cells via an adeno-associated virus vector injected into the vitreous. DESIGN, SETTING, AND PARTICIPANTS A prospective observational study initiated in 2008 was conducted in primary and referral institutional practice settings. Participants included 44 individuals with G11778A LHON, recruited between September 2008 and March 2012, who were evaluated every 6 months and returned for 1 or more follow-up visits (6-36 months) as of August 2012. EXPOSURES Complete neuro-ophthalmic examination and main measures. MAIN OUTCOMES AND MEASURES Visual acuity, automated visual field testing, pattern electroretinogram, and spectral-domain optical coherence tomography. RESULTS Clinical measures were stable during the follow-up period, and visual acuity was as good as or better than the other visual factors used for monitoring patients. Based on a criterion of 15 or more letters from the Early Treatment Diabetic Retinopathy Study chart, 13 eyes of 8 patients (18\%) improved, but 24 months after the onset of symptoms, any further improvements were to no better than 20/100. Acuity recovery occurred in some patients despite continued marked retinal nerve fiber layer thinning indistinguishable from that in patients who did not recover visual acuity. CONCLUSIONS AND RELEVANCE Spontaneous improvement of visual acuity in patients with G11778A LHON is not common and is partial and limited when it occurs, so improvements in vision with adeno-associated virus-mediated gene therapy of a synthetic wild-type ND4 subunit gene should be possible to detect with a reasonable sample size. Visual acuity appears to be the most suitable primary end point for the planned clinical trial.},
  number = {4},
  journal = {JAMA ophthalmology},
  author = {Lam, Byron L and Feuer, William J and Schiffman, Joyce C and Porciatti, Vittorio and Vandenbroucke, Ruth and Rosa, Potyra R and Gregori, Giovanni and Guy, John},
  year = {2014},
  keywords = {Adult,Female,Humans,Prospective Studies,DNA Mutational Analysis,Middle Aged,Male,Adolescent,Young Adult,Clinical Trials as Topic,VisualAcuity,Child,Dependovirus,Dependovirus: genetics,DNA; Mitochondrial,DNA; Mitochondrial: genetics,Electroretinography,Endpoint Determination,Genetic Therapy,Genetic Vectors,Intravitreal Injections,NADH Dehydrogenase,NADH Dehydrogenase: genetics,Nerve Fibers,Nerve Fibers: pathology,Optic Atrophy; Hereditary; Leber,Optic Atrophy; Hereditary; Leber: diagnosis,Optic Atrophy; Hereditary; Leber: genetics,Optic Atrophy; Hereditary; Leber: therapy,Retinal Ganglion Cells,Retinal Ganglion Cells: metabolism,Retinal Ganglion Cells: pathology,Tomography; Optical Coherence,Visual Acuity,Visual Acuity: physiology,Visual Field Tests,Visual Fields,Visual Fields: physiology},
  pages = {428-36},
  file = {/Users/k/Zotero/storage/KVIJ5U4U/Lam et al. - 2014 - Trial end points and natural history in patients with G11778A Leber hereditary optic neuropathy preparation for gen.pdf},
  pmid = {24525545}
}

@article{Wiley2016,
  title = {A Crossover Design for Comparative Efficacy: {{A}} 36-Week Randomized Trial of Bevacizumab and Ranibizumab for Diabetic Macular Edema},
  volume = {123},
  issn = {15494713},
  doi = {10.1016/j.ophtha.2015.11.021},
  abstract = {Purpose To investigate the comparative efficacy of bevacizumab (Avastin) and ranibizumab (Lucentis; both Genentech, Inc, South San Francisco, CA) for diabetic macular edema (DME) using a crossover study design. Design Randomized, double-masked, 36-week, 3-period crossover clinical trial. Participants Fifty-six subjects with DME involving the center of the macula in one or both eyes. Methods Monthly intravitreous injections of bevacizumab (1.25 mg) or ranibizumab (0.3 mg). Main Outcome Measures Comparison of mean changes in visual acuity and central retinal thickness, tested using a linear mixed-effects model. Results Based on the linear mixed-effects model, the 3-month estimated mean improvement in visual acuity was 5.3 letters for bevacizumab and 6.6 letters for ranibizumab (difference, 1.3 letters; P = 0.039). Estimated change in optical coherence tomography (OCT) central subfield mean thickness (CSMT) was -89 ??m for bevacizumab and -137 ??m for ranibizumab (difference, 48 ??m; P $<$ 0.001). Incorporating cumulative treatment benefit, the model yielded a predicted 36-week (9-month) average improvement in visual acuity of 7.1 letters (95\% confidence interval [CI], 5.0-9.2) for bevacizumab and 8.4 letters (95\% CI, 6.3-10.5) for ranibizumab, and a change in OCT CSMT of -128 ??m (95\% CI, -155 to -100) for bevacizumab and -176 ??m (95\% CI, -202 to -149) for ranibizumab. There was no significant treatment-by-period interaction (i.e., treatment difference was constant in all 3 periods), nor was there a significant differential carryover effect from one period to the next. Conclusions This trial demonstrated a statistically significant but small relative clinical benefit of ranibizumab compared with bevacizumab for treatment of DME, using a markedly reduced sample size relative to a full comparative efficacy study. The effects on visual acuity and central retinal thickness for the 2 drugs are consistent with those reported at 1 year for the concurrent parallel-group trial by the Diabetic Retinopathy Clinical Research Network testing bevacizumab, ranibizumab, and aflibercept for DME. The 3-period crossover design allowed for meaningful and efficient comparison, suggesting that this approach may be useful for future comparative efficacy studies of anti-vascular endothelial growth factor drugs for DME.},
  number = {4},
  journal = {Ophthalmology},
  author = {Wiley, Henry E. and Thompson, Darby J S and Bailey, Clare and Chew, Emily Y. and Cukras, Catherine A. and Jaffe, Glenn J. and Lee, Richard W J and Loken, Erin K. and Meyerle, Catherine B. and Wong, Wai and Ferris, Frederick L.},
  year = {2016},
  keywords = {VisualAcuity},
  pages = {841-849},
  file = {/Users/k/Zotero/storage/E8SVK7P9/Wiley et al. - 2016 - A crossover design for comparative efficacy A 36-week randomized trial of bevacizumab and ranibizumab for diabetic.pdf},
  pmid = {26875003}
}

@article{Bossuyt2003,
  title = {Towards Complete and,Accurate Reporting of Studies of Diagnostic Accuracy: {{The STARD}} Initiative},
  volume = {326},
  doi = {10.1136/bmj.326.7379.41},
  abstract = {Objective To improve the accuracy and completeness of reporting of studies of diagnostic accuracy, to allow readers to assess the potential for bias in a study, and to evaluate a study's generalisability. Methods The Standards for Reporting of Diagnostic Accuracy (STARD) steering committee searched the literature to identify publications on the appropriate conduct and reporting of diagnostic studies and extracted potential items into an extensive list. Researchers, editors, and members of professional organisations shortened this list during a two day consensus meeting, with the goal of developing a checklist and a generic flow diagram for studies of diagnostic accuracy. Results The search for published guidelines about diagnostic research yielded 33 previously published checklists, from which we extracted a list of 75 potential items. At the consensus meeting, participants shortened the list to a 25 item checklist, by using evidence, whenever available. A prototype of a flow diagram provides information about the method of patient recruitment, the order of test execution, and the numbers of patients undergoing the test under evaluation and the reference standard, or both. Conclusions Evaluation of research depends on complete and accurate reporting. If medical journals adopt the STARD checklist and flow diagram, the quality of reporting of studies of diagnostic accuracy should improve to the advantage of clinicians, researchers, reviewers, journals, and the public.},
  number = {7379},
  journal = {British Medical Journal},
  author = {Bossuyt, Patrick M and Reitsma, Johannes B and Bruns, David E and Gatsonis, Constantine A and Glasziou, Paul P and Irwig, Les M and Lijmer, Jeroen G and Moher, David and Rennie, Drummond and {de Vet}, H. C. W. and {STARD steering group}},
  year = {2003},
  keywords = {Diagnostic},
  pages = {41-44},
  file = {/Users/k/Zotero/storage/9DLBEVTR/Bossuyt et al. - 2003 - Towards complete and,accurate reporting of studies of diagnostic accuracy The STARD initiative.pdf}
}

@article{Lijmer1999,
  title = {Empirical Evidence of Bias},
  volume = {282},
  issn = {0098-7484},
  doi = {10.1001/jama.1995.03520290060030},
  abstract = {Objective. \textemdash{}To determine if inadequate approaches to randomized controlled trial design and execution are associated with evidence of bias in estimating treatment effects. Design. \textemdash{}An observational study in which we assessed the methodological quality of 250 controlled trials from 33 meta-analyses and then analyzed, using multiple logistic regression models, the associations between those assessments and estimated treatment effects. Data Sources. \textemdash{}Meta-analyses from the Cochrane Pregnancy and Childbirth Database. Main Outcome Measures. \textemdash{}The associations between estimates of treatment effects and inadequate allocation concealment, exclusions after randomization, and lack of double-blinding. Results. \textemdash{}Compared with trials in which authors reported adequately concealed treatment allocation, trials in which concealment was either inadequate or unclear (did not report or incompletely reported a concealment approach) yielded larger estimates of treatment effects (P$<$.001). Odds ratios were exaggerated by 41\% for inadequately concealed trials and by 30\% for unclearly concealed trials (adjusted for other aspects of quality). Trials in which participants had been excluded after randomization did not yield larger estimates of effects, but that lack of association may be due to incomplete reporting. Trials that were not double-blind also yielded larger estimates of effects (P=.01), with odds ratios being exaggerated by 17\%. Conclusions. \textemdash{}This study provides empirical evidence that inadequate methodological approaches in controlled trials, particularly those representing poor allocation concealment, are associated with bias. Readers of trial reports should be wary of these pitfalls, and investigators must improve their design, execution, and reporting of trials.},
  number = {11},
  journal = {JAMA: the journal of the American Medical Association},
  author = {Lijmer, Jeroen G. and Mol, Ben Willem and Heisterkamp, Siem and Bonsel, Gouke J. and Prins, Martin H. and van der Meulen, Jan H. P. and Bossuyt, Patrick M. M.},
  year = {1999},
  keywords = {Diagnostic,704-C,Randomisation-compulsory},
  pages = {1061-},
  file = {/Users/k/Zotero/storage/HQNIF5EL/Lijmer et al. - 1999 - Empirical evidence of bias.pdf},
  pmid = {1083}
}

@article{Jones2003,
  title = {An Introduction to Power and Sample Size Estimation},
  volume = {20},
  issn = {1472-0205},
  doi = {10.1136/emj.20.5.453},
  abstract = {The importance of power and sample size estimation for study design and analysis.},
  number = {5},
  journal = {Emerg. Med. J.},
  author = {Jones, S R},
  year = {2003},
  keywords = {Diagnostic},
  pages = {453-458},
  file = {/Users/k/Zotero/storage/7XXLZ289/Jones - 2003 - An introduction to power and sample size estimation.pdf},
  pmid = {12954688}
}

@article{Beishuizen2002,
  title = {Decreased Levels of Dehydroepiandrosterone Sulphate in Severe Critical Illness: A Sign of Exhausted Adrenal Reserve?},
  volume = {6},
  issn = {1364-8535},
  doi = {10.1186/cc1530},
  abstract = {INTRODUCTION: Dehydroepiandrosterone (DHEA) and its sulphate (DHEAS) are pleiotropic adrenal hormones with immunostimulating and antiglucocorticoid effects. The present study was conducted to evaluate the time course of DHEAS levels in critically ill patients and to study their association with the hypothalamic-pituitary-adrenal axis. MATERIALS AND METHOD: This was a prospective observational clinical and laboratory study, including 30 patients with septic shock, eight patients with multiple trauma, and 40 age- and sex-matched control patients. We took serial measurements of blood concentrations of DHEAS, cortisol, tumour necrosis factor-alpha and IL-6, and of adrenocorticotrophic hormone immunoreactivity over 14 days or until discharge/death. RESULTS: On admission, DHEAS was extremely low in septic shock (1.2 +/- 0.8 mol/l) in comparison with multiple trauma patients (2.4 +/- 0.5 micromol/l; P $<$ 0.05) and control patients (4.2 +/- 1.8; P $<$ 0.01). DHEAS had a significant (P $<$ 0.01) negative correlation with age, IL-6 and Acute Physiology and Chronic Health Evaluation II scores in both patient groups. Only during the acute phase did DHEAS negatively correlate with dopamine. Nonsurvivors of septic shock (n = 11) had lower DHEAS levels (0.4 +/- 0.3 micromol/l) than did survivors (1.7 +/- 1.1 micromol/l; P $<$ 0.01). The time course of DHEAS exhibited a persistent depletion during follow up, whereas cortisol levels were increased at all time points. CONCLUSION: We identified extremely low DHEAS levels in septic shock and, to a lesser degree, in multiple trauma patients as compared with those of age- and sex-matched control patients. There appeared to be a dissociation between DHEAS (decreased) and cortisol (increased) levels, which changed only slightly over time. Nonsurvivors of sepsis and patients with relative adrenal insufficiency had the lowest DHEAS values, suggesting that DHEAS might be a prognostic marker and a sign of exhausted adrenal reserve in critical illness.},
  number = {5},
  journal = {Critical care (London, England)},
  author = {Beishuizen, Albertus and Thijs, Lambertus G and Vermes, Istv\'an},
  year = {2002},
  keywords = {adrenal axis,adrenal insufficiency,dehydroepiandrosterone sulphate,hypothalamic,multiple trauma,pituitary,sepsis},
  pages = {434-438},
  file = {/Users/k/Zotero/storage/QDUUS7NZ/Beishuizen, Thijs, Vermes - 2002 - Decreased levels of dehydroepiandrosterone sulphate in severe critical illness a sign of exhausted ad.pdf},
  pmid = {12398784}
}

@article{Hajian-Tilaki2014,
  title = {Sample Size Estimation in Diagnostic Test Studies of Biomedical Informatics},
  volume = {48},
  issn = {15320464},
  doi = {10.1016/j.jbi.2014.02.013},
  abstract = {Objectives: This review provided a conceptual framework of sample size calculations in the studies of diagnostic test accuracy in various conditions and test outcomes. Methods: The formulae of sample size calculations for estimation of adequate sensitivity/specificity, likelihood ratio and AUC as an overall index of accuracy and also for testing in single modality and comparing two diagnostic tasks have been presented for desired confidence interval. Results: The required sample sizes were calculated and tabulated with different levels of accuracies and marginal errors with 95\% confidence level for estimating and for various effect sizes with 80\% power for purpose of testing as well. The results show how sample size is varied with accuracy index and effect size of interest. Conclusion: This would help the clinicians when designing diagnostic test studies that an adequate sample size is chosen based on statistical principles in order to guarantee the reliability of study. ?? 2014 Elsevier Inc.},
  journal = {Journal of Biomedical Informatics},
  author = {{Hajian-Tilaki}, Karimollah},
  year = {2014},
  keywords = {Sample size,Diagnostic,Area under the curve,Diagnostic studies,ROC analysis,Sensitivity,Specificity},
  pages = {193-204},
  file = {/Users/k/Zotero/storage/U84QKYDU/Hajian-Tilaki - 2014 - Sample size estimation in diagnostic test studies of biomedical informatics.pdf},
  pmid = {24582925}
}

@article{Seymour2017,
  title = {{{iRECIST}}: Guidelines for Response Criteria for Use in Trials Testing Immunotherapeutics},
  volume = {18},
  issn = {14702045},
  doi = {10.1016/S1470-2045(17)30074-8},
  number = {3},
  journal = {The Lancet Oncology},
  author = {Seymour, Lesley and Bogaerts, Jan and Perrone, Andrea and Ford, Robert and Schwartz, Lawrence H and Mandrekar, Sumithra and Lin, Nancy U and Liti\`ere, Saskia and Dancey, Janet and Chen, Alice and Hodi, F Stephen and Therasse, Patrick and Hoekstra, Otto S and Shankar, Lalitha K and Wolchok, Jedd D and Ballinger, Marcus and Caramella, Caroline and {de Vries}, Elisabeth G E},
  year = {2017},
  pages = {e143-e152},
  file = {/Users/k/Zotero/storage/XV7GQIWA/Seymour et al. - 2017 - iRECIST guidelines for response criteria for use in trials testing immunotherapeutics.pdf},
  pmid = {28271869}
}

@article{Halstead2015a,
  title = {The Antibacterial Activity of Acetic Acid against Biofilm-Producing Pathogens of Relevance to Burns Patients},
  volume = {10},
  issn = {19326203},
  doi = {10.1371/journal.pone.0136190},
  abstract = {INTRODUCTION Localised infections, and burn wound sepsis are key concerns in the treatment of burns patients, and prevention of colonisation largely relies on biocides. Acetic acid has been shown to have good antibacterial activity against various planktonic organisms, however data is limited on efficacy, and few studies have been performed on biofilms. OBJECTIVES We sought to investigate the antibacterial activity of acetic acid against important burn wound colonising organisms growing planktonically and as biofilms. METHODS Laboratory experiments were performed to test the ability of acetic acid to inhibit growth of pathogens, inhibit the formation of biofilms, and eradicate pre-formed biofilms. RESULTS Twenty-nine isolates of common wound-infecting pathogens were tested. Acetic acid was antibacterial against planktonic growth, with an minimum inhibitory concentration of 0.16-0.31\% for all isolates, and was also able to prevent formation of biofilms (at 0.31\%). Eradication of mature biofilms was observed for all isolates after three hours of exposure. CONCLUSIONS This study provides evidence that acetic acid can inhibit growth of key burn wound pathogens when used at very dilute concentrations. Owing to current concerns of the reducing efficacy of systemic antibiotics, this novel biocide application offers great promise as a cheap and effective measure to treat infections in burns patients.},
  number = {9},
  journal = {PLoS ONE},
  author = {Halstead, Fenella D. and Rauf, Maryam and Moiemen, Naiem S. and Bamford, Amy and Wearn, Christopher M. and Fraise, Adam P. and Lund, Peter A. and Oppenheim, Beryl A. and Webber, Mark A.},
  year = {2015},
  keywords = {Burns,README},
  pages = {1-15},
  file = {/Users/k/Zotero/storage/5VRJ3US5/Halstead et al. - 2015 - The antibacterial activity of acetic acid against biofilm-producing pathogens of relevance to burns patients.pdf},
  pmid = {26352256}
}

@article{Halstead2015,
  title = {Antimicrobial Dressings: {{Comparison}} of the Ability of a Panel of Dressings to Prevent Biofilm Formation by Key Burn Wound Pathogens},
  volume = {41},
  issn = {18791409},
  doi = {10.1016/j.burns.2015.06.005},
  abstract = {Antimicrobial medicated dressings (AMD) are often used to reduce bacterial infection of burns and other wounds. However, there is limited literature regarding comparative efficacies to inform effective clinical decision making. Objectives Following on from a previous study where we demonstrated good antibiofilm properties of acetic acid (AA), we assessed and compared the in vitro anti-biofilm activity of a range of AMDs and non-AMDs to AA. Methods Laboratory experiments determined the ability of a range of eleven commercial AMD, two nAMD, and AA, to prevent the formation of biofilms of a panel of four isolates of Pseudomonas aeruginosa and Acinetobacter baumannii. Results There is a large variation in ability of different dressings to inhibit biofilm formation, seen between dressings that contain the same, and those that contain other antimicrobial agents. The best performing AMD were Mepilex?? Ag and Acticoat. AA consistently prevented biofilm formation. Conclusions Large variation exists in the ability of AMD to prevent biofilm formation and colonisation of wounds. A standardised in vitro methodology should be developed for external parties to examine and compare the efficacies of commercially available AMDs, along with robust clinical randomised controlled trials. This is essential for informed clinical decision-making and optimal patient management.},
  number = {8},
  journal = {Burns},
  author = {Halstead, Fenella D. and Rauf, Maryam and Bamford, Amy and Wearn, Christopher M. and Bishop, Jonathan R B and Burt, Rebecca and Fraise, Adam P. and Moiemen, Naiem S. and Oppenheim, Beryl A. and Webber, Mark A.},
  year = {2015},
  keywords = {Burns,README,Antimicrobial,Biofilms,Dressings,Wounds},
  pages = {1683-1694},
  file = {/Users/k/Zotero/storage/EBMXT6CY/Halstead et al. - 2015 - Antimicrobial dressings Comparison of the ability of a panel of dressings to prevent biofilm formation by key b.pdf},
  pmid = {26188884}
}

@article{Zor2010,
  title = {Pain Relief during Dressing Changes of Major Adult Burns: {{Ideal}} Analgesic Combination with Ketamine},
  volume = {36},
  issn = {03054179},
  doi = {10.1016/j.burns.2009.08.007},
  abstract = {Pain management during burn dressing changes is a critical part of treatment in acute burn injuries. Although several treatment options have been suggested, it is still a challenge in a clinical setting. This study is aimed at finding out an ideal analgesic, sedative and/or anxiolytic combination that would minimise the unwanted effects of ketamine. A total of 24 patients, with burns up to 20-50\% of total body surface area (TBSA), were included in the study and randomly divided into three groups. In group I, 2 mg kg-1 ketamine was administered. In group II, 1 mg kg-1 tramadol was administered and 30 min later, 1 $\mu$g kg-1 dexmedetomidine and 2 mg kg-1 ketamine was administered. In group III, 1 mg kg-1 tramadol was applied and 30 min later, 0.05 mg kg-1 midazolam and 2 mg kg-1 ketamine was administered. The evaluation was performed with cardiopulmonary monitoring, sedation and visual analogue pain scores and overall patient satisfaction. Any adverse effects of ketamine were recorded. The results showed that group II had better outcomes with respect to pain management during dressing changes. As a conclusion, the use of the combination of ketamine, tramadol and dexmedetomidine was found to be a good treatment option for the prevention of the procedural pain suffered by adult patients during dressing changes. \textcopyright{} 2009 Elsevier Ltd and ISBI.},
  number = {4},
  journal = {Burns},
  author = {Zor, Fatih and Ozturk, Serdar and Bilgin, Ferruh and Isik, Selcuk and Cosar, Ahmet},
  year = {2010},
  keywords = {Burns,README,Burn dressing change,Dexmedetomidine,Ketamine,Midazolam,Pain management},
  pages = {501-505},
  file = {/Users/k/Zotero/storage/ETB3HGCM/Zor et al. - 2010 - Pain relief during dressing changes of major adult burns Ideal analgesic combination with ketamine.pdf},
  pmid = {19819634}
}

@article{Fraise2013,
  title = {The Antibacterial Activity and Stability of Acetic Acid},
  volume = {84},
  issn = {01956701},
  doi = {10.1016/j.jhin.2013.05.001},
  abstract = {Acetic acid has been shown to have good antibacterial activity against micro-organisms such as Pseudomonas aeruginosa. This study examined the activity against a range of bacterial pathogens and also assessed any reduction in antibacterial activity due to evaporation or inactivation by organic material in dressings. Acetic acid was active at dilutions as low as 0.166\% and the activity was not reduced by evaporation nor by inactivation by cotton swabs. Burn injuries are a major problem in countries with limited resources. Acetic acid is an ideal candidate for use in patients who are treated in those parts of the world. ?? 2013 The Healthcare Infection Society.},
  number = {4},
  journal = {Journal of Hospital Infection},
  author = {Fraise, A. P. and Wilkinson, M. A C and Bradley, C. R. and Oppenheim, B. and Moiemen, N.},
  year = {2013},
  keywords = {Burns,README,Acetic acid,Activity,Antibacterial},
  pages = {329-331},
  file = {/Users/k/Zotero/storage/9RYPP6EC/Fraise et al. - 2013 - The antibacterial activity and stability of acetic acid.pdf},
  pmid = {23747099}
}

@article{Rogatko2007,
  title = {Translation of Innovative Designs into Phase {{I}} Trials},
  volume = {25},
  issn = {0732183X},
  doi = {10.1200/JCO.2007.12.1012},
  abstract = {PURPOSE: Phase I clinical trials of new anticancer therapies determine suitable doses for further testing. Optimization of their design is vital in that they enroll cancer patients whose well-being is distinctly at risk. This study examines the effectiveness of knowledge transfer about more effective statistical designs to clinical practice. METHODS: We examined abstract records of cancer phase I trials from the Science Citation Index database between 1991 and 2006 and classified them into clinical (dose-finding trials) and statistical trials (methodologic studies of dose-escalation designs). We then mapped these two sets by tracking which trials adopted new statistical designs. RESULTS: One thousand two hundred thirty-five clinical and 90 statistical studies were identified. Only 1.6\% of the phase I cancer trials (20 of 1,235 trials) followed a design proposed in one of the statistical studies. These 20 clinical studies showed extensive lags between publication of the statistical paper and its translation into a clinical paper. These 20 clinical trials followed Bayesian adaptive designs. The remainder used variations of the standard up-and-down method. CONCLUSION: A consequence of using less effective designs is that more patients are treated with doses outside the therapeutic window. Simulation studies have shown that up-and-down designs treated only 35\% of patients at optimal dose levels versus 55\% for Bayesian adaptive designs. This implies needless loss of treatment efficacy and, possibly, lives. We suggest that regulatory agencies (eg, US Food and Drug Administration) should proactively encourage the adoption of statistical designs that would allow more patients to be treated at near-optimal doses while controlling for excessive toxicity.},
  number = {31},
  journal = {Journal of Clinical Oncology},
  author = {Rogatko, Andr\'e and Schoeneck, David and Jonas, William and Tighiouart, Mourad and Khuri, Fadlo R. and Porter, Alan},
  year = {2007},
  pages = {4982-4986},
  file = {/Users/k/Zotero/storage/3GRBPI6Q/Rogatko et al. - 2007 - Translation of innovative designs into phase I trials.pdf},
  pmid = {17971597}
}

@article{Simon2016a,
  title = {The {{Bayesian}} Basket Design for Genomic Variant-Driven Phase {{II}} Trials},
  volume = {43},
  issn = {15328708},
  doi = {10.1053/j.seminoncol.2016.01.002},
  abstract = {Basket clinical trials are a new category of early clinical trials in which a treatment is evaluated in a population of patients with tumors of various histologic types and primary sites selected for containing specific genomic abnormalities. The objective of such studies is generally to discover histologic types in which the treatment is active. Basket trials are early discovery trials whose results should be confirmed in expanded histology specific cohorts. In this report, we develop a design for planning, monitoring, and analyzing basket trials. A website for using the new design is available at https://brbnci.shinyapps.io/BasketTrials/ and the software is available at GitHub in the "Basket Trials" repository of account brbnci.},
  number = {1},
  journal = {Seminars in Oncology},
  author = {Simon, Richard and Geyer, Susan and Subramanian, Jyothi and Roychowdhury, Sameek},
  year = {2016},
  keywords = {Actionable mutations,Basket clinical trials,Genomic clinical trials},
  pages = {13-18},
  file = {/Users/k/Zotero/storage/P3NAX5ZN/Simon et al. - 2016 - The Bayesian basket design for genomic variant-driven phase II trials.pdf},
  pmid = {26970120}
}

@article{Mcmaster2010,
  title = {Conservative {{Sample Size Determination}} for {{Repeated Measures Analysis}} of {{Covariance}}},
  volume = {1},
  issn = {1878-5832},
  doi = {10.3816/CLM.2009.n.003.Novel},
  number = {1},
  journal = {Ann Biom Biostat},
  author = {Morgan, Timothy M. and Case, L. Douglas},
  year = {2010},
  keywords = {ANCOVA,genetic susceptibility,hypergammaglobulinemia,igm,mgus,monoclonal gammopathy of undetermined,polyclonal gammopathy,precursor disease,significance,waldenstrom macroglobulinemia},
  file = {/Users/k/Zotero/storage/8BEP2I6Q/Morgan, Case - 2010 - Conservative Sample Size Determination for Repeated Measures Analysis of Covariance.pdf},
  pmid = {21959306}
}

@article{Lambertus2016,
  title = {Progression of {{Late}}-{{Onset Stargardt Disease}}},
  volume = {57},
  issn = {1552-5783},
  doi = {10.1167/iovs.16-19833},
  abstract = {Purpose Identification of sensitive biomarkers is essential to determine potential effects of emerging therapeutic trials for Stargardt disease. This study aimed to describe the natural history of late-onset Stargardt, and demonstrates the accuracy of retinal pigment epithelium (RPE) atrophy progression as an outcome measure. Methods We performed a retrospective cohort study collecting multicenter data from 47 patients (91 eyes) with late-onset Stargardt, defined by clinical phenotype, at least one ABCA4 mutation, and age at disease onset $\geq$ 45 years. We analyzed RPE atrophy progression on fundus autofluorescence and near-infrared reflectance imaging using semiautomated software and a linear mixed model. We performed sample size calculations to assess the power in a simulated 2-year interventional study and assessed visual endpoints using time-to-event analysis. Results Over time, progression of RPE atrophy was observed (mean: 0.22 mm/year, 95\% confidence interval [CI]: 0.19-0.27). By including only patients with bilateral RPE atrophy in a future trial, 32 patients are needed to reach a power of 83.9\% (95\% CI: 83.1-84.6), assuming a fixed therapeutic effect size of 30\%. We found a median interval between disease onset and visual acuity decline to 20/32, 20/80, and 20/200 of 2.74 (95\% CI: 0.54-4.41), 10.15 (95\% CI: 6.13-11.38), and 11.38 (95\% CI: 6.13-13.34) years, respectively. Conclusions We show that RPE atrophy represents a robust biomarker to monitor disease progression in future therapeutic trials. In contrast, the variability in terms of the course of visual acuity was high.},
  number = {13},
  journal = {Investigative Opthalmology \& Visual Science},
  author = {Lambertus, Stanley and Lindner, Moritz and Bax, Nathalie M. and Mauschitz, Matthias M. and Nadal, Jennifer and Schmid, Matthias and {Schmitz-Valckenberg}, Steffen and {den Hollander}, Anneke I. and Weber, Bernhard H. F. and Holz, Frank G. and {van der Wilt}, Gert Jan and Fleckenstein, Monika and Hoyng, Carel B. and {Foveal sparing Atrophy Study Team (FAST)}},
  year = {2016},
  keywords = {biomarker,VisualAcuity,8000,and affects 1,autosomal recessive retinal dystrophy,caused by mutations in,disease progression,fundus autofluorescence,late-onset stargardt,retinal pigment epithelium atrophy,targardt disease is an,the abca4 gene},
  pages = {5186},
  file = {/Users/k/Zotero/storage/Q7VQL5C8/Lambertus et al. - 2016 - Progression of Late-Onset Stargardt Disease.pdf},
  pmid = {27699414}
}

@article{levyNonparametricApplicationsShaffer2017,
  title = {Nonparametric {{Applications}} of {{Shaffer}} ' s {{Extension}} of {{Dunnett}} ' s {{Procedure Author}} ( s ): {{Kenneth J}} . {{Levy Source}} : {{The American Statistician}} , {{Vol}} . 34 , {{No}} . 2 ( {{May}} , 1980 ), Pp . 99-102 {{Published}} by : {{Taylor}} \& {{Francis}} , {{Ltd}} . on Behalf of the {{America}}},
  volume = {34},
  number = {2},
  author = {Levy, Kenneth J},
  year = {2017},
  keywords = {1n,dunnett,let s2 be the,means t,multiple comparisons,nonparametric procedures,s procedure,then,u and variances -2,unbiased estimate of -2,usual},
  pages = {99-102},
  file = {/Users/k/Zotero/storage/S8R2L7UU/Levy - 2017 - Nonparametric Applications of Shaffer ' s Extension of Dunnett ' s Procedure Author ( s ) Kenneth J . Levy Source The Ame.pdf}
}

@article{VanRavenzwaaij2017,
  title = {A Simulation Study of the Strength of Evidence in the Recommendation of Medications Based on Two Trials with Statistically Significant Results},
  volume = {12},
  issn = {1932-6203},
  doi = {10.1371/journal.pone.0173184},
  number = {3},
  journal = {Plos One},
  author = {{van Ravenzwaaij}, Don and Ioannidis, John P. A. and Tiwari, RC and Liu, G and Natanegara, F and Railkar, R and Schmidli, H and Song, G},
  year = {2017},
  pages = {e0173184},
  file = {/Users/k/Zotero/storage/S7P4LM2W/van Ravenzwaaij et al. - 2017 - A simulation study of the strength of evidence in the recommendation of medications based on two trials.pdf},
  pmid = {28273140}
}

@article{Colquhoun2011,
  title = {In Praise of Randomisation: The Importance of Causality in Medicine and Its Subversion by Philosophers of Science},
  doi = {10.5871/bacad/9780197264843.003.0012},
  journal = {Evidence, Inference and Enquiry},
  author = {Colquhoun, David},
  year = {2011},
  keywords = {RCT},
  pages = {323-343},
  file = {/Users/k/Zotero/storage/BCLMAWV5/Colquhoun - 2011 - In praise of randomisation the importance of causality in medicine and its subversion by philosophers of science.pdf}
}

@article{Statistical,
  title = {Meta-{{Analysis}} of {{Hazard Ratios}}},
  volume = {chapter 45},
  number = {1995},
  journal = {NCSS Statistical Software},
  author = {Statistical, Ncss and Ncss, Software and Reserved, All Rights},
  keywords = {MetaAnalysis},
  pages = {1-13},
  file = {/Users/k/Zotero/storage/YJP8VYZ9/Statistical, Ncss, Reserved - Unknown - Meta-Analysis of Hazard Ratios.pdf}
}

@article{Thabane2010,
  title = {A Tutorial on Pilot Studies: The What, Why and How},
  volume = {10},
  issn = {1471-2288},
  doi = {10.1186/1471-2288-10-1},
  abstract = {Pilot studies for phase III trials - which are comparative randomized trials designed to provide preliminary evidence on the clinical efficacy of a drug or intervention - are routinely performed in many clinical areas. Also commonly know as "feasibility" or "vanguard" studies, they are designed to assess the safety of treatment or interventions; to assess recruitment potential; to assess the feasibility of international collaboration or coordination for multicentre trials; to increase clinical experience with the study medication or intervention for the phase III trials. They are the best way to assess feasibility of a large, expensive full-scale study, and in fact are an almost essential pre-requisite. Conducting a pilot prior to the main study can enhance the likelihood of success of the main study and potentially help to avoid doomed main studies. The objective of this paper is to provide a detailed examination of the key aspects of pilot studies for phase III trials including: 1) the general reasons for conducting a pilot study; 2) the relationships between pilot studies, proof-of-concept studies, and adaptive designs; 3) the challenges of and misconceptions about pilot studies; 4) the criteria for evaluating the success of a pilot study; 5) frequently asked questions about pilot studies; 7) some ethical aspects related to pilot studies; and 8) some suggestions on how to report the results of pilot investigations using the CONSORT format.},
  number = {August 2016},
  journal = {BMC Med Res Methodol},
  author = {Thabane, L and Ma, J and Chu, R and Cheng, J and Ismaila, A and Rios, L P and Robson, R and Thabane, M and Giangregorio, L and Goldsmith, C H},
  year = {2010},
  keywords = {Humans,Randomized Controlled Trials as Topic,*Pilot Projects,*Research Design/standards,Clinical Trials; Phase III as Topic/methods,PilotStudies},
  pages = {1},
  file = {/Users/k/Zotero/storage/GHQN5EBS/Thabane et al. - 2010 - A tutorial on pilot studies the what, why and how.pdf},
  pmid = {20053272}
}

@article{Tierney2007,
  title = {Practical Methods for Incorporating Summary Time-to-Event Data into Meta-Analysis.},
  volume = {8},
  issn = {1745-6215},
  doi = {10.1186/1745-6215-8-16},
  abstract = {BACKGROUND: In systematic reviews and meta-analyses, time-to-event outcomes are most appropriately analysed using hazard ratios (HRs). In the absence of individual patient data (IPD), methods are available to obtain HRs and/or associated statistics by carefully manipulating published or other summary data. Awareness and adoption of these methods is somewhat limited, perhaps because they are published in the statistical literature using statistical notation.$\backslash$n$\backslash$nMETHODS: This paper aims to 'translate' the methods for estimating a HR and associated statistics from published time-to-event-analyses into less statistical and more practical guidance and provide a corresponding, easy-to-use calculations spreadsheet, to facilitate the computational aspects.$\backslash$n$\backslash$nRESULTS: A wider audience should be able to understand published time-to-event data in individual trial reports and use it more appropriately in meta-analysis. When faced with particular circumstances, readers can refer to the relevant sections of the paper. The spreadsheet can be used to assist them in carrying out the calculations.$\backslash$n$\backslash$nCONCLUSION: The methods cannot circumvent the potential biases associated with relying on published data for systematic reviews and meta-analysis. However, this practical guide should improve the quality of the analysis and subsequent interpretation of systematic reviews and meta-analyses that include time-to-event outcomes.},
  number = {1},
  journal = {Trials},
  author = {Tierney, Jayne F and Stewart, Lesley A and Ghersi, Davina and Burdett, Sarah and Sydes, Matthew R},
  year = {2007},
  keywords = {README,MetaAnalysis,Biomedicine general,general,Health Sciences,Medicine,Medicine/Public Health,Statistics for Life Sciences},
  pages = {16},
  file = {/Users/k/Zotero/storage/4IPLCFG7/Tierney et al. - 2007 - Practical methods for incorporating summary time-to-event data into meta-analysis.pdf},
  pmid = {17555582}
}

@article{Teare2014,
  title = {Sample Size Requirements to Estimate Key Design Parameters from External Pilot Randomised Controlled Trials: A Simulation Study.},
  volume = {15},
  issn = {1745-6215},
  doi = {10.1186/1745-6215-15-264},
  abstract = {BACKGROUND: External pilot or feasibility studies can be used to estimate key unknown parameters to inform the design of the definitive randomised controlled trial (RCT). However, there is little consensus on how large pilot studies need to be, and some suggest inflating estimates to adjust for the lack of precision when planning the definitive RCT.$\backslash$n$\backslash$nMETHODS: We use a simulation approach to illustrate the sampling distribution of the standard deviation for continuous outcomes and the event rate for binary outcomes. We present the impact of increasing the pilot sample size on the precision and bias of these estimates, and predicted power under three realistic scenarios. We also illustrate the consequences of using a confidence interval argument to inflate estimates so the required power is achieved with a pre-specified level of confidence. We limit our attention to external pilot and feasibility studies prior to a two-parallel-balanced-group superiority RCT.$\backslash$n$\backslash$nRESULTS: For normally distributed outcomes, the relative gain in precision of the pooled standard deviation (SDp) is less than 10\% (for each five subjects added per group) once the total sample size is 70. For true proportions between 0.1 and 0.5, we find the gain in precision for each five subjects added to the pilot sample is less than 5\% once the sample size is 60. Adjusting the required sample sizes for the imprecision in the pilot study estimates can result in excessively large definitive RCTs and also requires a pilot sample size of 60 to 90 for the true effect sizes considered here.$\backslash$n$\backslash$nCONCLUSIONS: We recommend that an external pilot study has at least 70 measured subjects (35 per group) when estimating the SDp for a continuous outcome. If the event rate in an intervention group needs to be estimated by the pilot then a total of 60 to 100 subjects is required. Hence if the primary outcome is binary a total of at least 120 subjects (60 in each group) may be required in the pilot trial. It is very much more efficient to use a larger pilot study, than to guard against the lack of precision by using inflated estimates.},
  journal = {Trials},
  author = {Teare, M Dawn and Dimairo, Munyaradzi and Shephard, Neil and Hayman, Alex and Whitehead, Amy and Walters, Stephen J},
  year = {2014},
  keywords = {Humans,Randomized Controlled Trials as Topic,Data Interpretation,Statistical,Computer Simulation,Models,Randomized Controlled Trials as Topic: methods,README,PilotStudies,Feasibility Studies,Pilot Projects,Randomized Controlled Trials as Topic: statistics,Sample Size},
  pages = {264},
  file = {/Users/k/Zotero/storage/AESI9KQZ/Teare et al. - 2014 - Sample size requirements to estimate key design parameters from external pilot randomised controlled trials a simu.pdf},
  pmid = {24993581}
}

@article{Royston2013,
  title = {Restricted Mean Survival Time: An Alternative to the Hazard Ratio for the Design and Analysis of Randomized Trials with a Time-to-Event Outcome.},
  volume = {13},
  issn = {1471-2288},
  doi = {10.1186/1471-2288-13-152},
  abstract = {BACKGROUND: Designs and analyses of clinical trials with a time-to-event outcome almost invariably rely on the hazard ratio to estimate the treatment effect and implicitly, therefore, on the proportional hazards assumption. However, the results of some recent trials indicate that there is no guarantee that the assumption will hold. Here, we describe the use of the restricted mean survival time as a possible alternative tool in the design and analysis of these trials.$\backslash$n$\backslash$nMETHODS: The restricted mean is a measure of average survival from time 0 to a specified time point, and may be estimated as the area under the survival curve up to that point. We consider the design of such trials according to a wide range of possible survival distributions in the control and research arm(s). The distributions are conveniently defined as piecewise exponential distributions and can be specified through piecewise constant hazards and time-fixed or time-dependent hazard ratios. Such designs can embody proportional or non-proportional hazards of the treatment effect.$\backslash$n$\backslash$nRESULTS: We demonstrate the use of restricted mean survival time and a test of the difference in restricted means as an alternative measure of treatment effect. We support the approach through the results of simulation studies and in real examples from several cancer trials. We illustrate the required sample size under proportional and non-proportional hazards, also the significance level and power of the proposed test. Values are compared with those from the standard approach which utilizes the logrank test.$\backslash$n$\backslash$nCONCLUSIONS: We conclude that the hazard ratio cannot be recommended as a general measure of the treatment effect in a randomized controlled trial, nor is it always appropriate when designing a trial. Restricted mean survival time may provide a practical way forward and deserves greater attention.},
  number = {1},
  journal = {BMC medical research methodology},
  author = {Royston, Patrick and Parmar, Mahesh Kb},
  year = {2013},
  keywords = {time-to-event data,MetaAnalysis,hazard ratio,logrank test,non-proportional hazards,piecewise exponential distribution,randomized controlled trials,restricted mean survival time},
  pages = {152},
  file = {/Users/k/Zotero/storage/Q5FQGSW4/Royston, Parmar - 2013 - Restricted mean survival time an alternative to the hazard ratio for the design and analysis of randomized tria.pdf},
  pmid = {24314264}
}

@article{Cedarbaum1999,
  title = {The {{ALSFRS}}-{{R}} : A Revised {{ALS}} Functional Rating Scale That Incorporates Assessments of Respiratory Function},
  volume = {169},
  journal = {Journal of the Neurological Sciences},
  author = {Cedarbaum, Jesse M and Stambler, Nancy and Fuller, Cynthia and Hilt, Dana and Thurmond, Barbara and Nakanishi, Arline and Als, Bdnf and Group, Study and Iii, Phase},
  year = {1999},
  keywords = {ALS,amyotrophic lateral sclerosis,pulmonary function,rating scales},
  pages = {13-21},
  file = {/Users/k/Zotero/storage/IB388TIZ/Cedarbaum et al. - 1999 - The ALSFRS-R a revised ALS functional rating scale that incorporates assessments of respiratory function.pdf}
}

@article{Fearon2015,
  title = {{{HHS Public Access}}},
  volume = {20},
  doi = {10.1038/nm.3462.In},
  number = {3},
  journal = {Nature medicine},
  author = {Atreya, Raja and Neumann, Helmut and Neufert, Clemens and Waldner, Maximilian J and Willma, Marcus and App, Christine and Maas, Stefanie and Gebhardt, Bernd and {Heimke-brinck}, Ralph and Reuter, Eva and Rau, Tilman T and Uter, Wolfgang and Wang, Thomas D and Kiesslich, Ralf and Vieth, Michael and Hannappel, Ewald and Neurath, Markus F and Arbor, Ann and Bayreuth, Klinikum},
  year = {2015},
  keywords = {Crohns},
  pages = {313-318},
  file = {/Users/k/Zotero/storage/IT7Y22XZ/Atreya et al. - 2015 - HHS Public Access.pdf}
}

@article{Ribas2016,
  title = {Association of {{Pembrolizumab With Tumor Response}} and {{Survival Among Patients With Advanced Melanoma}}.},
  volume = {315},
  issn = {1538-3598},
  doi = {10.1001/jama.2016.4059},
  abstract = {IMPORTANCE The programmed death 1 (PD-1) pathway limits immune responses to melanoma and can be blocked with the humanized anti-PD-1 monoclonal antibody pembrolizumab. OBJECTIVE To characterize the association of pembrolizumab with tumor response and overall survival among patients with advanced melanoma. DESIGN, SETTINGS, AND PARTICIPANTS Open-label, multicohort, phase 1b clinical trials (enrollment, December 2011-September 2013). Median duration of follow-up was 21 months. The study was performed in academic medical centers in Australia, Canada, France, and the United States. Eligible patients were aged 18 years and older and had advanced or metastatic melanoma. Data were pooled from 655 enrolled patients (135 from a nonrandomized cohort [n = 87 ipilimumab naive; n = 48 ipilimumab treated] and 520 from randomized cohorts [n = 226 ipilimumab naive; n = 294 ipilimumab treated]). Cutoff dates were April 18, 2014, for safety analyses and October 18, 2014, for efficacy analyses. EXPOSURES Pembrolizumab 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 2 mg/kg every 3 weeks continued until disease progression, intolerable toxicity, or investigator decision. MAIN OUTCOMES AND MEASURES The primary end point was confirmed objective response rate (best overall response of complete response or partial response) in patients with measurable disease at baseline per independent central review. Secondary end points included toxicity, duration of response, progression-free survival, and overall survival. RESULTS Among the 655 patients (median [range] age, 61 [18-94] years; 405 [62\%] men), 581 had measurable disease at baseline. An objective response was reported in 194 of 581 patients (33\% [95\% CI, 30\%-37\%]) and in 60 of 133 treatment-naive patients (45\% [95\% CI, 36\% to 54\%]). Overall, 74\% (152/205) of responses were ongoing at the time of data cutoff; 44\% (90/205) of patients had response duration for at least 1 year and 79\% (162/205) had response duration for at least 6 months. Twelve-month progression-free survival rates were 35\% (95\% CI, 31\%-39\%) in the total population and 52\% (95\% CI, 43\%-60\%) among treatment-naive patients. Median overall survival in the total population was 23 months (95\% CI, 20-29) with a 12-month survival rate of 66\% (95\% CI, 62\%-69\%) and a 24-month survival rate of 49\% (95\% CI, 44\%-53\%). In treatment-naive patients, median overall survival was 31 months (95\% CI, 24 to not reached) with a 12-month survival rate of 73\% (95\% CI, 65\%-79\%) and a 24-month survival rate of 60\% (95\% CI, 51\%-68\%). Ninety-two of 655 patients (14\%) experienced at least 1 treatment-related grade 3 or 4 adverse event (AE) and 27 of 655 (4\%) patients discontinued treatment because of a treatment-related AE. Treatment-related serious AEs were reported in 59 patients (9\%). There were no drug-related deaths. CONCLUSIONS AND RELEVANCE Among patients with advanced melanoma, pembrolizumab administration was associated with an overall objective response rate of 33\%, 12-month progression-free survival rate of 35\%, and median overall survival of 23 months; grade 3 or 4 treatment-related AEs occurred in 14\%. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01295827.},
  number = {15},
  journal = {Jama},
  author = {Ribas, Antoni and Hamid, Omid and Daud, Adil and Hodi, F Stephen and Wolchok, Jedd D and Kefford, Richard and Joshua, Anthony M and Patnaik, Amita and Hwu, Wen-Jen and Weber, Jeffrey S and Gangadhar, Tara C and Hersey, Peter and Dronca, Roxana and Joseph, Richard W and Zarour, Hassane and Chmielowski, Bartosz and Lawrence, Donald P and Algazi, Alain and Rizvi, Naiyer A and Hoffner, Brianna and Mateus, Christine and Gergich, Kevin and Lindia, Jill A and Giannotti, Maxine and Li, Xiaoyun Nicole and Ebbinghaus, Scot and Kang, S Peter and Robert, Caroline},
  year = {2016},
  keywords = {Pembrolizumab,pembrolizumab},
  pages = {1600-9},
  file = {/Users/k/Zotero/storage/R9S4RU8N/Ribas et al. - 2016 - Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma.pdf},
  pmid = {27092830}
}

@article{Badala2008,
  title = {Sample Size Formulae for the {{Bayesian}} Continual Reassessment Method},
  volume = {10},
  issn = {15378276},
  doi = {10.1177/1740774513497294},
  number = {6},
  journal = {Clinical Trials},
  author = {Cheung, Ying Kuen},
  year = {2013},
  keywords = {README},
  file = {/Users/k/Zotero/storage/5VCNHXXF/Cheung - 2013 - Sample size formulae for the Bayesian continual reassessment method.pdf},
  pmid = {1000000221}
}

@article{Bauer2010a,
  title = {Selection and Bias-Two Hostile Brothers},
  volume = {29},
  issn = {02776715},
  doi = {10.1002/sim.3716},
  abstract = {We consider the situation where in a first stage of a clinical trial several treatments are compared with a single control and the 'best' treatment(s) are selected in an interim analysis to be carried on to the second stage. We quantify the mean bias and mean square error of the conventional estimates after selection depending on the number of treatments and the selection time during the trial. The cases without or with reshuffling the planned sample size of the dropped treatments to the selected ones are investigated. The mean bias shows very different patterns depending on the selection rule and the unknown parameter values. We stress the fact that the quantification of the bias is possible only in designs with planned adaptivity where the design allows reacting to new evidence, but the decision rules are laid down in advance. Finally, we calculate the mean bias which arises in a simple but influential regulatory selection rule, to register a new medical therapy only when two pivotal trials have both proven an effect by a statistical test.},
  number = {1},
  journal = {Statistics in Medicine},
  author = {Bauer, Peter and Koenig, Franz and Brannatha, Werner and Poscha, Martin},
  year = {2010},
  keywords = {Admission bias,Many one comparison,Mean bias,Mean square error,Sample size reassessment,Treatment selection},
  pages = {1-13},
  file = {/Users/k/Zotero/storage/FSTXFBIB/Bauer et al. - 2010 - Selection and bias-two hostile brothers.pdf},
  pmid = {19844944}
}

@article{Wheeler2017,
  title = {How to Design a Dose-Finding Study Using the {{Continual Reassessment Method}}},
  abstract = {To be completed.},
  author = {Wheeler, Graham M and Mander, Adrian P and Jaki, Thomas and Bedding, Alun and Yap, Christina and Brock, Kristian and Bond, Simon J},
  year = {2017},
  keywords = {CRM,Maximum Tolerated Dose,dose escalation,Bayesian adaptive designs,Continual Reassessment Method,phase I trials},
  file = {/Users/k/Zotero/storage/WC5LX34J/Wheeler et al. - 2017 - How to design a dose-finding study using the Continual Reassessment Method.pdf}
}

@article{Reinstein2009,
  title = {Stromal {{Thickness}} in the {{Normal Cornea}}: {{Three}}-Dimensional {{Display With Artemis Very High}}-Frequency {{Digital Ultrasound}}},
  volume = {25},
  issn = {09652140},
  doi = {10.1097/OPX.0b013e3182540562.The},
  number = {9},
  journal = {J Refract Surg},
  author = {Reinstein, Dan Z. and Archer, Timothy J. and Gobbe, Marine and Silverman, Ronald H. and Coleman, D. Jackson},
  year = {2009},
  keywords = {Corneal},
  pages = {776-86},
  file = {/Users/k/Zotero/storage/SP55Q2BZ/Reinstein et al. - 2009 - Stromal Thickness in the Normal Cornea Three-dimensional Display With Artemis Very High-frequency Digital Ultr.pdf},
  pmid = {20402989}
}

@article{Srinivasan2012,
  title = {Corticosteroids for {{Bacterial Keratitis}}: {{The Steroids}} for {{Corneal Ulcers Trial}} ({{SCUT}})},
  volume = {130},
  issn = {0003-9950},
  doi = {10.1001/archophthalmol.2011.315},
  number = {2},
  journal = {Archives of Ophthalmology},
  author = {Srinivasan, Muthiah and Mascarenhas, Jeena and Rajaraman, Revathi and Ravindran, Meenakshi and Lalitha, Prajna and Glidden, David V and Ray, Kathryn J and Hong, Kevin C and Oldenburg, Catherine E and Lee, Salena M and Zegans, Michael E and Mcleod, Stephen D and Lietman, Thomas M and Acharya, Nisha R.},
  year = {2012},
  keywords = {Corneal},
  pages = {143-150},
  file = {/Users/k/Zotero/storage/9TD96PXD/Srinivasan et al. - 2012 - Corticosteroids for Bacterial Keratitis The Steroids for Corneal Ulcers Trial (SCUT).pdf}
}

@article{Ji2013a,
  title = {Modified Toxicity Probability Interval Design: A Safer and More Reliable Method than the 3 + 3 Design for Practical Phase {{I}} Trials.},
  volume = {31},
  issn = {15277755},
  doi = {10.1200/JCO.2012.45.7903},
  abstract = {The 3 + 3 design is the most common choice among clinicians for phase I dose-escalation oncology trials. In recent reviews, more than 95\% of phase I trials have been based on the 3 + 3 design. Given that it is intuitive and its implementation does not require a computer program, clinicians can conduct 3 + 3 dose escalations in practice with virtually no logistic cost, and trial protocols based on the 3 + 3 design pass institutional review board and biostatistics reviews quickly. However, the performance of the 3 + 3 design has rarely been compared with model-based designs in simulation studies with matched sample sizes. In the vast majority of statistical literature, the 3 + 3 design has been shown to be inferior in identifying true maximum-tolerated doses (MTDs), although the sample size required by the 3 + 3 design is often orders-of-magnitude smaller than model-based designs. In this article, through comparative simulation studies with matched sample sizes, we demonstrate that the 3 + 3 design has higher risks of exposing patients to toxic doses above the MTD than the modified toxicity probability interval (mTPI) design, a newly developed adaptive method. In addition, compared with the mTPI design, the 3 + 3 design does not yield higher probabilities in identifying the correct MTD, even when the sample size is matched. Given that the mTPI design is equally transparent, costless to implement with free software, and more flexible in practical situations, we highly encourage its adoption in early dose-escalation studies whenever the 3 + 3 design is also considered. We provide free software to allow direct comparisons of the 3 + 3 design with other model-based designs in simulation studies with matched sample sizes.},
  number = {14},
  journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology},
  author = {Ji, Yuan and Wang, Sue Jane},
  year = {2013},
  keywords = {DoseFinding,README},
  pages = {1785-1791},
  file = {/Users/k/Zotero/storage/H2ISANSQ/Ji, Wang - 2013 - Modified toxicity probability interval design a safer and more reliable method than the 3 3 design for practical phas.pdf},
  pmid = {23569307}
}

@article{James2016,
  title = {Continual Reassessment Method for Dose Escalation Clinical Trials in Oncology: A Comparison of Prior Skeleton Approaches Using {{AZD3514}} Data},
  volume = {16},
  issn = {1471-2407},
  doi = {10.1186/s12885-016-2702-6},
  number = {1},
  journal = {BMC Cancer},
  author = {James, Gareth D. and Symeonides, Stefan N. and Marshall, Jayne and Young, Julia and Clack, Glen},
  year = {2016},
  keywords = {oncology,clinical trial,CRM,bayesian,continual reassessment method,Clinical trial,Continual reassessment meth,phase 1,Phase 1,skeleton},
  pages = {703},
  file = {/Users/k/Zotero/storage/NHM745G2/James et al. - 2016 - Continual reassessment method for dose escalation clinical trials in oncology a comparison of prior skeleton appro.pdf}
}

@article{Arlt1998,
  title = {Oral {{Dehydroepiandrosterone}} for {{Adrenal Androgen Replacement}} : {{Pharmacokinetics}} and {{Peripheral Conversion}} to {{Androgens}} and {{Estrogens}} in {{Young}}},
  volume = {83},
  number = {6},
  journal = {Journal of Clinical Endocrinology and Metabolism},
  author = {Arlt, Wiebke and Justl, Hans-georg and Callies, Frank and Reincke, Martin and Oettel, Michael and Ernst, Michael and Hu, Doris and Schulte, Heinrich Maria and Allolio, Bruno and Wuerzburg, Clinic},
  year = {1998},
  keywords = {ADaPT},
  pages = {1928-1934},
  file = {/Users/k/Zotero/storage/Q96BLIKN/Arlt et al. - 1998 - Oral Dehydroepiandrosterone for Adrenal Androgen Replacement Pharmacokinetics and Peripheral Conversion to Androge.pdf}
}

@article{Hinson1999,
  title = {{{DHEA}} Deficiency Syndrome: {{A}} New Term for Old Age?},
  volume = {163},
  issn = {00220795},
  doi = {10.1677/joe.0.1630001},
  abstract = {Dehydroepiandrosterone (DHEA) is a steroid secreted by the adrenal cortex, with a characteristic, age-related, pattern of secretion. The decline of DHEA concentrations with age has led to the suggestion that old age represents a DHEA deficiency syndrome and that the effects of ageing can be counteracted by DHEA 'replacement therapy'. DHEA is increasingly being used in the USA, outside medical supervision, for its supposed anti-ageing effects. This commentary weighs the evidence for the existence of a DHEA deficiency syndrome and considers the value of DHEA 'replacement therapy'.},
  number = {1},
  journal = {Journal of Endocrinology},
  author = {Hinson, J. P. and Raven, P. W.},
  year = {1999},
  keywords = {ADaPT,DHEA},
  pages = {1-5},
  file = {/Users/k/Zotero/storage/QFN6T68E/Hinson, Raven - 1999 - DHEA deficiency syndrome A new term for old age.pdf},
  pmid = {10495400}
}

@article{Arlt1999,
  title = {Biotransformation of Oral Dehydroepiandrosterone in Elderly Men: {{Significant}} Increase in Circulating Estrogens},
  volume = {84},
  issn = {0021972X},
  doi = {10.1210/jc.84.6.2170},
  abstract = {The most abundant human steroids, dehydroepiandrosterone (DHEA) and its sulfate ester DHEAS, may have a multitude of beneficial effects, but decline with age. DHEA possibly prevents immunosenescence, and as a neuroactive steroid it may influence processes of cognition and memory. Epidemiological studies revealed an inverse correlation between DHEAS levels and the incidence of cardiovascular disease in men, but not in women. To define a suitable dose for DHEA substitution in elderly men we studied pharmacokinetics and biotransformation of orally administered DHEA in 14 healthy male volunteers (mean age, 58.8 $\lnot\pm$ 5.1 yr; mean body mass index, 25.5 $\lnot\pm$ 1.5 kg/m2) with serum DHEAS concentrations below 4.1 \OE\textordmasculine{}mol/L (1500 ng/mL). Diurnal blood sampling was performed on 3 occasions in a single dose, randomized, cross-over design (oral administration of placebo, 50 mg DHEA, or 100 mg DHEA). The intake of 50 mg DHEA led to an increase in serum DHEAS to mean levels of young adult men, whereas 100 mg DHEA induced supraphysiological concentrations [placebo vs. 50 mg DHEA vs. 100 mg DHEA; area under the curve (AUC) 0,\"A\`i12 h (mean $\lnot\pm$ sd) for DHEA, 108 $\lnot\pm$ 22 vs. 252 $\lnot\pm$ 45 vs. 349 $\lnot\pm$ 72 nmol/L$\lnot\sum$h; AUC 0,\"A\`i12 h for DHEAS, 33 $\lnot\pm$ 9 vs. 114 $\lnot\pm$. 19 vs. 164$\lnot\pm$ 36 \OE\textordmasculine{}mol/L$\lnot\sum$h]. Serum testosterone and dihydrotestosterone remained unchanged after DHEA administration. In contrast, 17\OE$\leq$-estradiol and estrone significantly increased in a dose-dependent manner to concentrations still within the upper normal range for men[ placebo vs. 50 mg DHEA vs. 100 mg DHEA; AUC 0,\"A\`i12 h for 17\OE$\leq$-estradiol, 510 $\lnot\pm$ 198 vs. 635 $\lnot\pm$ 156 vs. 700 $\lnot\pm$ 209 pmol/L$\lnot\sum$h (P $<$ 0.0001); AUC 0,\"A\`i12 h for estrone, 1443 $\lnot\pm$ 269 vs. 2537 $\lnot\pm$ 434 vs. 3254 $\lnot\pm$ 671 pmol/L$\lnot\sum$h (P$<$ 0.0001)]. In conclusion, 50 mg DHEA seems to be a suitable substitution dose in elderly men, as it leads to serum DHEAS concentrations usually measured in young healthy adults. The DHEA-induced increase in circulating estrogens may contribute to beneficial effects of DHEA in men.},
  number = {6},
  journal = {Journal of Clinical Endocrinology and Metabolism},
  author = {Arlt, Wiebke and Haas, Joachim and Callies, Frank and Reincke, Martin and H\"ubler, Doris and Oettel, Michael and Ernst, Michael and Schulte, Heinrich Maria and Allolio, Bruno},
  year = {1999},
  keywords = {ADaPT},
  pages = {2170-2176},
  file = {/Users/k/Zotero/storage/ZMNTXTV2/Arlt et al. - 1999 - Biotransformation of oral dehydroepiandrosterone in elderly men Significant increase in circulating estrogens.pdf},
  pmid = {10372727}
}

@article{Hirsch2016,
  title = {{{PD}}-{{L1 Immunohistochemistry Assays}} for {{Lung Cancer}}: {{Results}} from {{Phase}} 1 of the ``{{Blueprint PD}}-{{L1 IHC Assay Comparison Project}}''},
  volume = {12},
  issn = {15560864},
  doi = {10.1016/j.jtho.2016.11.2228},
  abstract = {BACKGROUND The "Blueprint PD-L1 IHC Assay Comparison Project" is an industrial-academic collaborative partnership to provide information on the analytical and clinical comparability of four PD-L1 IHC assays used in clinical trials. METHODS 39 NSCLC tumors were stained with four PD-L1 IHC assays (22C3, 28-8, SP 142 and SP 263) as used in the clinical trials. Three experts in interpreting their respective assays independently evaluated the percentages of tumor and immune cells staining positive at any intensity. Clinical diagnostic performance was assessed through comparisons of patient classification, above and below a selected expression cut-off, and by agreement using various combinations of assays and cutoffs. RESULTS Analytical comparison demonstrated the percentage of PD-L1-stained tumor cells was comparable with 22C3, 28-8 and SP263 assays, while SP142 assay exhibited fewer stained tumor cells overall. The variability of immune cell staining across four assays appears to be higher than for tumor cell staining. 19/38 cases (50.0 \%) were classified above, 5/38 cases (13\%) below the selected cutoffs of all assays. For 14/38 (37\%) cases, different PD-L1 classification would be made depending on which assay / scoring system is used. CONCLUSION The "Blueprint PD-L1 IHC Assay Comparison Project" revealed that three of the four assays were closely aligned on tumor cell staining whilst a fourth showed consistently fewer tumor cells stained. All assays demonstrated immune cell staining, but with greater variability compared to tumor cell staining. By comparing assays and cut-offs, the study indicates that despite similar analytical performance of PD-L1 expression for three assays, interchanging assays and cut-offs will lead to "misclassification" of PD-L1 status for some patients. . More data are required to inform on the use of alternative staining assays upon which to read different specific therapy-related PD-L1 cutoffs.},
  number = {2},
  journal = {Journal of Thoracic Oncology},
  author = {Hirsch, Fred R. and McElhinny, Abigail and Stanforth, Dave and {Ranger-Moore}, James and Jansson, Malinka and Kulangara, Karina and Richardson, William and Towne, Penny and Hanks, Debra and Vennapusa, Bharathi and Mistry, Amita and Kalamegham, Rasika and Averbuch, Steve and Novotny, James and Rubin, Eric and Emancipator, Kenneth and McCaffery, Ian and Williams, J. Andrew and Walker, Jill and Longshore, John and Tsao, Ming S. and Kerr, Keith M.},
  year = {2016},
  keywords = {Immunotherapy,lung cancer,Immunohistochemistry,PD-L1 assays},
  pages = {208-222},
  file = {/Users/k/Zotero/storage/CLCLCXS4/Hirsch et al. - 2016 - PD-L1 Immunohistochemistry Assays for Lung Cancer Results from Phase 1 of the “Blueprint PD-L1 IHC Assay Comp.pdf},
  pmid = {27913228}
}

@book{Machin2008,
  edition = {3rd},
  title = {Sample {{Size Tables}} for {{Clinical Studies}}},
  isbn = {978-1-4051-4650-0},
  publisher = {{Wiley}},
  author = {Machin, David and Campbell, Michael J. and Tan, Say Beng and Ta, Sze Huey},
  year = {2008}
}

@misc{Pinheiro2016,
  title = {Nlme: {{Linear}} and {{Nonlinear Mixed Effects Models}}},
  author = {Pinheiro, Jose and Bates, Douglas and DebRoy, Saikat and Sarkar, Deepayan and {R Development Core Team}},
  year = {2016}
}

@article{Julious2004,
  title = {Tutorial in Biostatistics: {{Sample}} Sizes for Clinical Trials with {{Normal}} Data},
  volume = {23},
  issn = {02776715},
  doi = {10.1002/sim.1783},
  abstract = {This article gives an overview of sample size calculations for parallel group and cross-over studies with Normal data. Sample size derivation is given for trials where the objective is to demonstrate: superiority, equivalence, non-inferiority, bioequivalence and estimation to a given precision, for different types I and II errors. It is demonstrated how the different trial objectives influence the null and alternative hypotheses of the trials and how these hypotheses influence the calculations. Sample size tables for the different types of trials and worked examples are given.},
  number = {12},
  journal = {Statistics in Medicine},
  author = {Julious, Steven A.},
  year = {2004},
  keywords = {Type I error,Power,Sample size,Baselines,Bioequivalence,Cross-over trials,Equivalence trials,Non-inferiority trials,Parallel group trials,Precision,Superiority trials,Type II error},
  pages = {1921-1986},
  file = {/Users/k/Zotero/storage/4GR9J94G/Julious - 2004 - Tutorial in biostatistics Sample sizes for clinical trials with Normal data.pdf},
  pmid = {15195324}
}

@article{Haines2003,
  title = {Bayesian {{Optimal Designs}} for {{Phase I Clinical Trials}}},
  volume = {64},
  journal = {Applied Statistics Series C},
  author = {Liu, Suyu and Yuan, Ying},
  year = {2015},
  keywords = {constrained optimal design,maximum tolerated dose,sequential design},
  pages = {507-523},
  file = {/Users/k/Zotero/storage/DBL5L52F/Liu, Yuan - 2015 - Bayesian Optimal Designs for Phase I Clinical Trials.pdf}
}

@article{Brock2017,
  title = {165: {{PePS2}}: {{Pembrolizumab}} in {{Performance Status}} 2 Non-Small-Cell Lung Cancer},
  volume = {103},
  issn = {01695002},
  doi = {10.1016/S0169-5002(17)30215-5},
  journal = {Lung Cancer},
  author = {Brock, K. and Billingham, C. and Llewellyn, L. and Smith, H. and McNab, G. and Middleton, G.},
  year = {2017},
  keywords = {MyPubs},
  pages = {S76},
  file = {/Users/k/Zotero/storage/DTRA2RMV/Brock et al. - 2017 - 165 PePS2 Pembrolizumab in Performance Status 2 non-small-cell lung cancer.pdf}
}

@article{hirschSeminarLungCancer2017,
  title = {Seminar {{Lung}} Cancer: Current Therapies and New Targeted Treatments},
  volume = {389},
  doi = {10.1016/S0140-6736(16)30958-8},
  abstract = {Lung cancer is the most frequent cause of cancer-related deaths worldwide. Every year, 1$\cdot$8 million people are diagnosed with lung cancer, and 1$\cdot$6 million people die as a result of the disease. 5-year survival rates vary from 4\textendash{}17\% depending on stage and regional diff erences. In this Seminar, we discuss existing treatment for patients with lung cancer and the promise of precision medicine, with special emphasis on new targeted therapies. Some subgroups, eg\textemdash{}patients with poor performance status and elderly patients\textemdash{}are not specifi cally addressed, because these groups require special treatment considerations and no frameworks have been established in terms of new targeted therapies. We discuss prevention and early detection of lung cancer with an emphasis on lung cancer screening. Although we acknowledge the importance of smoking prevention and cessation, this is a large topic beyond the scope of this Seminar.},
  number = {21},
  journal = {www.thelancet.com},
  author = {Hirsch, Fred R and Scagliotti, Giorgio V and Mulshine, James L and Kwon, Regina and Curran, Walter J and Wu, Yi-Long and {Paz-Ares}, Luis},
  year = {2017},
  file = {/Users/k/Zotero/storage/93XQ3GPS/Hirsch et al. - 2017 - Seminar Lung cancer current therapies and new targeted treatments.pdf}
}

@article{Hui2017,
  title = {Pembrolizumab as First-Line Therapy for Patients with {{PD}}-{{L1}}\textendash{}Positive Advanced Non\textendash{}Small Cell Lung Cancer: A Phase 1 Trial},
  doi = {10.1093/annonc/mdx008},
  journal = {Annals of Oncology},
  author = {Hui, R. and Garon, E. B. and Goldman, J. W. and Leighl, N. B. and Hellmann, M. D. and Patnaik, A. and Gandhi, L. and Eder, J. P. and Ahn, M.-J. and Horn, L. and Felip, E. and Carcereny, E. and Rangwala, R. and Lubiniecki, G. M. and Zhang, J. and Emancipator, K. and Roach, C. and Rizvi, N. A.},
  year = {2017},
  keywords = {NSCLC,Pembrolizumab,README,pembrolizumab},
  file = {/Users/k/Zotero/storage/Y25XP3I4/Hui et al. - 2017 - Pembrolizumab as first-line therapy for patients with PD-L1–positive advanced non–small cell lung cancer a phase.pdf},
  pmid = {28168303}
}

@article{Manuscript2011,
  title = {Continual {{Reassessment}} and {{Related Dose}}-{{Finding Designs}}},
  volume = {25},
  doi = {10.1214/10-STS332.Continual},
  number = {2},
  journal = {Statistical Science},
  author = {O'Quigley, John and Conaway, Mark},
  year = {2011},
  keywords = {DoseFinding,efficacy,toxicity,clinical trial,CRM,dose-finding,and phrases,dose escalation,continual reassessment method,trials,phase 1,maximum tolerated dose,bayesian methods,maximum likelihood,most successful dose,phase 2 trials,studies},
  pages = {202-216},
  file = {/Users/k/Zotero/storage/R7RKEVVW/O'Quigley, Conaway - 2011 - Continual Reassessment and Related Dose-Finding Designs.pdf}
}

@article{Tighiouart2010,
  archivePrefix = {arXiv},
  eprinttype = {arxiv},
  eprint = {1011.6479v1},
  title = {Dose {{Finding}} with {{Escalation}} with {{Overdose Control}} ({{EWOC}}) in {{Cancer Clinical Trials}}},
  volume = {25},
  issn = {0883-4237},
  doi = {10.1214/10-STS333},
  abstract = {Traditionally, the major objective in phase I trials is to identify a working-dose for subsequent studies, whereas the major endpoint in phase II and III trials is treatment efficacy. The dose sought is typically referred to as the maximum tolerated dose (MTD). Several statistical methodologies have been proposed to select the MTD in cancer phase I trials. In this manuscript, we focus on a Bayesian adaptive design, known as escalation with overdose control (EWOC). Several aspects of this design are discussed, including large sample properties of the sequence of doses selected in the trial, choice of prior distributions, and use of covariates. The methodology is exemplified with real-life examples of cancer phase I trials. In particular, we show in the recently completed ABR-217620 (naptumomab estafenatox) trial that omitting an important predictor of toxicity when dose assignments to cancer patients are determined results in a high percent of patients experiencing severe side effects and a significant proportion treated at sub-optimal doses.},
  number = {2},
  journal = {Statistical Science},
  author = {Tighiouart, Mourad and Rogatko, Andr\'e},
  year = {2010},
  keywords = {and phrases,cancer phase i trials,dose-limiting toxicity,escalation with overdose control,optimal bayesian fea-,tolerated dose},
  pages = {217-226},
  file = {/Users/k/Zotero/storage/WBRHDKVV/Tighiouart, Rogatko - 2010 - Dose Finding with Escalation with Overdose Control (EWOC) in Cancer Clinical Trials.pdf},
  pmid = {24825779}
}

@article{Chan2017,
  title = {Low-Dose Pembrolizumab for Relapsed/Refractory {{Hodgkin}} Lymphoma: High Efficacy with Minimal Toxicity},
  issn = {0939-5555},
  doi = {10.1007/s00277-017-2931-z},
  journal = {Annals of Hematology},
  author = {Chan, Thomas S. Y. and Luk, Tsan-Hei and Lau, June S. M. and Khong, Pek-Lan and Kwong, Yok-Lam},
  year = {2017},
  keywords = {Pembrolizumab,pembrolizumab,\& Kwong,hodgkin lymphoma,Hodgkin lymphoma,J. S. M.,Khong,Lau,Luk,P.-L.,Refractory,Relapse,relapseChan,T. S. Y.,T.-H.,Y.-L. (2017). Low-dose pembrolizumab for relapsed/},
  file = {/Users/k/Zotero/storage/QXXKX7VZ/Chan et al. - 2017 - Low-dose pembrolizumab for relapsedrefractory Hodgkin lymphoma high efficacy with minimal toxicity.pdf}
}

@article{Shien2016a,
  title = {Predictive Biomarkers of Response to {{PD}}-1/{{PD}}-{{L1}} Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer},
  volume = {99},
  issn = {18728332},
  doi = {10.1016/j.lungcan.2016.06.016},
  abstract = {Inhibitors of the programmed cell death 1 (PD-1) pathway show the potential to substantially increase the efficacy of therapy for various malignancies, including non???small cell lung cancer (NSCLC). At the same time, substantial effort has been invested in finding biomarkers predicting which patients will respond best to this immune checkpoint inhibition. PD-L1 expression in tumor cells and the tumor microenvironment, genetic alterations and mutational load in tumor cells, and pre-existing immunity and its enhancement during treatment through tumor-infiltrating immune cells have been associated with outcomes of immune checkpoint inhibition. Here, we review the reported predictive biomarkers of response to PD-1 pathway immune checkpoint inhibitors in NSCLC, mainly focusing on results obtained with clinical trials.},
  journal = {Lung Cancer},
  author = {Shien, Kazuhiko and Papadimitrakopoulou, Vassiliki A. and Wistuba, Ignacio I.},
  year = {2016},
  keywords = {NSCLC,PD1,Pembrolizumab,pembrolizumab,Biomarker,PD-1,PD-L1,Immune checkpoint inhibition},
  pages = {79-87},
  file = {/Users/k/Zotero/storage/WCNMESFH/Shien, Papadimitrakopoulou, Wistuba - 2016 - Predictive biomarkers of response to PD-1PD-L1 immune checkpoint inhibitors in non-small ce.pdf},
  pmid = {27565919}
}

@article{Lunn2000,
  archivePrefix = {arXiv},
  eprinttype = {arxiv},
  eprint = {1011.1669v3},
  title = {{{WinBUGS}} \textendash{} {{A Bayesian}} Modelling Framework: {{Concepts}}, Structure, and Extensibility},
  volume = {10},
  issn = {09603174},
  doi = {10.1023/A:1008929526011},
  abstract = {WinBUGS is a fully extensible modular framework for constructing and analysing Bayesian full probability models. Models may be specified either textually via the BUGS language or pictorially using a graphical interface called DoodleBUGS. WinBUGS processes the model specification and constructs an object-oriented representation of the model. The software offers a user-interface, based on dialogue boxes and menu commands, throughwhich the modelmay then be analysed using Markov chain Monte Carlo techniques. In this paper we discuss how and why various modern computing concepts, such as object-orientation and run-time linking, feature in the software's design. We also discuss how the framework may be extended. It is possible to write specific applications that form an apparently seamless interface with WinBUGS for users with specialized requirements. It is also possible to interface withWinBUGS at a lower level by incorporating new object types that may be used by WinBUGS without knowledge of the modules in which they are implemented. Neither of these types of extension require access to, or even recompilation of, theWinBUGS source-code.},
  journal = {Statistics and Computing},
  author = {Lunn, David J. and Thomas, Andrew and Best, Nicky and Spiegelhalter, David},
  year = {2000},
  keywords = {bugs,directed acyclic graphs,markov chain monte carlo,object-,orientation,run-time linking,type extension,winbugs},
  pages = {325-337},
  file = {/Users/k/Zotero/storage/Q5XI6PAE/Lunn et al. - 2000 - WinBUGS – A Bayesian modelling framework Concepts, structure, and extensibility.pdf},
  pmid = {2601}
}

@article{Herbst2015,
  title = {Lung {{Master Protocol}} ({{Lung}}-{{MAP}}) - {{A}} Biomarker-Driven Protocol for Accelerating Development of Therapies for Squamous Cell Lung Cancer: {{SWOG S1400}}},
  volume = {21},
  issn = {15573265},
  doi = {10.1158/1078-0432.CCR-13-3473},
  abstract = {The Lung Master Protocol (Lung-MAP, S1400) is a groundbreaking clinical trial designed to advance the efficient development of targeted therapies for squamous cell cancer (SCCA) of the lung. There are no approved targeted therapies specific to advanced lung SCCA, although The Cancer Genome Atlas (TCGA) project and similar studies have detected a significant number of somatic gene mutations/amplifications in lung SCCA, some of which are targetable by investigational agents. However, the frequency of these changes is low (5-20\%), making recruitment and study conduct challenging in the traditional clinical trial setting. Here we describe our approach to development of a biomarker-driven phase 2/3 multi-substudy "Master Protocol," employing a common platform (Next Generation DNA Sequencing) to identify actionable molecular abnormalities, followed by randomization to the relevant targeted therapy versus standard of care.},
  number = {7},
  journal = {Clinical Cancer Research},
  author = {Herbst, Roy S and Gandara, David R and Hirsch, Fred R and Redman, Mary W and LeBlanc, Michael and Mack, Philip C and Schwartz, Lawrence H and Vokes, Everett and Ramalingam, Suresh S and Bradley, Jeffrey D and Sparks, Dana and Zhou, Yang and Miwa, Crystal and Miller, Vincent A and Yelensky, Roman and Li, Yali and Allen, Jeff D and Sigal, Ellen V and Wholley, David and Sigman, Caroline C. and Blumenthal, Gideon M. and Malik, Shakun and Kelloff, Gary J. and Abrams, Jeffrey S. and Blanke, Charles D. and Papadimitrakopoulou, Vassiliki A.},
  year = {2015},
  pages = {1514-1524},
  file = {/Users/k/Zotero/storage/385FSRDC/Herbst et al. - 2015 - Lung Master Protocol (Lung-MAP) - A biomarker-driven protocol for accelerating development of therapies for squam.pdf},
  pmid = {25680375}
}

@article{Stock2012,
  title = {Efficacy and Safety of {{CE}}-224,535, an Antagonist of {{P2X7}} Receptor, in Treatment of Patients with Rheumatoid Arthritis Inadequately Controlled by Methotrexate},
  volume = {39},
  issn = {0315162X},
  doi = {10.3899/jrheum.110874},
  abstract = {OBJECTIVE: To evaluate efficacy and safety of CE-224,535, a selective P2X(7) receptor antagonist, versus placebo, in patients with active rheumatoid arthritis (RA) and inadequate response to methotrexate (MTX).$\backslash$n$\backslash$nMETHODS: In our phase IIA study (ClinicalTrials.gov no. NCT00628095; A6341009), patients aged $\geq$ 18 years with active RA were randomized to receive either CE-224,535 (500 mg bid) or placebo for 12 weeks; all patients continued a stable background dose of $\geq$ 7.5 mg MTX.$\backslash$n$\backslash$nRESULTS: The American College of Rheumatology 20\% (ACR20) response rate (primary efficacy endpoint) was not significantly different from placebo for CE-224,535 (34.0\% vs 36.2\%; p = 0.591) at Week 12, or at any timepoint over the 12-week treatment period. There was no significant difference at Week 12 for the ACR20 response rate following subgroup analyses by age, sex, baseline disease activity, baseline duration of disease, geographic region, or concomitant use of steroids. ACR50/ACR70 response rates and change from baseline in Disease Activity Score 28-joint C-reactive protein (DAS28-3-CRP) and Health Assessment Questionnaire-Disability Index for CE-224,535 were not significant at Week 12 versus placebo. Treatment-emergent adverse events (AE) were reported by 62.3\% (CE-224,535) and 55.3\% (placebo) of patients; the most common AE were nausea (11.3\%, CE-224,535; 4.3\%, placebo) and diarrhea (7.5\%, CE-224,535; 4.3\%, placebo). The proportion of patients discontinuing due to an AE was 9.4\% (CE-224,535) and 6.4\% (placebo); no deaths were reported. Serious AE occurred in 3.8\% (CE-224,535) and 2.1\% (placebo) of patients; none was considered treatment-related.$\backslash$n$\backslash$nCONCLUSION: CE-224,535 was not efficacious, compared with placebo, for the treatment of RA in patients with an inadequate response to MTX. CE-224,535 demonstrated an acceptable safety and tolerability profile.},
  number = {4},
  journal = {Journal of Rheumatology},
  author = {Stock, Thomas C. and Bloom, Bradley J. and Wei, Nathan and Ishaq, Saliha and Park, Won and Wang, Xin and Gupta, Pankaj and Mebus, Charles A.},
  year = {2012},
  keywords = {TBI,CE-224-535,Interleukin 1,Interleukin 18,Purinergic P2X7 receptor,Rheumatoid arthritis},
  pages = {720-727},
  file = {/Users/k/Zotero/storage/BZVX8VUV/Stock et al. - 2012 - Efficacy and safety of CE-224,535, an antagonist of P2X7 receptor, in treatment of patients with rheumatoid arthri.pdf},
  pmid = {22382341}
}

@article{Armstrong2016,
  title = {Liraglutide Safety and Efficacy in Patients with Non-Alcoholic Steatohepatitis ({{LEAN}}): {{A}} Multicentre, Double-Blind, Randomised, Placebo-Controlled Phase 2 Study},
  volume = {387},
  issn = {1474547X},
  doi = {10.1016/S0140-6736(15)00803-X},
  abstract = {Summary Background Glucagon-like peptide-1 (GLP-1) analogues reduce hepatic steatosis, concentrations of liver enzymes, and insulin resistance in murine models of fatty liver disease. These analogues are licensed for type 2 diabetes, but their efficacy in patients with non-alcoholic steatohepatitis is unknown. We assessed the safety and efficacy of the long-acting GLP-1 analogue, liraglutide, in patients with non-alcoholic steatohepatitis. Methods This multicentre, double-blinded, randomised, placebo-controlled phase 2 trial was conducted in four UK medical centres to assess subcutaneous injections of liraglutide (1??8 mg daily) compared with placebo for patients who are overweight and show clinical evidence of non-alcoholic steatohepatitis. Patients were randomly assigned (1:1) using a computer-generated, centrally administered procedure, stratified by trial centre and diabetes status. The trial was designed using A'Hern's single-group method, which required eight (38\%) of 21 successes in the liraglutide group for the effect of liraglutide to be considered clinically significant. Patients, investigators, clinical trial site staff, and pathologists were masked to treatment assignment throughout the study. The primary outcome measure was resolution of definite non-alcoholic steatohepatitis with no worsening in fibrosis from baseline to end of treatment (48 weeks), as assessed centrally by two independent pathologists. Analysis was done by intention-to-treat analysis, which included all patients who underwent end-of-treatment biopsy. The trial was registered with ClinicalTrials.gov, number NCT01237119. Findings Between Aug 1, 2010, and May 31, 2013, 26 patients were randomly assigned to receive liraglutide and 26 to placebo. Nine (39\%) of 23 patients who received liraglutide and underwent end-of-treatment liver biopsy had resolution of definite non-alcoholic steatohepatitis compared with two (9\%) of 22 such patients in the placebo group (relative risk 4??3 [95\% CI 1??0-17??7]; p=0??019). Two (9\%) of 23 patients in the liraglutide group versus eight (36\%) of 22 patients in the placebo group had progression of fibrosis (0??2 [0??1-1??0]; p=0??04). Most adverse events were grade 1 (mild) to grade 2 (moderate) in severity, transient, and similar in the two treatment groups for all organ classes and symptoms, with the exception of gastrointestinal disorders in 21 (81\%) of 23 patients in the liraglutide group and 17 (65\%) of 22 patients in the placebo group, which included diarrhoea (ten [38\%] patients in the liraglutide group vs five [19\%] in the placebo group), constipation (seven [27\%] vs none), and loss of appetite (eight [31\%] vs two [8\%]). Interpretation Liraglutide was safe, well tolerated, and led to histological resolution of non-alcoholic steatohepatitis, warranting extensive, longer-term studies. Funding Wellcome Trust, National Institute of Health Research, and Novo Nordisk.},
  number = {10019},
  journal = {The Lancet},
  author = {Armstrong, Matthew James and Gaunt, Piers and Aithal, Guruprasad P. and Barton, Darren and Hull, Diana and Parker, Richard and Hazlehurst, Jonathan M. and Guo, Kathy and Abouda, George and Aldersley, Mark A. and Stocken, Deborah and Gough, Stephen C. and Tomlinson, Jeremy W. and Brown, Rachel M. and H\"ubscher, Stefan G. and Newsome, Philip N.},
  year = {2016},
  keywords = {Piers,Steatohepatitis},
  pages = {679-690},
  file = {/Users/k/Zotero/storage/6BHBZSMU/Armstrong et al. - 2016 - Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN) A multicentre, double-bl.pdf},
  pmid = {26608256}
}

@article{Wages2014a,
  title = {Pocrm: {{An R}}-Package for {{Phase I}} Trials of Combinations of Agents},
  volume = {112},
  doi = {10.1016/j.cmpb.2013.05.020.pocrm},
  number = {1},
  journal = {Comput Methods Programs Biomed},
  author = {Wages, Nolan A. and Varhegyir, Nikole},
  year = {2014},
  keywords = {drug combination,continual reassessment method,dose finding,partial ordering,phase i trials},
  pages = {211-8},
  file = {/Users/k/Zotero/storage/NXXIJHC6/Wages, Varhegyir - 2014 - pocrm An R-package for Phase I trials of combinations of agents.pdf}
}

@article{Helmy2012,
  title = {Principal Component Analysis of the {{Cytokine}} and {{Chemokine}} Response to Human Traumatic Brain Injury},
  volume = {7},
  issn = {19326203},
  doi = {10.1371/journal.pone.0039677},
  abstract = {There is a growing realisation that neuro-inflammation plays a fundamental role in the pathology of Traumatic Brain Injury (TBI). This has led to the search for biomarkers that reflect these underlying inflammatory processes using techniques such as cerebral microdialysis. The interpretation of such biomarker data has been limited by the statistical methods used. When analysing data of this sort the multiple putative interactions between mediators need to be considered as well as the timing of production and high degree of statistical co-variance in levels of these mediators. Here we present a cytokine and chemokine dataset from human brain following human traumatic brain injury and use principal component analysis and partial least squares discriminant analysis to demonstrate the pattern of production following TBI, distinct phases of the humoral inflammatory response and the differing patterns of response in brain and in peripheral blood. This technique has the added advantage of making no assumptions about the Relative Recovery (RR) of microdialysis derived parameters. Taken together these techniques can be used in complex microdialysis datasets to summarise the data succinctly and generate hypotheses for future study.},
  number = {6},
  journal = {PLoS ONE},
  author = {Helmy, Adel and Antoniades, Chrystalina A. and Guilfoyle, Mathew R. and Carpenter, Keri L H and Hutchinson, Peter J.},
  year = {2012},
  keywords = {TBI,P2X7Project},
  pages = {1-14},
  file = {/Users/k/Zotero/storage/S4KP3Q4M/Helmy et al. - 2012 - Principal component analysis of the Cytokine and Chemokine response to human traumatic brain injury.pdf},
  pmid = {22745809}
}

@article{Morganti-Kossman1997,
  title = {Production of Cytokines Following Brain Injury: Beneficial and Deleterious for the Damaged Tissue.},
  volume = {2},
  issn = {1359-4184},
  doi = {10.1038/sj.mp.4000227},
  abstract = {A profound inflammatory response is initiated immediately following traumatic brain injury (TBI) and is characterized by the release of several cytokines with pro- and anti-inflammatory functions. In order to elucidate which cytokines are released in the human brain in response to injury as well as in the peripheral compartment, IL-1, IL-6, IL-8, IL-10, TNF-alpha and TGF-beta were monitored in CSF and serum of severely brain-injured patients. Furthermore, we investigated the possible modulation of systemic reactions by IL-6 and the ability of IL-6 and IL-8 to promote the synthesis of nerve growth factor.},
  journal = {Molecular psychiatry},
  author = {{Morganti-Kossman}, M C and Lenzlinger, P M and Hans, V and Stahel, P and Csuka, E and Ammann, E and Stocker, R and Trentz, O and Kossmann, T},
  year = {1997},
  keywords = {TBI,P2X7Project,a profound inflammatory response,acute-phase-response,alpha,astrocytes,blood,brain barrier,brain injury,interleukins,is initiated immedi-,nerve growth factor,transforming growth factor-beta,tumor necrosis factor-},
  pages = {133-136},
  file = {/Users/k/Zotero/storage/SGCV9U3L/Morganti-Kossman et al. - 1997 - Production of cytokines following brain injury beneficial and deleterious for the damaged tissue.pdf},
  pmid = {9106236}
}

@article{CytokineMeans,
  title = {Cytokine Means},
  keywords = {TBI,P2X7Project},
  file = {/Users/k/Zotero/storage/N8U5FHMV/Unknown - Unknown - Cytokine means.pdf}
}

@article{Helmy2011,
  archivePrefix = {arXiv},
  eprinttype = {arxiv},
  eprint = {0808.1443},
  title = {Cytokines and Innate Inflammation in the Pathogenesis of Human Traumatic Brain Injury},
  volume = {95},
  issn = {03010082},
  doi = {10.1016/j.pneurobio.2011.09.003},
  abstract = {There is an increasing recognition that following traumatic brain injury, a cascade of inflammatory mediators is produced, and contributes to the pathological consequences of central nervous system injury. This review summarises the key literature from pre-clinical models that underlies our understanding of innate inflammation following traumatic brain injury before focussing on the growing evidence from human studies. In addition, the underlying molecular mediators responsible for blood brain barrier dysfunction have been discussed. In particular, we have highlighted the different sampling methodologies available and the difficulties in interpreting human data of this sort. Ultimately, understanding the innate inflammatory response to traumatic brain injury may provide a therapeutic avenue in the treatment of central nervous system disease. ?? 2011 Elsevier Ltd.},
  number = {3},
  journal = {Progress in Neurobiology},
  author = {Helmy, Adel and De Simoni, Maria Grazia and Guilfoyle, Mathew R. and Carpenter, Keri L H and Hutchinson, Peter J.},
  year = {2011},
  keywords = {TBI,P2X7Project,Blood brain barrier,Cerebrospinal fluid,Cytokines,Inflammation,Microdialysis,Traumatic brain injury},
  pages = {352-372},
  file = {/Users/k/Zotero/storage/NYH6V7QB/Helmy et al. - 2011 - Cytokines and innate inflammation in the pathogenesis of human traumatic brain injury.pdf},
  pmid = {21939729}
}

@article{Hutchinson2007,
  title = {Inflammation in Human Brain Injury: Intracerebral Concentrations of {{IL}}-1alpha, {{IL}}-1beta, and Their Endogenous Inhibitor {{IL}}-1ra.},
  volume = {24},
  issn = {0897-7151},
  doi = {10.1089/neu.2007.0295},
  abstract = {Following traumatic brain injury (TBI), cascades of inflammatory processes occur. Laboratory studies implicate the cytokines interleukin-1alpha (IL-1alpha) and IL-1beta in the pathophysiology of TBI and cerebral ischemia, whilst exogenous and endogenous interleukin-1 receptor antagonist (IL-1ra) is neuroprotective. We analyzed IL-1alpha, IL-1beta, and IL-1ra in brain microdialysates (100-kDa membrane) in 15 TBI patients. We also analyzed energy-related molecules (glucose, lactate, pyruvate, glutamate, and the lactate/pyruvate ratio) in these brain microdialysates. Mean of mean (+/-SD) in vitro microdialysis percentage recoveries (extraction efficiencies) were IL-1alpha 19.7+/-7.6\%, IL-1beta 23.9+/-10.5\%, and IL-1ra 20.9+/-6.3\%. In the patients' brain microdialysates, mean of mean cytokine concentrations (not corrected for percentage recovery) were IL-1alpha 5.6+/-14.8 pg/mL, IL-1beta 10.4+/-14.7 pg/mL, and IL-1ra 2796+/-2918 pg/mL. IL-1ra was consistently much higher than IL-1alpha and IL-1beta. There were no significant relationships between IL-1 family cytokines and energy-related molecules. There was a significant correlation between increasing IL-1beta and increasing IL-1ra (Spearman r=0.59, p=0.028). There was also a significant relationship between increasing IL-1ra and decreasing intracranial pressure (Spearman r=-0.57, p=0.041). High concentrations of IL-1ra, and also high IL-1ra/IL-1beta ratio, were associated with better outcome (Mann Whitney, p=0.018 and p=0.0201, respectively), within these 15 patients. It is unclear whether these IL-1ra concentrations are sufficient to antagonize the effects of IL-1beta in vivo. This study demonstrates feasibility of our microdialysis methodology in recovering IL-1 family cytokines for assessing their inter-relationships in the injured human brain, and suggests a neuroprotective role for IL-1ra. It remains to be seen whether exogenous IL-1ra or other agents can be used to manipulate cytokine levels in the brain, for potential therapeutic effect.},
  number = {10},
  journal = {Journal of neurotrauma},
  author = {Hutchinson, Peter J and O'Connell, Mark T and Rothwell, Nancy J and Hopkins, Stephen J and Nortje, J\"urgens and Carpenter, Keri L H and Timofeev, Ivan and {Al-Rawi}, Pippa G and Menon, David K and Pickard, John D},
  year = {2007},
  keywords = {TBI,P2X7Project,head trauma,inflammation,microdialysis},
  pages = {1545-1557},
  file = {/Users/k/Zotero/storage/JRCTZQHH/Hutchinson et al. - 2007 - Inflammation in human brain injury intracerebral concentrations of IL-1alpha, IL-1beta, and their endogenous.pdf},
  pmid = {17970618}
}

@article{Oriana2013,
  title = {Complete Cytogenetic Response and Major Molecular Response as Surrogate Outcomes for Overall Survival in First-Line Treatment of Chronic Myelogenous Leukemia: {{A}} Case Study for Technology Appraisal on the Basis of Surrogate Outcomes Evidence},
  volume = {16},
  issn = {10983015},
  doi = {10.1016/j.jval.2013.07.004},
  abstract = {Objectives In 2012, the National Institute for Health and Care Excellence assessed dasatinib, nilotinib, and standard-dose imatinib as first-line treatment of chronic phase chronic myelogenous leukemia (CML). Licensing of these alternative treatments was based on randomized controlled trials assessing complete cytogenetic response (CCyR) and major molecular response (MMR) at 12 months as primary end points. We use this case study to illustrate the validation of CCyR and MMR as surrogate outcomes for overall survival in CML and how this evidence was used to inform National Institute for Health and Care Excellence's recommendation on the public funding of these first-line treatments for CML. Methods We undertook a systematic review and meta-analysis to quantify the association between CCyR and MMR at 12 months and overall survival in patients with chronic phase CML. We estimated life expectancy by extrapolating long-term survival from the weighted overall survival stratified according to the achievement of CCyR and MMR. Results Five studies provided data on the observational association between CCyR or MMR and overall survival. Based on the pooled association between CCyR and MMR and overall survival, our modeling showed comparable predicted mean duration of survival (21-23 years) following first-line treatment with imatinib, dasatinib, or nilotinib. Conclusions This case study illustrates the consideration of surrogate outcome evidence in health technology assessment. Although it is often recommended that the acceptance of surrogate outcomes be based on randomized controlled trial data demonstrating an association between the treatment effect on both the surrogate outcome and the final outcome, this case study shows that policymakers may be willing to accept a lower level of evidence (i.e., observational association). ?? 2013 International Society for Pharmacoeconomics and Outcomes Research (ISPOR).},
  number = {6},
  journal = {Value in Health},
  author = {Oriana, Ciani and Martin, Hoyle and Toby, Pavey and Chris, Cooper and Ruth, Garside and Claudius, Rudin and Rod, Taylor},
  year = {2013},
  keywords = {SurrogateOutcomes,CML,chronic myeloid leukemia complete cytogenetic resp},
  pages = {1081-1090},
  file = {/Users/k/Zotero/storage/MBTBTKKF/Oriana et al. - 2013 - Complete cytogenetic response and major molecular response as surrogate outcomes for overall survival in first-li.pdf},
  pmid = {24041359}
}

@article{Morris,
  title = {Using Simulation Studies to Evaluate Statistical Methods},
  abstract = {Simulation studies are computer experiments which involve creating data by pseudo-random sampling. The key strength of simulation studies is the ability to understand the behaviour of statistical methods because some 'truth' is known from the pro-cess of generating the data. This allows us to consider properties of methods, such as bias. While widely used, simulation studies are often poorly designed, analysed and reported. This article outlines the rationale for using simulation studies and offers guidance for design, execution, analysis, reporting and presentation. In par-ticular, we provide: a structured approach for planning and reporting simulation studies; coherent terminology for simulation studies; guidance on coding simulation studies; a critical discussion of key performance measures and their computation; ideas on structuring tabular and graphical presentation of results; and new graphical presentations. With a view to describing current practice and identifying areas for improvement, we review 100 articles taken from Volume 34 of Statistics in Medicine which included at least one simulation study.},
  author = {Morris, Tim P and White, Ian R and Crowther, Michael J},
  file = {/Users/k/Zotero/storage/B858ZY2T/Morris, White, Crowther - Unknown - Using simulation studies to evaluate statistical methods(2).pdf;/Users/k/Zotero/storage/CPA7ISHN/Morris et al - Simulations tutorial - Jul 2018 version.pdf}
}

@article{Mayo2011,
  title = {You {{May Believe You Are}} a {{Bayesian But You Are Probably Wrong}}},
  volume = {2},
  abstract = {An elementary sketch of some issues in statistical inference and in particular of the cen-tral role of likelihood is given. This is followed by brief outlines of what George Barnard considered were the four great systems of statistical inferences. These can be thought of terms of the four combinations of two factors at two levels. The first is fundamental pur-pose (decision or inference) and the second probability argument (direct or inverse). Of these four systems the 'fully Bayesian' approach of decision-making using inverse proba-bility particularly associated with the Ramsay, De Finetti, Savage and Lindley has some claims to be the most impressive. It is claimed, however, and illustrated by example, that this approach seems to be impossible to follow. It is speculated that there may be some advantage to the practising statistician to follow George Barnard's advice of being familiar with all four systems.},
  journal = {RMM},
  author = {Mayo, Deborah G and Spanos, Aris and Staley, Kent W and Senn, Stephen},
  year = {2011},
  pages = {48-66},
  file = {/Users/k/Zotero/storage/65DM6M2K/Mayo et al. - 2011 - You May Believe You Are a Bayesian But You Are Probably Wrong.pdf}
}

@article{Dohner2017,
  title = {Diagnosis and Management of {{AML}} in Adults: 2017 {{ELN}} Recommendations from an International Expert Panel},
  volume = {129},
  issn = {0006-4971 (Print)},
  doi = {10.1182/blood-2016-08-733196},
  abstract = {The first edition of the European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) in adults, published in 2010, has found broad acceptance by physicians and investigators caring for patients with AML. Recent advances, for example, in the discovery of the genomic landscape of the disease, in the development of assays for genetic testing and for detecting minimal residual disease (MRD), as well as in the development of novel antileukemic agents, prompted an international panel to provide updated evidence- and expert opinion-based recommendations. The recommendations include a revised version of the ELN genetic categories, a proposal for a response category based on MRD status, and criteria for progressive disease.},
  language = {eng},
  number = {4},
  journal = {Blood},
  author = {D\"ohner, Hartmut and Estey, Elihu and Grimwade, David and Amadori, Sergio and Appelbaum, Frederick R and B\"uchner, Thomas and Dombret, Herv\'e and Ebert, Benjamin L and Fenaux, Pierre and Larson, Richard A and Levine, Ross L and {Lo-Coco}, Francesco and Naoe, Tomoki and Niederwieser, Dietger and Ossenkoppele, Gert J and Sanz, Miguel and Sierra, Jorge and Tallman, Martin S and Tien, Hwei-Fang and Wei, Andrew H and L\"owenberg, Bob and Bloomfield, Clara D},
  month = jan,
  year = {2017},
  pages = {424-447},
  pmid = {27895058},
  note = {Place: Washington, DC}
}

@article{Konopleva2015,
  title = {Phase {{I}}/{{II}} Study of the Hypoxia-Activated Prodrug {{PR104}} in Refractory/Relapsed Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia},
  volume = {100},
  issn = {15928721},
  doi = {10.3324/haematol.2014.118455},
  abstract = {We previously demonstrated vast expansion of hypoxic areas in the leukemic microenvironment and provided rationale for using hypoxia-activated prodrugs. PR104 is a phosphate ester that is rapidly hydrolyzed in vivo to the corresponding alcohol PR-104A and further reduced to the amine and hydroxyl-amine nitrogen mustards that induce DNA cross-linking in hypoxic cells under low oxygen concentrations. In this phase I/II study, patients with relapsed/refractory acute myeloid leukemia (n=40) after 1 or 2 prior treatments or acute lymphoblastic leukemia (n=10) after any number of prior treatments received PR104, dose ranges of 1.1 to 4 g/m2. The most common treatment-related grade 3/4 adverse events were myelosuppression (anemia 62\%, neutropenia 50\%, thrombocytopenia 46\%), febrile neutropenia (40\%), infection (24\%), and enterocolitis (14\%). Ten of 31 patients with acute myeloid leukemia (32\%) and 2 of 10 patients with acute lymphoblastic leukemia (20\%) who received 3 g/m2 or 4 g/m2 had a response (complete response, n=1; complete response without platelet recovery, n=5; morphologic leukemia-free state, n=6). The extent of hypoxia was evaluated by the hypoxia tracer pimonidazole administered prior to a bone marrow biopsy and by immunohistochemical assessments of hypoxia-inducible factor alpha and carbonic anhydrase IX. A high fraction of leukemic cells expressed these markers, and PR104 administration resulted in measurable decrease of the proportions of hypoxic cells. These findings indicate that hypoxia is a prevalent feature of the leukemic microenvironment and that targeting hypoxia with hypoxia-activated prodrugs warrants further evaluation in acute leukemia. The trial is registered at ClinicalTrials.gov as NCT 01037556.},
  number = {7},
  journal = {e},
  author = {Konopleva, Marina and Thall, Peter F. and Yi, Cecilia Arana and Borthakur, Gautam and Coveler, Andrew and {Bueso-Ramos}, Carlos and Benito, Juliana and Konoplev, Sergej and Gu, Yongchuan and Ravandi, Farhad and Jabbour, Elias and Faderl, Stefan and Thomas, Deborah and Cortes, Jorge and Kadia, Tapan and Kornblau, Steven and Daver, Naval and Pemmaraju, Naveen and Nguyen, Hoang Q. and Feliu, Jennie and Lu, Hongbo and Wei, Caimiao and Wilson, William R. and Melink, Teresa J. and Gutheil, John C. and Andreeff, Michael and Estey, Elihu H. and Kantarjian, Hagop},
  year = {2015},
  pages = {927-934},
  file = {/Users/k/Zotero/storage/GXLLJFTI/Konopleva et al. - 2015 - Phase III study of the hypoxia-activated prodrug PR104 in refractoryrelapsed acute myeloid leukemia and acute.pdf},
  pmid = {25682597}
}

@article{Petrillo2017,
  title = {Development of a New {{Rasch}}-Based Scoring Algorithm for the {{National Eye Institute Visual Functioning Questionnaire}} to Improve Its Interpretability},
  volume = {15},
  issn = {1477-7525},
  doi = {10.1186/s12955-017-0726-5},
  number = {1},
  journal = {Health and Quality of Life Outcomes},
  author = {Petrillo, Jennifer and Bressler, Neil M. and Lamoureux, Ecosse and Ferreira, Alberto and Cano, Stefan},
  year = {2017},
  keywords = {functioning questionnaire,national eye institute visual,National Eye Institute Visual Functioning Question,rasch measurement theory,vision-related},
  pages = {157},
  file = {/Users/k/Zotero/storage/P3PLNNGS/Petrillo et al. - 2017 - Development of a new Rasch-based scoring algorithm for the National Eye Institute Visual Functioning Questionna.pdf}
}

@article{Burkner2017a,
  archivePrefix = {arXiv},
  eprinttype = {arxiv},
  eprint = {1705.11123},
  title = {Bayesian {{Distributional Non}}-{{Linear Multilevel Modeling}} with the {{R Package}} Brms},
  abstract = {The brms package allows R users to easily specify a wide range of Bayesian multilevel models, which are fitted with the probabilistic programming language Stan behind the scenes. A wide range of response distributions are supported in combination with an intuitive and powerful multilevel formula syntax. Non-linear relationships may be specified using non-linear predictor terms, splines or Gaussian processes. Additionally, all parameters of the response distribution can be predicted at the same time allowing for distributional regression. Model fit can be investigated and compared using leave-one-out cross-validation and graphical posterior-predictive checks. Many more post-processing and plotting methods are implemented.},
  number = {1},
  author = {B\"urkner, Paul-Christian},
  year = {2017},
  keywords = {bayesian inference,distributional models,lme4,multilevel models,r,stan},
  file = {/Users/k/Zotero/storage/RSSF8FB9/Bürkner - 2017 - Bayesian Distributional Non-Linear Multilevel Modeling with the R Package brms.pdf}
}

@article{Gelman2017a,
  archivePrefix = {arXiv},
  eprinttype = {arxiv},
  eprint = {1708.07487v2},
  title = {The Prior Can Generally Only Be Understood in the Context of the Likelihood},
  abstract = {A key sticking point of Bayesian analysis is the choice of prior distribution, and there is a vast literature on potential defaults including uniform priors, Jeffreys' priors, reference pri-ors, maximum entropy priors, and weakly informative priors. These methods, however, often manifest a key conceptual tension in prior modeling: a model encoding true prior information should be chosen without reference to the model of the measurement process, but almost all common prior modeling techniques are implicitly motivated by a reference likelihood. In this paper we resolve this apparent paradox by placing the choice of prior into the context of the entire Bayesian analysis, from inference to prediction to model evaluation.},
  author = {Gelman, Andrew and Simpson, Daniel and Betancourt, Michael},
  year = {2017},
  keywords = {BayesCore},
  file = {/Users/k/Zotero/storage/37E3DHPV/Gelman, Simpson, Betancourt - 2017 - Priors can only be understood.pdf}
}

@article{Ying2017a,
  title = {Tutorial on {{Biostatistics}}: {{Linear Regression Analysis}} of {{Continuous Correlated Eye Data}}},
  volume = {24},
  issn = {17445086},
  doi = {10.1080/09286586.2016.1259636},
  number = {2},
  journal = {Ophthalmic Epidemiology},
  author = {shuang Ying, Gui and Maguire, Maureen G. and Glynn, Robert and Rosner, Bernard},
  year = {2017},
  keywords = {Correlated data,generalized estimating equations,inter-eye correlation,linear regression models,marginal model,mixed effects model},
  pages = {130-140},
  file = {/Users/k/Zotero/storage/B4Z2B9MN/Ying et al_2017_Tutorial on Biostatistics.pdf},
  pmid = {28102741}
}

@article{Ying2017,
  title = {Tutorial on {{Biostatistics}}: {{Statistical Analysis}} for {{Correlated Binary Eye Data}}},
  volume = {6586},
  issn = {17445086},
  doi = {10.1080/09286586.2017.1320413},
  abstract = {PURPOSE: To describe and demonstrate methods for analyzing correlated binary eye  data. METHODS: We describe non-model based (McNemar's test, Cochran-Mantel-Haenszel test) and model-based methods (generalized linear mixed effects model, marginal model) for analyses involving both eyes. These methods were applied to: (1) CAPT (Complications of Age-related Macular Degeneration Prevention Trial) where one eye was treated and the other observed (paired design); (2) ETROP (Early Treatment for Retinopathy of Prematurity) where bilaterally affected infants had one eye treated conventionally and the other treated early and unilaterally affected infants had treatment assigned randomly; and (3) AREDS (Age-Related Eye Disease Study) where treatment was systemic and outcome was eye-specific (both eyes in the same treatment group). RESULTS: In the CAPT (n = 80), treatment group (30\% vision loss in treated vs. 44\% in observed eyes) was not statistically significant (p = 0.07) when inter-eye correlation was ignored, but was significant (p = 0.01) with McNemar's test and the marginal model. Using standard logistic regression for unfavorable vision in ETROP, standard errors and p-values were larger for person-level covariates and were smaller for ocular covariates than using models accounting for inter-eye correlation. For risk factors of geographic atrophy in AREDS, two-eye analyses accounting for inter-eye correlation yielded more power than one-eye analyses and provided larger standard errors and p-values than invalid two-eye analyses ignoring inter-eye correlation. CONCLUSION: Ignoring inter-eye correlation can lead to larger p-values for paired designs and smaller p-values when both eyes are in the same group. Marginal models or mixed effects models using the eye as the unit of analysis provide valid inference.},
  number = {May},
  journal = {Ophthalmic Epidemiology},
  author = {shuang Ying, Gui and Maguire, Maureen G. and Glynn, Robert and Rosner, Bernard},
  year = {2017},
  keywords = {Correlated binary data,generalized estimating equations,inter-eye correlation,marginal model,generalized linear mixed effects model},
  pages = {1-12},
  file = {/Users/k/Zotero/storage/JFLB2CIS/Ying et al_2017_Tutorial on Biostatistics.pdf},
  pmid = {28532207}
}

@article{Senn2005,
  title = {Dichotomania: An Obsessive Compulsive Disorder That Is Badly Affecting the Quality of Analysis of Pharmaceutical Trials},
  number = {May},
  journal = {Proceedings of the International Statistical Institute, 55th Session},
  author = {Senn, Stephen J},
  year = {2005},
  pages = {1-13},
  file = {/Users/k/Zotero/storage/VIMARLCB/Senn - 2005 - Dichotomania an obsessive compulsive disorder that is badly affecting the quality of analysis of pharmaceutical trials.pdf}
}

@article{Hornik,
  title = {Who {{Did What}}? {{The Roles}} of {{R Package Authors}} and {{How}} to {{Refer}} to {{Them}}},
  abstract = {Computational infrastructure for rep-resenting persons and citations has been avail-able in R for several years, but has been restruc-tured through enhanced classes "person" and "bibentry" in recent versions of R. The new features include support for the specification of the roles of package authors (e.g. maintainer, author, contributor, translator, etc.) and more flexible formatting/printing tools among vari-ous other improvements. Here, we introduce the new classes and their methods and indicate how this functionality is employed in the man-agement of R packages. Specifically, we show how the authors of R packages can be specified along with their roles in package 'DESCRIPTION' and/or 'CITATION' files and the citations pro-duced from it. R packages are the result of scholarly activity and as such constitute scholarly resources which must be clearly identifiable for the respective scientific com-munities and, more generally, today's information society. In particular, packages published by stan-dard repositories can be regarded as reliable sources which can and should be referenced (i.e. cited) by sci-entific works such as articles or other packages. This requires conceptual frameworks and computational infrastructure for describing bibliographic resources, general enough to encompass the needs of commu-nities with an interest in R. These needs include sup-port for exporting bibliographic metadata in stan-dardized formats such as BIBT E X (Berry and Patash-nik, 2010), but also facilitating bibliometric analyses and investigations of the social fabric underlying the creation of scholarly knowledge. The latter requires a richer vocabulary than com-monly employed by reference management software such as BIBT E X, identifying persons and their roles in relation to bibliographic resources. For example, a thesis typically has an author and advisors. Software can have an (original) author and a translator to an-other language (such as from S to R). The maintainer of an R package is not necessarily an author. In this paper, we introduce the base R infras-tructure (as completely available in R since version 2.14.0) for representing and manipulating such schol-arly data: objects of class "person" (hereafter, per-son objects) hold information about persons, possi-bly including their roles; objects of class "bibentry" (hereafter, bibentry objects) hold bibliographic infor-mation in enhanced BIBT E X style, ideally using per-son objects when referring to persons (such as au-thors or editors). Furthermore, we indicate how this functionality is employed in the management of R packages, in particular in their 'CITATION' and 'DESCRIPTION' files.},
  author = {Hornik, Kurt and Murdoch, Duncan and Zeileis, Achim},
  file = {/Users/k/Zotero/storage/FZ72SKGR/Hornik, Murdoch, Zeileis - Unknown - Who Did What The Roles of R Package Authors and How to Refer to Them.pdf}
}

@article{Gelman2012a,
  archivePrefix = {arXiv},
  eprinttype = {arxiv},
  eprint = {0907.2478},
  title = {Why {{We}} ({{Usually}}) {{Don}}'t {{Have}} to {{Worry About Multiple Comparisons}}},
  volume = {5},
  issn = {19345747},
  doi = {10.1080/19345747.2011.618213},
  abstract = {Applied researchers often find themselves making statistical inferences in settings that would seem to require multiple comparisons adjustments. We challenge the Type I error paradigm that underlies these corrections. Moreover we posit that the problem of multiple comparisons can disappear entirely when viewed from a hierarchical Bayesian perspective. We propose building multilevel models in the settings where multiple comparisons arise. Multilevel models perform partial pooling (shifting estimates toward each other), whereas classical procedures typically keep the centers of intervals stationary, adjusting for multiple comparisons by making the intervals wider (or, equivalently, adjusting the \$p\$-values corresponding to intervals of fixed width). Thus, multilevel models address the multiple comparisons problem and also yield more efficient estimates, especially in settings with low group-level variation, which is where multiple comparisons are a particular concern.},
  number = {2},
  journal = {Journal of Research on Educational Effectiveness},
  author = {Gelman, Andrew and Hill, Jennifer and Yajima, Masanao},
  year = {2012},
  keywords = {Bayesian inference,multiple comparisons,hierarchical modeling,statistical significance,Type S error},
  pages = {189-211},
  file = {/Users/k/Zotero/storage/Z6RWWBMZ/Gelman, Hill, Yajima - 2012 - Why We (Usually) Don't Have to Worry About Multiple Comparisons.pdf},
  pmid = {74012688}
}

@article{Cumberland2014,
  title = {Ophthalmic Statistics Note: The Perils of Dichotomising Continuous Variables},
  volume = {98},
  issn = {0007-1161},
  doi = {10.1136/bjophthalmol-2014-304930},
  abstract = {Continuous variables (such as intraocular pressure (IOP), visual acuity, contrast sensitivity) are commonly measured in clinical ophthalmology and vision research. In clinical practice, a `status' (category) can sometimes be assigned to an individual patient using a cutpoint in the value of a continuous variable; for example, a diagnosis of glaucoma might be confirmed by an elevated IOP measurement (eg, IOP $>$21 mm Hg). Indeed much of medicine revolves around an implicit classification of individuals into diseased and non-diseased. In clinical research, continuous variables may likewise be converted to categorical variables, assigning individuals to one of two groups. Although this may be appropriate for some specific studies where the underlying distribution of the variable shows a clear grouping, such dichotomisation has several drawbacks.1 Dichotomisation may be driven by the research question, for example, a study to investigate the health service needs of those with low vision, in which dichotomisation uses WHO visual acuity threshold for low vision.2 It may sometimes be used to bring the data in line with the clinical classification of patients but often the reason for dichotomisation of data is that it is thought to simplify the statistical analysis (eg, to enable use of a t test or a $\chi$2 test) and the presentation and interpretation of data. However, this simplification has a cost in terms of loss of information3 and may compromise the validity of the statistical analysis. We will discuss the disadvantages of dichotomisation and outline some points to consider before categorising continuous data. It should be noted that while the focus here is on categorisation of data into two groups, the problems arising when dichotomising data are inherent with any categorisation of data (two or more groups). Dichotomisation results, first, in the loss of descriptive information on the study population. For example, the \ldots{}},
  number = {6},
  journal = {British Journal of Ophthalmology},
  author = {Cumberland, Phillippa M and Czanner, Gabriela and Bunce, Catey and Dor\'e, Caroline J and Freemantle, Nick and {Garc\'ia-Fi\~nana}, Marta},
  year = {2014},
  keywords = {Anti-dichotomisation},
  pages = {841-843},
  file = {/Users/k/Zotero/storage/3PQM8KB7/Cumberland et al. - 2014 - Ophthalmic statistics note the perils of dichotomising continuous variables.pdf},
  pmid = {24682179}
}

@article{Vehtari2016,
  archivePrefix = {arXiv},
  eprinttype = {arxiv},
  eprint = {1507.04544},
  title = {Practical {{Bayesian}} Model Evaluation Using Leave-One-out Cross-Validation and {{WAIC}}},
  issn = {15731375},
  doi = {10.1007/s11222-016-9696-4},
  abstract = {Leave-one-out cross-validation (LOO) and the widely applicable information criterion (WAIC) are methods for estimating pointwise out-of-sample prediction accuracy from a fitted Bayesian model using the log-likelihood evaluated at the posterior simulations of the parameter values. LOO and WAIC have various advantages over simpler estimates of predictive error such as AIC and DIC but are less used in practice because they involve additional computational steps. Here we lay out fast and stable computations for LOO and WAIC that can be performed using existing simulation draws. We introduce an efficient computation of LOO using Pareto-smoothed importance sampling (PSIS), a new procedure for regularizing importance weights. Although WAIC is asymptotically equal to LOO, we demonstrate that PSIS-LOO is more robust in the finite case with weak priors or influential observations. As a byproduct of our calculations, we also obtain approximate standard errors for estimated predictive errors and for comparing of predictive errors between two models. We implement the computations in an R package called 'loo' and demonstrate using models fit with the Bayesian inference package Stan.},
  number = {September},
  journal = {Statistics and Computing},
  author = {Vehtari, Aki and Gelman, Andrew and Gabry, Jonah},
  year = {2016},
  keywords = {Stan,BayesCore,Bayesian computation,K-fold cross-validation,Leave-one-out cross-validation (LOO),Pareto smoothed importance sampling (PSIS),Widely applicable information criterion (WAIC)},
  pages = {1-20},
  file = {/Users/k/Zotero/storage/R5HNSNWV/Vehtari, Gelman, Gabry - 2016 - Practical Bayesian model evaluation using leave-one-out cross-validation and WAIC.pdf}
}

@article{Berry2017,
  title = {Association of {{Minimal Residual Disease With Clinical Outcome}} in {{Pediatric}} and {{Adult Acute Lymphoblastic Leukemia}}},
  volume = {3},
  issn = {2374-2437},
  doi = {10.1001/jamaoncol.2017.0580},
  abstract = {Importance Minimal residual disease (MRD) refers to the presence of disease in cases deemed to be in complete remission by conventional pathologic analysis. Assessing the association of MRD status following induction therapy in patients with acute lymphoblastic leukemia (ALL) with relapse and mortality may improve the efficiency of clinical trials and accelerate drug development. Objective To quantify the relationships between event-free survival (EFS) and overall survival (OS) with MRD status in pediatric and adult ALL using publications of clinical trials and other databases. Data Sources Clinical studies in ALL identified via searches of PubMed, MEDLINE, and clinicaltrials.gov. Study Selection Our search and study screening process adhered to the PRISMA Guidelines. Studies that addressed EFS or OS by MRD status in patients with ALL were included; reviews, abstracts, and studies with fewer than 30 patients or insufficient MRD description were excluded. Data Extraction and Synthesis Study sample size, patient age, follow-up time, timing of MRD assessment (postinduction or consolidation), MRD detection method, phenotype/genotype (B cell, T cell, Philadelphia chromosome), and EFS and OS. Searches of PubMed and MEDLINE identified 566 articles. A parallel search on clinicaltrials.gov found 67 closed trials and 62 open trials as of 2014. Merging results of 2 independent searches and applying exclusions gave 39 publications in 3 arms of patient populations (adult, pediatric, and mixed). We performed separate meta-analyses for each of these 3 subpopulations. Results The 39 publications comprised 13 637 patients: 16 adult studies (2076 patients), 20 pediatric (11 249 patients), and 3 mixed (312 patients). The EFS hazard ratio (HR) for achieving MRD negativity is 0.23 (95\% Bayesian credible interval [BCI] 0.18-0.28) for pediatric patients and 0.28 (95\% BCI, 0.24-0.33) for adults. The respective HRs in OS are 0.28 (95\% BCI, 0.19-0.41) and 0.28 (95\% BCI, 0.20-0.39). The effect was similar across all subgroups and covariates. Conclusions and Relevance The value of having achieved MRD negativity is substantial in both pediatric and adult patients with ALL. These results are consistent across therapies, methods of and times of MRD assessment, cutoff levels, and disease subtypes. Minimal residual disease status warrants consideration as an early measure of disease response for evaluating new therapies, improving the efficiency of clinical trials, accelerating drug development, and for regulatory approval. A caveat is that an accelerated approval of a particular new drug using an intermediate end point, such as MRD, would require confirmation using traditional efficacy end points.},
  number = {7},
  journal = {JAMA Oncology},
  author = {Berry, Donald A. and Zhou, Shouhao and Higley, Howard and Mukundan, Lata and Fu, Shuangshuang and Reaman, Gregory H. and Wood, Brent L. and Kelloff, Gary J. and Jessup, J. Milburn and Radich, Jerald P.},
  year = {2017},
  pages = {e170580},
  file = {/Users/k/Zotero/storage/MZ59YS6R/Berry et al. - 2017 - Association of Minimal Residual Disease With Clinical Outcome in Pediatric and Adult Acute Lymphoblastic Leukemia.pdf},
  pmid = {28494052}
}

@article{Senn2003,
  title = {Bayesian, {{Likelihood}}, and {{Frequentist Approaches}} to {{Statistics}}},
  journal = {Applied Clinical Trials},
  author = {Senn, Stephen},
  year = {2003},
  file = {/Users/k/Zotero/storage/5NNXQ6M5/Senn - 2003 - Bayesian, Likelihood, and Frequentist Approaches to Statistics.pdf}
}

@article{Vickers2001,
  title = {Statistics {{Notes}}: {{Analysing}} Controlled Trials with Baseline and Follow up Measurements},
  volume = {323},
  issn = {0959-8138},
  doi = {10.1136/bmj.323.7321.1123},
  abstract = {In many randomised trials researchers measure a continuous variable at baseline and again as an outcome assessed at follow up. Baseline measurements are common in trials of chronic conditions where researchers want to see whether a treatment can reduce pre-existing levels of pain, anxiety, hypertension, and the like.$\backslash$n$\backslash$nStatistical comparisons in such trials can be made in several ways. Comparison of follow up (post-treatment) scores will give a result such as ``at the end of the trial, mean pain scores were 15 mm (95\% confidence interval 10 to 20 mm) lower in the treatment group.'' Alternatively a change score can be calculated by subtracting the follow up score from the baseline score, leading to a statement such as ``pain reductions were 20 mm (16 to 24 mm) greater on treatment than control.'' If the average baseline scores are the same in each group the estimated treatment effect will be the same using these two simple approaches. If the treatment is effective the statistical significance of the treatment effect by the two methods will depend on the correlation between baseline and follow up scores. If the correlation is low using the change score will \ldots{}},
  number = {7321},
  journal = {Bmj},
  author = {Vickers, A. J and Altman, D. G},
  year = {2001},
  pages = {1123-1124},
  file = {/Users/k/Zotero/storage/YUSV26F5/Vickers, Altman - 2001 - Statistics Notes Analysing controlled trials with baseline and follow up measurements.pdf},
  pmid = {11701584}
}

@article{Bolker2012,
  title = {Owls Example: A Zero-Inflated, Generalized Linear Mixed Model for Count Data},
  abstract = {1 The model Data collected in ecological studies are often complex. Studies may involve repeat observations on the same units (e.g., individuals, quadrats, stations). Predictor variables may be categorical or continuous, and interactions may be of interest. In addition, such data may contain excess zero-valued observations (with respect to a Poisson model) because of sampling variability and/or incom-plete knowledge of processes that generated the data (e.g., factors that define suitable species habitat) Zuur et al. (2009). Zero-inflated generalized linear mixed-effects models (ZIGLMMs) are a class of models, incorporating aspects of generalized linear models, mixed models, and zero-inflated models, that are both flexible and computationally efficient tools for data of this sort. The data for this example, taken from Zuur et al. (2009) and ultimately from Roulin and Bersier (2007), quantify the amount of sibling negotiation (vo-calizations when parents are absent) by owlets (owl chicks) in different nests as a function of food treatment (deprived or satiated), the sex of the parent, and arrival time of the parent at the nest. Since the same nests are observed repeatedly, it is natural to consider a mixed-effects model for these data, with the nest as a random effect. Because we are interested in explaining variability in the number of vocalizations per chick, the total brood size in each nest is used as an offset in the model. Since the same nests are measured repeatedly, Zuur et al. (2009) fitted a Poisson generalized linear mixed-effects model to these data (see their Section 13.2.2). We extend that example by considering zero-inflation. We use a zero-inflated Poisson model with a log link function for the count (Poisson) part [i.e., the inverse link is exponential] of the model and a logit link for the binary part [i.e., the inverse link is logistic] Y ij $\sim$ ZIPois($\lambda$ = exp($\eta$ ij), p = logistic(z i)) (1) where ZIPois represents the zero-inflated Poisson distribution, and logistic(z) $\equiv$ (1+exp(-z)) -1 . The zero-inflated Poisson with parameters $\lambda$, p has probability p + (1 - p) exp(-$\lambda$) if Y = 0 and (1 - p)Pois(X, $\lambda$) if Y $>$ 0.},
  author = {Bolker, Ben and Brooks, Mollie and Gardner, Beth and Lennert, Cleridy and Minami, Mihoko},
  year = {2012},
  file = {/Users/k/Zotero/storage/F3IJK8ZG/Bolker et al. - 2012 - Owls example a zero-inflated, generalized linear mixed model for count data.pdf}
}

@article{Glasbey2017,
  title = {Overview {{Recommendations}} for {{Randomised Trials}} in {{Surgical Oncology}}},
  doi = {10.1016/j.clon.2017.10.002},
  abstract = {Trials of surgical procedures in the treatment of malignant disease face a unique set of challenges. This review aimed to describe recommendations for the design, delivery and reporting of randomised trials in surgical oncology. A literature search was carried out without date limits to identify articles related to trial methodology research in surgery and surgical oncology. A narrative review was framed around two open National Institute of Health Research portfolio trials in colon and rectal cancer: the STAR-TREC trial (ISRCTN14240288) and the ROCCS trial (ISRCTN46330337). Twelve specific challenges were highlighted: stand-ardisation of technique; pilot and feasibility studies; balancing treatments; the recruitment pathway; outcome measures; patient and public representation; trainee-led networks; randomisation; novel techniques and training; learning curves; blinding; follow-up. Evidence-based recommendations were made for the future design and conduct of surgical oncology trials. Better understanding of the challenges facing trials in the surgical treatment of cancer will accelerate high-quality evaluation and rapid adoption of innovation for the benefit of patient care.},
  author = {Glasbey, J C and Magill, E L and Brock, K and Bach, S P},
  year = {2017},
  keywords = {MyPubs},
  file = {/Users/k/Zotero/storage/S2NKFDUT/Glasbey et al. - 2017 - Overview Recommendations for Randomised Trials in Surgical Oncology.pdf}
}

@article{Kass2011,
  title = {Statistical {{Inference}}: {{The Big Picture}} 1},
  volume = {26},
  doi = {10.1214/10-STS337},
  abstract = {Statistics has moved beyond the frequentist-Bayesian controver-sies of the past. Where does this leave our ability to interpret results? I suggest that a philosophy compatible with statistical practice, labeled here statisti-cal pragmatism, serves as a foundation for inference. Statistical pragmatism is inclusive and emphasizes the assumptions that connect statistical models with observed data. I argue that introductory courses often mischaracterize the process of statistical inference and I propose an alternative " big picture " depiction.},
  number = {1},
  journal = {Statistical Science},
  author = {Kass, Robert E},
  year = {2011},
  pages = {1-9},
  file = {/Users/k/Zotero/storage/73H6X925/Kass - 2011 - Statistical Inference The Big Picture 1.pdf}
}

@article{Guo2017,
  title = {Bayesian {{Phase I}} / {{II Biomarker}}-Based {{Dose Finding}} for {{Precision Medicine}}},
  volume = {112},
  doi = {10.1080/01621459.2016.1228534},
  number = {518},
  journal = {Journal of the American Statistical Association},
  author = {Guo, Beibei and Yuan, Ying},
  year = {2017},
  keywords = {personalized medicine,bayesian adaptive design,dose,finding,beibei guo is assistant,department of experimental statistics,louisiana state uni-,partial least squares,personalized dose finding,professor},
  pages = {508-520},
  file = {/Users/k/Zotero/storage/NEMRCYKW/Guo, Yuan - 2017 - Bayesian Phase I II Biomarker-based Dose Finding for Precision Medicine.pdf}
}

@article{Thall2008,
  title = {Patient-Specific Dose Finding Based on Bivariate Outcomes and Covariates},
  volume = {64},
  issn = {0006341X},
  doi = {10.1111/j.1541-0420.2008.01009.x},
  abstract = {SUMMARY: A Bayesian sequential dose-finding procedure based on bivariate (efficacy, toxicity) outcomes that accounts for patient covariates and dose-covariate interactions is presented. Historical data are used to obtain an informative prior on covariate main effects, with uninformative priors assumed for all dose effect parameters. Elicited limits on the probabilities of efficacy and toxicity for each of a representative set of covariate vectors are used to construct bounding functions that determine the acceptability of each dose for each patient. Elicited outcome probability pairs that are equally desirable for a reference patient are used to define two different posterior criteria, either of which may be used to select an optimal covariate-specific dose for each patient. Because the dose selection criteria are covariate specific, different patients may receive different doses at the same point in the trial, and the set of eligible patients may change adaptively during the trial. The method is illustrated by a dose-finding trial in acute leukemia, including a simulation study.},
  number = {4},
  journal = {Biometrics},
  author = {Thall, Peter F. and Nguyen, Hoang Q. and Estey, Elihu H.},
  year = {2008},
  keywords = {Bayesian design,Adaptive design,Phase I clinical trial,Biologic agents,Individualized treatment,Phase I/II clinical trial},
  pages = {1126-1136},
  file = {/Users/k/Zotero/storage/WU9B8CMH/Thall, Nguyen, Estey - 2008 - Patient-specific dose finding based on bivariate outcomes and covariates.pdf},
  pmid = {18355387}
}

@article{Senn2007,
  title = {Stratification for the Propensity Score Compared with Linear Regression Techniques to Assess the Effect of Treatment or Exposure},
  volume = {26},
  doi = {10.1002/sim.3133},
  abstract = {SUMMARY Stratifying and matching by the propensity score are increasingly popular approaches to deal with confounding in medical studies investigating effects of a treatment or exposure. A more traditional alternative technique is the direct adjustment for confounding in regression models. This paper discusses fundamental differences between the two approaches, with a focus on linear regression and propensity score stratification, and identifies points to be considered for an adequate comparison. The treatment estimators are examined for unbiasedness and efficiency. This is illustrated in an application to real data and supplemented by an investigation on properties of the estimators for a range of underlying linear models. We demonstrate that in specific circumstances the propensity score estimator is identical to the effect estimated from a full linear model, even if it is built on coarser covariate strata than the linear model. As a consequence the coarsening property of the propensity score\textemdash{}adjustment for a one-dimensional confounder instead of a high-dimensional covariate\textemdash{}may be viewed as a way to implement a pre-specified, richly parametrized linear model. We conclude that the propensity score estimator inherits the potential for overfitting and that care should be taken to restrict covariates to those relevant for outcome.},
  journal = {STATISTICS IN MEDICINE Statist. Med},
  author = {Senn, Stephen and Graf, Erika and Caputo, Angelika},
  year = {2007},
  pages = {5529-5544},
  file = {/Users/k/Zotero/storage/DWPVKGWN/Senn, Graf, Caputo - 2007 - Stratification for the propensity score compared with linear regression techniques to assess the effect of t.pdf}
}

@article{Pronin2017,
  title = {Measurement of {{Intraocular Pressure}} by {{Patients With Glaucoma}}},
  issn = {21686165},
  doi = {10.1001/jamaophthalmol.2017.3151},
  abstract = {IMPORTANCE The ability of patients to measure their own intraocular pressure (IOP) would allow more frequent measurements and better appreciation of peak IOP and IOP fluctuation. OBJECTIVE To examine whether patients with glaucoma can perform self-tonometry using a rebound tonometer and examine patient acceptability. DESIGN, SETTING, AND PARTICIPANTS An observational study in which IOP was assessed using Goldmann applanation tonometry and a rebound tonometer. Consecutive patients were provided with a patient information sheet and those consenting to take part in the study received standardized self-tonometry training and were then instructed to measure their own IOP under observation. This study was conducted at a glaucoma clinic at a university hospital from March 1, 2016, to December 30, 2016, and included both eyes of 100 patients with glaucoma or ocular hypertension. MAIN OUTCOMES AND MEASURES The percentage of patients who could successfully perform self-tonometry. Complete success was defined by a good technique and an IOP reading within 5 mm Hg of that obtained by a clinician using the same device. A 3-item questionnaire was used to examine perceptions of self-tonometry among patients. RESULTS Among the 100 patients, the mean (SD) age was 67.5 (10.9) years (53\% female). A total 73 of 100 patients (73\%) met the complete success criteria. An additional 6 patients could use the device but had IOP readings greater than 5 mm Hg different from those obtained by the clinician. On average, IOP by the rebound tonometer was 2.66 mm Hg lower than Goldmann applanation tonometry (95\% limits of agreement, -3.48 to 8.80 mm Hg). The IOPs with the rebound tonometer were similar whether obtained by self-tonometry or investigator, with excellent reproducibility with an intraclass correlation coefficient of 0.903 (95\% CI, 0.867-0.928). A total of 56 of 79 successful or partially successful patients (71\%) felt self-tonometry was easy, with 73 of 79 (92\%) reporting self-tonometry to be comfortable, and a similar number happy to perform self-tonometry in the future. CONCLUSIONS AND RELEVANCE Most patients could perform self-tonometry and the method was acceptable to patients. Self-tonometry has the potential to improve patient engagement, while also providing a more complete picture of IOP changes over time.},
  author = {Pronin, Savva and Brown, Lyndsay and Megaw, Roly and Tatham, Andrew J},
  year = {2017},
  keywords = {The JAMA Network},
  pages = {1-6},
  file = {/Users/k/Zotero/storage/48SVAB4T/Pronin et al. - 2017 - Measurement of Intraocular Pressure by Patients With Glaucoma.pdf},
  pmid = {28859192}
}

@article{Senn2009,
  title = {Three Things That Every Medical Writer Should Know about Statistics},
  volume = {18},
  number = {3},
  journal = {The Write Stuff},
  author = {Senn, Stephen},
  year = {2009},
  pages = {159-162},
  file = {/Users/k/Zotero/storage/LACDQQID/Senn - 2009 - Three things that every medical writer should know about statistics.pdf}
}

@article{Cudkowicz2013,
  title = {Dexpramipexole versus Placebo for Patients with Amyotrophic Lateral Sclerosis ({{EMPOWER}}): {{A}} Randomised, Double-Blind, Phase 3 Trial},
  volume = {12},
  issn = {14744422},
  doi = {10.1016/S1474-4422(13)70221-7},
  abstract = {Background: In a phase 2 study, dexpramipexole (25-150 mg twice daily) was well tolerated for up to 9 months and showed a significant benefit at the high dose in a combined assessment of function and mortality in patients with amyotrophic lateral sclerosis. We aimed to assess efficacy and safety of dexpramipexole in a phase 3 trial of patients with familial or sporadic disease. Methods: In our randomised, double-blind, placebo-controlled phase 3 trial (EMPOWER), we enrolled participants aged 18-80 years (with first amyotrophic lateral sclerosis symptom onset 24 months or less before baseline) at 81 academic medical centres in 11 countries. We randomly allocated eligible participants (1:1) with a centralised voice-interactive online system to twice-daily dexpramipexole 150 mg or matched placebo for 12-18 months, stratified by trial site, area of disease onset (bulbar vs other areas), and previous use of riluzole. The primary endpoint was the combined assessment of function and survival (CAFS) score, based on changes in amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R) total scores and time to death up to 12 months. We assessed the primary endpoint in all participants who received at least one dose and had at least one post-dose ALSFRS-R measurement or died. We monitored adverse events in all participants. This study is registered with ClinicalTrials.gov, number NCT01281189. Findings: Between March 28, 2011, and Sept 30, 2011, we enrolled 943 participants (474 randomly allocated dexpramipexole, 468 randomly allocated placebo, and one withdrew). Least-square mean CAFS scores at 12 months did not differ between participants in the dexpramipexole group (score 441$\cdot$76, 95\% CI 415$\cdot$43-468$\cdot$08) and those in the placebo group (438$\cdot$84, 412$\cdot$81-464$\cdot$88; p=0$\cdot$86). At 12 months, we noted no differences in mean change from baseline in ALSFRS-R total score (-13$\cdot$34 in the dexpramipexole group vs -13$\cdot$42 in the placebo group; p=0$\cdot$90) or time to death (74 [16\%] vs 79 [17\%]; hazard ratio 1$\cdot$03 [0$\cdot$75-1$\cdot$43]; p=0$\cdot$84). 37 (8\%) participants in the dexpramipexole group developed neutropenia compared with eight (2\%) participants in the placebo group, and incidence of other adverse events was similar between groups. Interpretation: Dexpramipexole was generally well tolerated but did not differ from placebo on any prespecified efficacy endpoint measurement. Our trial can inform the design of future clinical research strategies in amyotrophic lateral sclerosis. Funding: Biogen Idec. \textcopyright{} 2013 Elsevier Ltd.},
  number = {11},
  journal = {The Lancet Neurology},
  author = {Cudkowicz, Merit E. and {van den Berg}, Leonard H. and Shefner, Jeremy M. and Mitsumoto, Hiroshi and Mora, Jesus S. and Ludolph, Albert and Hardiman, Orla and Bozik, Michael E. and Ingersoll, Evan W. and Archibald, Donald and Meyers, Adam L. and Dong, Yingwen and Farwell, Wildon R. and Kerr, Douglas A.},
  year = {2013},
  keywords = {ALS},
  pages = {1059-1067},
  file = {/Users/k/Zotero/storage/LBD7WDF8/Cudkowicz et al. - 2013 - Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER) A randomised, double-b.pdf},
  pmid = {24067398}
}

@article{Cudkowicz2011,
  title = {The Effects of Dexpramipexole ({{KNS}}-760704) in Individuals with Amyotrophic Lateral Sclerosis},
  volume = {17},
  issn = {1078-8956},
  doi = {10.1038/nm.2579},
  abstract = {Nature Medicine,  (2011). doi:10.1038/nm.2579},
  number = {12},
  journal = {Nature Medicine},
  author = {Cudkowicz, Merit and Bozik, Michael E and Ingersoll, Evan W and Miller, Robert and Mitsumoto, Hiroshi and Shefner, Jeremy and Moore, Dan H and Schoenfeld, David and Mather, James L and Archibald, Donald and Sullivan, Mary and Amburgey, Craig and Moritz, Juliet and Gribkoff, Valentin K},
  year = {2011},
  keywords = {ALS},
  pages = {1652-1656},
  file = {/Users/k/Zotero/storage/74UZMKDP/Cudkowicz et al. - 2011 - The effects of dexpramipexole (KNS-760704) in individuals with amyotrophic lateral sclerosis.pdf},
  pmid = {22101764}
}

@article{Bates2015,
  archivePrefix = {arXiv},
  eprinttype = {arxiv},
  eprint = {1406.5823},
  title = {Fitting {{Linear Mixed}}-{{Effects Models Using}} Lme4},
  volume = {67},
  issn = {0092-8615},
  doi = {10.18637/jss.v067.i01},
  abstract = {Maximum likelihood or restricted maximum likelihood (REML) estimates of the parameters in linear mixed-effects models can be determined using the lmer function in the lme4 package for R. As for most model-fitting functions in R, the model is described in an lmer call by a formula, in this case including both fixed- and random-effects terms. The formula and data together determine a numerical representation of the model from which the profiled deviance or the profiled REML criterion can be evaluated as a function of some of the model parameters. The appropriate criterion is optimized, using one of the constrained optimization functions in R, to provide the parameter estimates. We describe the structure of the model, the steps in evaluating the profiled deviance or REML criterion, and the structure of classes or types that represents such a model. Sufficient detail is included to allow specialization of these structures by users who wish to write functions to fit specialized linear mixed models, such as models incorporating pedigrees or smoothing splines, that are not easily expressible in the formula language used by lmer.},
  number = {1},
  journal = {J Stat Soft},
  author = {Bates, Douglas and M\"achler, Martin and Bolker, Ben and Walker, Steve},
  year = {2015},
  keywords = {Cholesky decomposition,linear mixed models,LME,penalized least squares,sparse matrix methods},
  pages = {48},
  file = {/Users/k/Zotero/storage/K9MWP5IF/Bates et al. - 2015 - Fitting Linear Mixed-Effects Models Using lme4.pdf},
  pmid = {20043131029}
}

@article{Paganoni2014,
  title = {Outcome Measures in Amyotrophic Lateral Sclerosis Clinical Trials},
  volume = {4},
  issn = {2041-6792},
  doi = {10.4155/cli.14.52},
  abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with an average survival of 3-5 years. While therapies for ALS remain limited, basic and translational ALS research has been host to numerous influential discoveries in recent years. These discoveries have led to a large pipeline of potential therapies that await testing in clinical trials. Until recently, ALS clinical trials have relied on a limited cadre of 'traditional' outcome measures, including survival and measures of function. These measures have proven useful, although imperfect, in Phase III ALS trials. However, their utility in early-phase ALS trials is limited. For these early trials, outcome measures focused on target engagement or biological pathway analysis might improve trial outcomes and better support the drug development process.},
  number = {7},
  journal = {Clinical Investigation},
  author = {Paganoni, Sabrina and Cudkowicz, Merit and Berry, James D},
  year = {2014},
  keywords = {biomarker,ALS,amyotrophic lateral sclerosis,als,als is,and eventually death,characterized by motor neuron,disability,disease,end point,function,is a progressive neurodegenerative,loss resulting in weakness,surrogate,survival},
  pages = {605-618},
  file = {/Users/k/Zotero/storage/MC56E5P9/Paganoni, Cudkowicz, Berry - 2014 - Outcome measures in amyotrophic lateral sclerosis clinical trials.pdf},
  pmid = {28203356}
}

@article{Miller2012,
  title = {Riluzole for Amyotrophic Lateral Sclerosis ({{ALS}})/ Motor Neuron Disease ({{MND}})},
  issn = {14660822},
  doi = {10.1002/14651858.CD001447.pub3.www.cochranelibrary.com},
  number = {3},
  journal = {The Cochrane Database of Systematic Reviews},
  author = {Miller, RG and Mitchell, JD and Moore, DH},
  year = {2012},
  keywords = {ALS},
  file = {/Users/k/Zotero/storage/2MYXNMJU/Miller, Mitchell, Moore - 2012 - Riluzole for amyotrophic lateral sclerosis (ALS) motor neuron disease (MND).pdf},
  pmid = {17253460}
}

@article{Mcshane,
  title = {Statistical {{Significance}} and the {{Dichotomization}} of {{Evidence}}},
  abstract = {In light of recent concerns about reproducibility and replicability, the ASA issued a Statement on Statistical Significance and p-values aimed at those who are not primarily statisticians. While the ASA State-ment notes that statistical significance and p-values are " commonly misused and misinterpreted, " it does not discuss and document broader implications of these errors for the interpretation of evidence. In this article, we review research on how applied researchers who are not primarily statisticians misuse and misin-terpret p-values in practice and how this can lead to errors in the interpretation of evidence. We also present new data showing, perhaps surprisingly, that researchers who are primarily statisticians are also prone to misuse and misinterpret p-values thus resulting in similar errors. In particular, we show that statisticians tend to interpret evidence dichotomously based on whether or not a p-value crosses the conventional 0.05 threshold for statistical significance. We discuss implications and offer recommendations.},
  author = {Mcshane, Blakeley B and Gal, David},
  file = {/Users/k/Zotero/storage/7BHNFM6F/Mcshane, Gal - Unknown - Statistical Significance and the Dichotomization of Evidence.pdf}
}

@article{Laptook,
  title = {Effect of {{Therapeutic Hypothermia Initiated After}} 6 {{Hours}} of {{Age}} on {{Death}} or {{Disability Among Newborns With Hypoxic}}-{{Ischemic Encephalopathy A Randomized Clinical Trial}}},
  doi = {10.1001/jama.2017.14972},
  abstract = {IMPORTANCE Hypothermia initiated at less than 6 hours after birth reduces death or disability for infants with hypoxic-ischemic encephalopathy at 36 weeks' or later gestation. To our knowledge, hypothermia trials have not been performed in infants presenting after 6 hours. OBJECTIVE To estimate the probability that hypothermia initiated at 6 to 24 hours after birth reduces the risk of death or disability at 18 months among infants with hypoxic-ischemic encephalopathy. DESIGN, SETTING, AND PARTICIPANTS A randomized clinical trial was conducted between April 2008 and June 2016 among infants at 36 weeks' or later gestation with moderate or severe hypoxic-ischemic encephalopathy enrolled at 6 to 24 hours after birth. Twenty-one US Neonatal Research Network centers participated. Bayesian analyses were prespecified given the anticipated limited sample size. INTERVENTIONS Targeted esophageal temperature was used in 168 infants. Eighty-three hypothermic infants were maintained at 33.5$^\circ$C (acceptable range, 33$^\circ$C-34$^\circ$C) for 96 hours and then rewarmed. Eighty-five noncooled infants were maintained at 37.0$^\circ$C (acceptable range, 36.5$^\circ$C-37.3$^\circ$C).},
  author = {Laptook, Abbot R and Shankaran, Seetha and Tyson, Jon E and Munoz, Breda and Bell, Edward F and Goldberg, Ronald N and Parikh, Nehal A and Ambalavanan, Namasivayam and Pedroza, Claudia and Pappas, Athina and Das, Abhik and Chaudhary, Aasma S and Ehrenkranz, Richard A and Hensman, Angelita M and Van Meurs, Krisa P and Chalak, Lina F and G Hamrick, Shannon E and Sokol, Gregory M and Walsh, Michele C and Poindexter, Brenda B and Faix, Roger G and Watterberg, Kristi L and Frantz III, Ivan D and Guillet, Ronnie and Devaskar, Uday and Truog, William E and Chock, Valerie Y and Wyckoff, Myra H and McGowan, Elisabeth C and Carlton, David P and Harmon, Heidi M and Brumbaugh, Jane E and Michael Cotten, C and S\'anchez, Pablo J and Maria Hibbs, Anna and Higgins, Rosemary D},
  file = {/Users/k/Zotero/storage/C4Q7DN2J/Laptook et al. - Unknown - Effect of Therapeutic Hypothermia Initiated After 6 Hours of Age on Death or Disability Among Newborns With H.pdf}
}

@article{Berry1987,
  title = {Interim {{Analysis}} in {{Clinical Trials}} : {{The Role}} of the {{Likelihood Principle}}},
  volume = {41},
  number = {2},
  journal = {The American Statistitican},
  author = {Berry, Donald A},
  year = {1987},
  keywords = {an unconditional analysis requires,bayesian statistics,bility that azt is,conditional inference,effective given these data,group sequential methods,hand,nificance testing,on the other,other information,repeated sig-},
  pages = {117-122},
  file = {/Users/k/Zotero/storage/VVDQDZXZ/Berry - 1987 - Interim Analysis in Clinical Trials The Role of the Likelihood Principle.pdf}
}

@article{Chen2012,
  title = {Curtailed Two-Stage Designs with Two Dependent Binary Endpoints},
  volume = {11},
  issn = {15391604},
  doi = {10.1002/pst.496},
  abstract = {When phase I clinical trials were found to be unable to precisely estimate the frequency of toxicity, Brayan and Day proposed incorporating toxicity considerations into two-stage designs in phase II clinical trials. Conaway and Petroni further pointed out that it is important to evaluate the clinical activity and safety simultaneously in studying cancer treatments with more toxic chemotherapies in a phase II clinical trial. Therefore, they developed multi-stage designs with two dependent binary endpoints. However, the usual sample sizes in phase II trials make these designs difficult to control the type I error rate at a desired level over the entire null region and still have sufficient power against reasonable alternatives. Therefore, the curtailed sampling procedure summarized by Phatak and Bhatt will be applied to the two-stage designs with two dependent binary endpoints in this paper to reduce sample sizes and speed up the development process for drugs.},
  number = {1},
  journal = {Pharmaceutical Statistics},
  author = {Chen, Chia Min and Chi, Yunchan},
  year = {2012},
  keywords = {curtailed sampling procedure,dependent binary endpoints,two-stage designs,type I error rate},
  pages = {57-62},
  file = {/Users/k/Zotero/storage/IJ8XMWTC/Chen, Chi - 2012 - Curtailed two-stage designs with two dependent binary endpoints.pdf},
  pmid = {22162348}
}

@article{Jairath2017,
  title = {Systematic Review with Meta-Analysis: Placebo Rates in Induction and Maintenance Trials of {{Crohn}}'s Disease},
  volume = {45},
  issn = {13652036},
  doi = {10.1111/apt.13973},
  abstract = {BACKGROUND AND AIMS Minimisation of the placebo responses in randomised controlled trials [RCTs] is essential for efficient evaluation of new interventions. Placebo rates have been high in ulcerative colitis [UC] clinical trials, and factors influencing this are poorly understood. We quantify placebo response and remission rates in UC RCTs and identify trial design factors influencing them. METHODS MEDLINE, EMBASE, and the Cochrane Library were searched from inception through April 2014 for placebo-controlled trials in adult patients with UC of a biological agent, corticosteroid, immunosuppressant, or aminosalicylate. Data were independently doubly extracted. Quality was assessed using the Cochrane risk of bias tool. RESULTS In all, 51 trials [48 induction and 10 maintenance phases] were identified. Placebo response and remission rates were pooled according to random-effects models, and mixed-effects meta-regression models were used to evaluate effects of study-level characteristics on these rates. Pooled estimates of placebo remission and response rates for induction trials were 10\% (95\% confidence interval [CI] 7-13\%) and 33\% [95\% CI 29-37\%], respectively. Corresponding values for maintenance trials were 19\% [95\% CI 11-30\%] and 22\% [95\% CI 17-28\%]. Trials enrolling patients with more active disease confirmed by endoscopy [endoscopy subscore $\geq$ 2] were associated with lower placebo rates. Conversely, placebo rates increased with increasing trial duration and number of study visits. CONCLUSIONS Objective assessment of greater disease activity at trial entry by endoscopy lowered placebo rates, whereas increasing trial duration and more interactions with healthcare providers increased placebo rates. These findings have important implications for design and conduct of clinical trials.},
  number = {8},
  journal = {Alimentary Pharmacology and Therapeutics},
  author = {Jairath, V. and Zou, G. and Parker, C. E. and MacDonald, J. K. and Mosli, M. H. and AlAmeel, T. and Al Beshir, M. and AlMadi, M. and {Al-Taweel}, T. and Atkinson, N. S.S. and Biswas, S. and Chapman, T. P. and Dulai, P. S. and Glaire, M. A. and Hoekman, D. and Kherad, O. and Koutsoumpas, A. and Minas, E. and Restellini, S. and Samaan, M. A. and Khanna, R. and Levesque, B. G. and D'Haens, G. and Sandborn, W. J. and Feagan, B. G.},
  year = {2017},
  keywords = {Crohns},
  pages = {1021-1042},
  file = {/Users/k/Zotero/storage/7FPNQWVE/Jairath et al. - 2017 - Systematic review with meta-analysis placebo rates in induction and maintenance trials of Crohn's disease.pdf},
  pmid = {26746169}
}

@article{Su2007,
  title = {A {{Meta}}-{{Analysis}} of the {{Placebo Rates}} of {{Remission}} and {{Response}} in {{Clinical Trials}} of {{Active Ulcerative Colitis}}},
  volume = {126},
  issn = {00165085},
  doi = {10.1053/j.gastro.2006.12.037},
  abstract = {Background \& Aims: Knowledge of the placebo outcomes and understanding specific study features that influence these outcomes is important for designing future clinical trials evaluating therapy of ulcerative colitis (UC). The aims of this study were to estimate the placebo rates of remission and response in placebo-controlled, randomized clinical trials for active UC and to identify factors influencing these rates. Methods: We performed a systematic review and meta-analysis of placebo-controlled, randomized clinical trials evaluating therapies for active UC identified from MEDLINE from 1966 through 2005. Results: Forty studies met the inclusion criteria. The pooled estimates of the placebo rates of remission and response were 13\% (95\% confidence interval, 9\%-18\%; range, 0\%-40\%; median, 12\%) and 28\% (95\% confidence interval, 23\%-33\%; range, 0\%-67\%; median, 30\%), respectively, both with significant heterogeneity. Studies that used more stringent definitions of outcomes had lower placebo rates of remission and response. Study duration, number of study visits, disease duration, baseline composite and rectal bleeding scores of the disease activity index, and inclusion of endoscopic mucosal healing as the remission definition all were associated with the placebo remission rate. Conclusions: Rates of remission in the placebo arm of UC clinical trials ranges from 0\% to 40\%. The placebo remission rates are influenced by the trial length, number of study visits, use of stricter remission definitions, and design features that enroll patients with more active disease. These factors should be considered when designing future placebo-controlled clinical trials in patients with active UC. ?? 2007 AGA Institute.},
  journal = {Gastroenterology},
  author = {Su, Chinyu and Lewis, James D. and Goldberg, Brittany and Brensinger, Colleen and Lichtenstein, Gary R.},
  year = {2004},
  keywords = {Crohns},
  pages = {1257-69},
  file = {/Users/k/Zotero/storage/LM7ZIYF9/Su et al. - 2004 - A Meta-Analysis of the Placebo Rates of Remission and Response in Clinical Trials of Active Ulcerative Colitis.pdf},
  pmid = {17258720}
}

@article{Sandborn2017a,
  title = {Phase {{II}} Evaluation of Anti-{{MAdCAM}} Antibody {{PF}}- 00547659 in the Treatment of {{Crohn}} ' s Disease : Report of the {{OPERA}} Study},
  issn = {1468-3288},
  doi = {10.1136/gutjnl-2016-313457},
  author = {Sandborn, William J and Lee, Scott D and Tarabar, Dino and Louis, Edouard and Klopocka, Maria and Klaus, Jochen and Reinisch, Walter and H\'ebuterne, Xavier and Park, Dong-il and Schreiber, Stefan and Nayak, Satyaprakash and Ahmad, Alaa and Banerjee, Anindita and Brown, Lisa S and Cataldi, Fabio and Gorelick, Kenneth J and Cheng, John B and {Hassan-zahraee}, Mina and Clare, Robert and Haens, Geert R D},
  year = {2017},
  keywords = {Crohns},
  pages = {1-12},
  file = {/Users/k/Zotero/storage/9NM4V9VR/Sandborn et al. - 2017 - Phase II evaluation of anti-MAdCAM antibody PF- 00547659 in the treatment of Crohn ’ s disease report of the.pdf},
  pmid = {28982740}
}

@article{Pocock1992,
  title = {When to Stop a Clinical Trial},
  volume = {305},
  issn = {0959-8138},
  doi = {10.1136/bmj.305.6847.235},
  abstract = {Images: FIG 1:},
  number = {May 2009},
  journal = {Bmj},
  author = {Pocock, Stuart J},
  year = {1992},
  pages = {235-240},
  file = {/Users/k/Zotero/storage/668IEKPE/Pocock - 1992 - When to stop a clinical trial.pdf},
  pmid = {1392832}
}

@article{Pratt2017,
  title = {A Multi-Centre Phase {{I}} Trial of the {{PARP}} Inhibitor Olaparib in Patients with Relapsed Chronic Lymphocytic Leukaemia, {{T}}-Prolymphocytic Leukaemia or Mantle Cell Lymphoma},
  issn = {13652141},
  doi = {10.1111/bjh.14793},
  number = {Cll},
  journal = {British Journal of Haematology},
  author = {Pratt, Guy and Yap, Christina and Oldreive, Ceri and Slade, Daniel and Bishop, Rebecca and Griffiths, Mike and Dyer, Martin J.S. and Fegan, Chris and Oscier, David and Pettitt, Andrew and Matutes, Estella and Devereux, Stephen and Allsup, David and Bloor, Adrian and Hillmen, Peter and Follows, George and Rule, Simon and Moss, Paul and Stankovic, Tatjana},
  year = {2017},
  keywords = {Chronic lymphocytic leukaemia,DNA damage,Mantle cell lymphoma,Olaparib},
  file = {/Users/k/Zotero/storage/YKWJGICP/Pratt et al. - 2017 - A multi-centre phase I trial of the PARP inhibitor olaparib in patients with relapsed chronic lymphocytic leukaemi.pdf},
  pmid = {28643365}
}

@article{ICH-E9,
  title = {{{ICH E9}} - {{STATISTICAL PRINCIPLES FOR CLINICAL TRIALSICH HARMONISED TRIPARTITE GUIDELINE STATISTICAL}}},
  number = {February},
  year = {1998},
  file = {/Users/k/Zotero/storage/SDJM3JUR/Unknown - 1998 - ICH E9 - STATISTICAL PRINCIPLES FOR CLINICAL TRIALSICH HARMONISED TRIPARTITE GUIDELINE STATISTICAL.pdf}
}

@article{Sorensen2016,
  title = {{{PD}}-{{L1}} Expression and Survival among Patients with Advanced Non\textendash{}Small Cell Lung Cancer Treated with Chemotherapy},
  volume = {9},
  issn = {19365233},
  doi = {10.1016/j.tranon.2016.01.003},
  abstract = {BACKGROUND: Recent clinical trial results have suggested that programmed cell death ligand 1 (PD-L1) expression measured by immunohistochemistry may predict response to anti\textendash{}programmed cell death 1 (PD-1) therapy. Results on the association between PD-L1 expression and survival among patients with advanced non\textendash{}small cell lung cancer (NSCLC) treated with chemotherapy are inconsistent. MATERIAL AND METHODS: We evaluated the relationship between PD-L1 expression and overall survival (OS) among 204 patients with advanced NSCLC treated at Aarhus University Hospital, Aarhus, Denmark, from 2007 to 2012. PD-L1 expression was measured using a prototype immunohistochemistry assay with the anti\textendash{}PD-L1 22C3 antibody (Merck). PD-L1 strong positivity and weak positivity were defined to be traceable to the clinical trial version of the assay. RESULTS: Twenty-five percent of patients had PD-L1 strong-positive tumors, and 50\% had PD-L1 weak-positive tumors. No statistically significant association was found between PD-L1 expression and survival; adjusted hazard ratio of 1.34 (95\% confidence interval, 0.88-2.03; median OS, 9.0 months) for the PD-L1 strong-positive group and 1.07 (0.74- 1.55; median OS, 9.8 months) for the PD-L1 weak-positive group compared with the PD-L1\textendash{}negative group (median OS, 7.5 months). No association was seen between PD-L1 expression and OS when PD-L1 expression levels were stratified by median or tertiles. CONCLUSIONS: In concordance with previous studies, we found PD-L1 measured by immunohistochemistry to be frequently expressed in patients with advanced NSCLC. However, PD-L1 expression is not a strong prognostic marker in patients with advanced NSCLC treated with chemotherapy.},
  number = {1},
  journal = {Translational Oncology},
  author = {Sorensen, Steffen Filskov and Zhou, Wei and {Dolled-Filhart}, Marisa and Georgsen, Jeanette Baehr and Wang, Zhen and Emancipator, Kenneth and Wu, Dianna and {Busch-S\o{}rensen}, Michael and Meldgaard, Peter and Hager, Henrik},
  year = {2016},
  keywords = {NSCLC,PDL1},
  pages = {64-69},
  file = {/Users/k/Zotero/storage/E8FPEYWL/Sorensen et al. - 2016 - PD-L1 expression and survival among patients with advanced non–small cell lung cancer treated with chemothera.pdf},
  pmid = {26947883}
}

@phdthesis{ChangfuXiao2011,
  title = {{{DOSE}}-{{FINDING DESIGNS FOR PHASE II CLINICAL TRIALS}}},
  author = {Xiao, Changfu},
  year = {2011},
  file = {/Users/k/Zotero/storage/29VARJYN/Xiao - 2011 - DOSE-FINDING DESIGNS FOR PHASE II CLINICAL TRIALS.pdf}
}

@article{Altman1994,
  title = {The Scandal of Poor Medical Research},
  volume = {308},
  issn = {0959-8138},
  doi = {10.1136/bmj.308.6924.283},
  abstract = {We need less research, better research, and research done for the right reasons$\backslash$n$\backslash$nWhat should we think about a doctor who uses the wrong treatment, either wilfully or through ignorance, or who uses the right treatment wrongly (such as by giving the wrong dose of a drug)? Most people would agree that such behaviour was unprofessional, arguably unethical, and certainly unacceptable.$\backslash$n$\backslash$nWhat, then, should we think about researchers who use the wrong techniques (either wilfully or in ignorance), use the right techniques wrongly, misinterpret their results, report their results selectively, cite the literature selectively, and draw unjustified conclusions? We should be appalled. Yet numerous studies of the medical literature, in both general and specialist journals, have shown that all of the above phenomena are common.1 2 3 4 5 6 7 This is surely a scandal.$\backslash$n$\backslash$nWhen I tell friends outside medicine that many papers published in medical journals are misleading because of methodological weaknesses they are rightly shocked. Huge sums of money are spent annually on research that is seriously flawed through the use of inappropriate designs, unrepresentative samples, small samples, incorrect methods \ldots{}},
  number = {6924},
  journal = {Bmj},
  author = {Altman, D G},
  year = {1994},
  pages = {283-284},
  file = {/Users/k/Zotero/storage/3NSYKXMX/Altman - 1994 - The scandal of poor medical research.pdf},
  pmid = {8124111}
}

@article{Zhang2017,
  title = {Umbilical {{Cord Mesenchymal Stem Cell Treatment}} for {{Crohn}}'s {{Disease}}: {{A Randomized Controlled Clinical Trial}}},
  doi = {10.5009/gnl17035},
  number = {256},
  journal = {Gut and Liver},
  author = {Zhang, Jian and Lv, Samei and Liu, Xiaojing and Song, Bin and Shi, Liping},
  year = {2017},
  keywords = {2,the,Crohns,3 however,ally need surgery to,among other symptoms,autoimmune,cellular therapy,crohn disease,eventu-,mesenchymal stromal cells,remove the diseased bowel,the majority of patients,tion,umbilical cord},
  pages = {1-6},
  file = {/Users/k/Zotero/storage/IUIYGVND/Zhang et al. - 2017 - Umbilical Cord Mesenchymal Stem Cell Treatment for Crohn's Disease A Randomized Controlled Clinical Trial.pdf}
}

@article{Lange2009,
  title = {Resolving the Clinical Acuity Categories "Hand Motion" and "Counting Fingers" Using the {{Freiburg Visual Acuity Test}} ({{FrACT}})},
  volume = {247},
  issn = {0721832X},
  doi = {10.1007/s00417-008-0926-0},
  abstract = {Purpose The Freiburg Visual Acuity Test (FrACT) has been suggested as a promising test for quantifying the visual acuity (VA) of patients with very low vision, a condition often classified using the semi-quantitative clinical scale " counting fingers " (CF), " hand motion " (HM), " light perception " (LP) and " no light perception " . The present study was designed to assess FrACT perfor-mance in a sizable number of CF, HM, and LP patients in order to generate a setting for future clinical studies in the low vision range. Methods We examined a total of 41 patients (LP, n=11; CF, n=15; HM, n=15) with various eye diseases (e.g., diabetic retinopathy, ARMD), covering the clinical VA scale from LP to CF. The FrACT optotypes were presented at a distance of 50 cm on a 17-inch LCD monitor with four random orientations. After training, two FrACT measure-ments (test and retest) were taken, each comprising 30 trials. Results FrACT measures reproducibly the VA of CF and HM patients. In CF patients, FrACT resulted in a mean logMAR=1.98$\pm$0.24 (corresponding to a decimal VA of 0.010), for HM in a mean logMAR = 2.28 $\pm$ 0.15 (corresponding to a decimal VA of 0.0052). In all LP patients the FrACT values were close to what would be obtained by random guessing. The mean test\textendash{}retest 95\% confidence interval was 0.21 logMAR for CF patients and 0.31 logMAR for HM respectively. Test-retest variability declined from 24 to 30 trials, showing that at least 30 trials are necessary. Conclusion FrACT can reproducibly quantify VA in the CF and HM range. We observed a floor effect for LP, and it was not quantifiable further. Quantitative VA measures are thus obtainable in the very low-vision range using FrACT.},
  number = {1},
  journal = {Graefe's Archive for Clinical and Experimental Ophthalmology},
  author = {Lange, C. and Feltgen, N. and Junker, B. and {Schulze-Bonsel}, K. and Bach, Michael},
  year = {2009},
  keywords = {Visual acuity,Low-vision assessment,Psychophysics},
  pages = {137-142},
  file = {/Users/k/Zotero/storage/NQZPAWQH/Lange et al. - 2009 - Resolving the clinical acuity categories hand motion and counting fingers using the Freiburg Visual Acuity Test (F.pdf},
  pmid = {18766368}
}

@article{Sedgwick2013,
  title = {Treatment Allocation by Minimisation},
  volume = {347},
  issn = {1756-1833},
  doi = {10.1136/bmj.f6569},
  abstract = {In almost all controlled trials treatments are allocated by randomisation. Blocking and stratification can be used to ensure balance between groups in size and patient characteristics.1 But stratified randomisation using several variables is not effective in small trials. The only widely acceptable alternative approach is minimisation,2 3 a method of ensuring excellent balance between groups for several prognostic factors, even in small samples. With minimisation the treatment allocated to the next participant enrolled in the trial depends (wholly or partly) on the characteristics of those participants already enrolled. The aim is that each allocation should minimise the imbalance across multiple factors.$\backslash$n$\backslash$nTable 1 shows some baseline characteristics in a controlled trial comparing two types of counselling in relation to dietary intake.4 Minimisation was used for the \ldots{}},
  number = {nov01 2},
  journal = {Bmj},
  author = {Sedgwick, P.},
  year = {2013},
  pages = {f6569-f6569},
  file = {/Users/k/Zotero/storage/WQCBJM49/Sedgwick - 2013 - Treatment allocation by minimisation.pdf},
  pmid = {15817555}
}

@article{Simmons2011,
  title = {False-{{Positive Psychology}}: {{Undisclosed Flexibility}} in {{Data Collection}} and {{Analysis Allows Presenting Anything}} as {{Significant Psychological}}},
  volume = {22},
  doi = {10.1177/0956797611417632},
  number = {11},
  journal = {Psychological Science},
  author = {Simmons, Joseph P. and Nelson, Leif D. and Simonsohn, Uri},
  year = {2011},
  pages = {1359-1366},
  file = {/Users/k/Zotero/storage/MP8TI464/Simmons, Nelson, Simonsohn - 2011 - False-Positive Psychology Undisclosed Flexibility in Data Collection and Analysis Allows Presenting.pdf}
}

@article{Thompson1993,
  title = {The {{X2}} Test for Data Collected on Eyes},
  volume = {77},
  abstract = {The need for caution when analysing data from the two eyes of the same subject has become widely appreciated among ophthalmologists and eye researchers, but the statistical techniques available to overcome the resulting difficulties are much less well understood. In a recent survey of the statistical content of papers in the BritishJournal ofOphthal-mology' it was evident that most papers used only relatively simple statistical techniques such as the XI test or t test; that data are frequently collected on pairs of eyes; and that few people know how to analyse such data in ways which are both valid and efficient. The problems ofcorrectly analysing correlated data are not trivial and this whole area is currently the subject ofextensive theoretical research. It is thus not surprising that there is a lag between methods becoming available and their widespread use. A recent review published in the Archives of Ophthal-mology' has described many of the latest developments. However, without a knowledge of statistical theory it is not easy to put such information to practical use. In this paper we consider one simple technique, the XI test, and show how easy},
  journal = {British Journal of Ophthalmology},
  author = {Thompson, John},
  year = {1993},
  pages = {115-117},
  file = {/Users/k/Zotero/storage/C5VSFY22/Thompson - 1993 - The X2 test for data collected on eyes.pdf}
}

@article{Mcshane2017,
  title = {Abandon {{Statistical Significance}} *},
  abstract = {In science publishing and many areas of research, the status quo is a lexicographic decision rule in which any result is first required to have a p-value that surpasses the 0.05 threshold and only then is consideration\textemdash{}often scant\textemdash{}given to such factors as prior and related evidence, plausibility of mechanism, study design and data quality, real world costs and benefits, novelty of finding, and other factors that vary by research domain. There have been recent proposals to change the p-value threshold, but instead we recommend abandoning the null hypothesis significance testing paradigm entirely, leaving p-values as just one of many pieces of information with no privileged role in scientific publication and decision making. We argue that this radical approach is both practical and sensible.},
  author = {Mcshane, Blakeley B and Gal, David and Gelman, Andrew and Robert, Christian and Tackett, Jennifer L},
  year = {2017},
  file = {/Users/k/Zotero/storage/PDNFG73V/Mcshane et al. - 2017 - Abandon Statistical Significance.pdf}
}

@article{Burkner2017,
  title = {Brms: {{An R Package}} for {{Bayesian Multilevel Models Using Stan}}},
  volume = {80},
  doi = {10.18637/jss.v080.i01},
  abstract = {The brms package implements Bayesian multilevel models in R using the probabilis-tic programming language Stan. A wide range of distributions and link functions are supported, allowing users to fit \textendash{} among others \textendash{} linear, robust linear, binomial, Pois-son, survival, ordinal, zero-inflated, hurdle, and even non-linear models all in a multilevel context. Further modeling options include autocorrelation of the response variable, user defined covariance structures, censored data, as well as meta-analytic standard errors. Prior specifications are flexible and explicitly encourage users to apply prior distributions that actually reflect their beliefs. In addition, model fit can easily be assessed and com-pared with the Watanabe-Akaike information criterion and leave-one-out cross-validation.},
  number = {1},
  journal = {JSS Journal of Statistical Software},
  author = {B\"urkner, Paul-Christian},
  year = {2017},
  file = {/Users/k/Zotero/storage/A9TAKPGF/Bürkner - 2017 - brms An R Package for Bayesian Multilevel Models Using Stan.pdf}
}

@article{Chiuzan2017,
  title = {Dose-Finding Designs for Trials of Molecularly Targeted Agents and Immunotherapies},
  volume = {27},
  issn = {1054-3406},
  doi = {10.1080/10543406.2017.1289952},
  abstract = {ABSTRACT Recently, there has been a surge of early phase trials of molecularly targeted agents (MTAs) and immunotherapies. These new therapies have different toxicity profiles compared to cytotoxic therapies. MTAs can benefit from new trial designs that allow inclusion of low-grade toxicities, late-onset toxicities, addition of an efficacy endpoint, and flexibility in the specification of a target toxicity probability. To study the degree of adoption of these methods, we conducted a Web of Science search of articles published between 2008 and 2014 that describe phase 1 oncology trials. Trials were categorized based on the dose-finding design used and the type of drug studied. Out of 1,712 dose- finding trials that met our criteria, 1,591 (92.9\%) utilized a rule-based design, and 92 (5.4\%; range 2.3\% in 2009 to 9.7\% in 2014) utilized a model-based or novel design. Over half of the trials tested an MTA or immunotherapy.Among the MTA and immunotherapy trials, 5.8\% used model-based methods, com- pared to 3.9\% and 8.3\% of the chemotherapy or radiotherapy trials, respec- tively. While the percentage of trials using novel dose-finding designs has tripled since 2007, the adoption of these designs continues to remain low.},
  number = {3},
  journal = {Journal of Biopharmaceutical Statistics},
  author = {Chiuzan, Cody and Shtaynberger, Jonathan and Manji, Gulam A. and Duong, Jimmy K. and Schwartz, Gary K. and Ivanova, Anastasia and Lee, Shing M.},
  year = {2017},
  keywords = {Chiuzan},
  pages = {477-494},
  file = {/Users/k/Zotero/storage/9SQGTU2N/Chiuzan et al. - 2017 - Dose-finding designs for trials of molecularly targeted agents and immunotherapies.pdf}
}

@article{Levy2006,
  title = {A Phase {{I}} Dose-Finding and Pharmacokinetic Study of Subcutaneous Semisynthetic Homoharringtonine ({{ssHHT}}) in Patients with Advanced Acute Myeloid Leukaemia},
  volume = {95},
  issn = {0007-0920},
  doi = {10.1038/sj.bjc.6603265},
  abstract = {To det. the max.-tolerated dose (MTD), dose-limiting toxicities and pharmacokinetic of semisynthetic homoharringtonine (ssHHT), given as a twice daily s.c. injections for 9 days, in patients with advanced acute leukemia, 18 patients with advanced acute myeloid leukemia were included in this sequential Bayesian phase I dose-finding trial. A starting dose of 0.5 mg m-2 day-1 was explored with subsequent dose escalations of 1, 3, 5, and 6 mg m-2 day-1. Myelosuppression was const. The MTD was estd. as the dose level of 5 mg m-2 day-1 for 9 consecutive days by s.c. route. Dose-limiting toxicities were hyperglycemia with hyperosmolar coma at 3 mg m-2, and (i) one anasarque and haematemesis, (ii) one life-threatening pulmonary aspergillosis, (iii) one skin rash and (iv) one scalp pain at dose level of 5 mg m-2 day-1. The mean half-life of ssHHT was 11.01 $\pm$ 3.4 h, the vol. of distribution at steady state was 2 $\pm$ 1.4 l kg-1 and the plasma clearance was 11.6 $\pm$ 10.4 l h-1. Eleven of the 12 patients with circulating leukemic cells had blood blast clearance, two achieved complete remission and one with blast crisis of CMML returned in chronic phase. The recommended daily dose of ssHHT on the 9-day schedule is 5 mg m-2 day-1. [on SciFinder(R)]},
  number = {3},
  journal = {British Journal of Cancer},
  author = {Levy, V and Zohar, S and Bardin, C and Vekhoff, A and Chaoui, D and Rio, B and Legrand, O and Sentenac, S and Rousselot, P and Raffoux, E and Chast, F and Chevret, S and Marie, J P},
  year = {2006},
  keywords = {CRM,leukemia pharmacokinetics subcutaneous semisynthet},
  pages = {253-259},
  file = {/Users/k/Zotero/storage/FMZYPERQ/Levy et al. - 2006 - A phase I dose-finding and pharmacokinetic study of subcutaneous semisynthetic homoharringtonine (ssHHT) in patient.pdf},
  pmid = {16847470}
}

@article{Noble2004,
  title = {Comparison of Autologous Serum Eye Drops with Conventional Therapy in a Randomised Controlled Crossover Trial for Ocular Surface Disease},
  volume = {88},
  issn = {0007-1161},
  doi = {10.1136/bjo.2003.026211},
  abstract = {Aims: To evaluate the efficacy of 50\% autologous serum drops against conventional treatment in ocular surface disorders refractory to normal treatments in a prospective randomised crossover trial.  Method: Patients fulfilling ophthalmological and haematological entry criteria were randomised to either 3 months of autologous serum 50\% followed by 3 months of their conventional treatment, or 3 months of conventional treatment, followed by 3 months of autologous serum. Clinical assessments, including Schirmer's test, rose Bengal, and fluorescein staining, were carried out on entry and at monthly intervals. Impression cytology was performed at entry, 3 and 6 months. Grading was carried out on degrees of squamous metaplasia and goblet cell density. Subjective comfort was recorded daily using the "faces" scale. These categorical scores were converted to linear measurement using Rasch analysis. Statistical analysis was carried out using Wilcoxon's signed rank test and ANOVA.  Results: 16 patients were recruited with 31 eyes studied. The ocular surface diseases chiefly included Sjogren's syndrome (n = 6) and keratoconjunctivitis sicca (n = 5). Impression cytology available in 25 of 31 eyes showed significant improvement on serum treatment, p$<$0.02. Rasch weighted faces scores were statistically significantly better with serum, p$<$0.01.  Conclusion: The results of this randomised study provide further evidence of the beneficial effects of autologous serum in severe ocular surface disorders. For most of these patients, autologous serum was superior to conventional treatment for improving ocular surface health and subjective comfort.},
  number = {5},
  journal = {British Journal of Ophthalmology},
  author = {Noble, B A},
  year = {2004},
  pages = {647-652},
  file = {/Users/k/Zotero/storage/M4NC7UGM/Noble - 2004 - Comparison of autologous serum eye drops with conventional therapy in a randomised controlled crossover trial for ocular.pdf}
}

@book{Pinheiro2000,
  edition = {1st},
  title = {Mixed-{{Effects Models}} in {{S}} and {{S}}-{{PLUS}}},
  isbn = {0-387-98957-9},
  publisher = {{Springer}},
  author = {Pinheiro, Jose and Bates, Douglas},
  year = {2000},
  keywords = {MixedModels}
}

@article{Pocock1975,
  title = {Sequential Treatment Assignment with Balancing for Prognostic Factors in the Controlled Clinical Trial},
  volume = {31},
  number = {1},
  journal = {Biometrics},
  author = {Pocock, Stuart J. and Simon, Richard},
  year = {1975},
  pages = {103-15},
  file = {/Users/k/Zotero/storage/A4GSFR5S/Pocock, Simon - 1975 - Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial.pdf}
}

@article{Senn2012,
  title = {Sevenmyths of Randomisation in Clinical Trials},
  volume = {32},
  abstract = {I consider seven misunderstandings that may be encountered about the nature, purpose and properties of ran- domisation in clinical trials. Some concern the practical realities of clinical research on patients. Others are to do with the value and purpose of balance. Still others are to do with a confusion about the role of conditioning in valid statistical inference. I consider a simple game of chance involving two dice to illustrate some points about inference and then consider the seven misunderstandings in turn. I conclude that although one should not make a fetish of randomisation, when proposing alternatives to randomisation in clinical trials, one should be very careful to be precise about the exact nature of the alternative being considered if one is to avoid the danger of underestimating the advantages that randomisation can offer. Copyright},
  number = {21},
  journal = {Statistics in Medicine},
  author = {Senn, Stephen},
  year = {2012},
  keywords = {randomization,blinding,conditioning,covariates},
  pages = {1439-1450},
  file = {/Users/k/Zotero/storage/YKRTZ7TJ/Senn - 2012 - Sevenmyths of randomisation in clinical trials.pdf}
}

@article{Desfrere2005,
  title = {Dose-Finding Study of Ibuprofen in Patent Ductus Arteriosus Using the Continual Reassessment Method},
  volume = {30},
  issn = {02694727},
  doi = {10.1111/j.1365-2710.2005.00630.x},
  abstract = {OBJECTIVE: Intravenous ibuprofen (IBU) has been found to be as effective as indomethacin for the treatment of patent ductus arteriosus (PDA) in preterm infants and has been associated with fewer adverse effects in comparative phase III studies. The dose regimen used (10-5-5 mg/kg/day) was based on limited pharmacokinetic data and no phase II study was available to determine the optimal dose of IBU for this indication. The present study was designed to determine the minimum effective dose regimen (MEDR) of IBU (one course) required to close ductus arteriosus in preterm infants. METHOD: A double-blind dose-finding study was conducted using the continual reassessment method, a Bayesian sequential design. Two distinct target closure rates were initially chosen according to postmenstrual age (PMA) at birth: 80\% in infants with a PMA of 27-29 weeks, and 50\% in infants with a PMA $<$ 27 weeks. Forty neonates (20 in each PMA group) with PDA were treated between days 3 and 5 of life. Four different dose regimens were tested: loading doses of 5, 10, 15 or 20 mg/kg, followed by two doses (1/2 loading dose) at 24-h intervals. Efficacy was evaluated by echocardiography 24 h after the third infusion. RESULTS: In infants with a PMA of 27-29 weeks, the estimated MEDR was 10-5-5 mg/kg with a final estimated probability of success of 77\% (95\% credibility interval: 56-92\%). The 15-7.5-7.5 mg/kg dose regimen had a better estimated probability of success (88\%, 95\% credibility interval: 68-97\%), but resulted in more minor renal adverse effects. In contrast, in infants with a PMA $<$ 27 weeks, the estimated MEDR was 20-10-10 mg/kg with an estimated probability of success of 54.8\% (95\% credibility interval: 22-84\%), whereas the conventional dose regimen resulted in a low estimated probability of success (30.6\%, 95\% credibility interval: 13-56\%). In these infants, compared with those with a PMA of 27-29 weeks, minor renal adverse effects were more frequent from the 10-5-5 mg/kg/day dose regimen and did not appear to be clearly dose related. CONCLUSION: This study confirms that the currently recommended dose regimen (10-5-5 mg/kg) of IBU is associated with a high closure rate (80\%) and few adverse effects in premature infants with a PMA of 27-29 weeks. The failure rate was much higher below 27 weeks. A higher dose regimen (20-10-10 mg/kg) might achieve a higher closure rate. However, tolerability and safety of this dose regimen should be assessed in a larger population before considering the use of these doses for ductus arteriosus closure.},
  number = {2},
  journal = {Journal of Clinical Pharmacy and Therapeutics},
  author = {Desfrere, Luc and Zohar, S. and Morville, P. and Brunhes, A. and Chevret, S. and Pons, G. and Moriette, G. and Rey, E. and Treluyer, J. M.},
  year = {2005},
  keywords = {Continual reassessment method,CRM,Bayesian design,Dose-ranging study,Ductus arteriosus,Ibuprofen,Premature neonate},
  pages = {121-132},
  file = {/Users/k/Zotero/storage/Q4WCQESB/Desfrere et al. - 2005 - Dose-finding study of ibuprofen in patent ductus arteriosus using the continual reassessment method.pdf},
  pmid = {15811164}
}

@article{Senn2004a,
  title = {Individual Response to Treatment: Is It a Valid Assumption?},
  volume = {329},
  issn = {1756-1833},
  doi = {10.1136/bmj.329.7472.966},
  abstract = {Most drug trials assume that patients respond consistently to treatment, but the assumption is rarely tested. If patients vary randomly in their response to a drug rather than some patients never responding, searches for a genetic basis for non-response are futile.},
  number = {7472},
  journal = {BMJ (Clinical research ed.)},
  author = {Senn, Stephen},
  year = {2004},
  keywords = {Humans,Treatment Outcome,Clinical Trials as Topic,Drug Therapy,Pharmacogenetics,precmed},
  pages = {966-8},
  file = {/Users/k/Zotero/storage/WHFBLRLR/Senn - 2004 - Individual response to treatment is it a valid assumption.pdf},
  pmid = {15499115}
}

@article{Gabry,
  title = {Visualization in {{Bayesian}} Workflow},
  author = {Gabry, Jonah and Simpson, Daniel and Vehtari, Aki and Betancourt, Michael and Gelman, Andrew},
  keywords = {BayesCore},
  file = {/Users/k/Zotero/storage/NJ3ZKX4C/Gabry et al. - Unknown - Visualization in Bayesian workflow.pdf}
}

@article{Senn2002a,
  title = {A Comment on Replication, p-Values and Evidence},
  volume = {21},
  doi = {10.1002/sim.1072},
  abstract = {Some years ago, in the pages of this journal, Goodman gave an interesting analysis of 'replication probabilities' of p-values. Speci\"ycally, he considered the possibility that a given experiment had produced a p-value that indicated 'signi\"ycance' or near signi\"ycance (he con-sidered the range p = 0:10 to 0.001) and then calculated the probability that a study with equal power would produce a signi\"ycant result at the conventional level of signi\"ycance of 0.05. He showed, for example, that given an uninformative prior, and (subsequently) a result-ing p-value that was exactly 0.05 from the \"yrst experiment, the probability of signi\"ycance in the second experiment was 50 per cent. A more general form of this result is as follows. If the \"yrst trial yields p = then the probability that a second trial will be signi\"ycant at signi\"ycance level (and in the same direction as the \"yrst trial) is 0.5. I share many of Goodman's misgiving about p-values and I do not disagree with his calculations (except in slight numerical details). I also consider that his demonstration is useful for two reasons. First, it serves as a warning for anybody planning a further similar study to one just completed (and which has a marginally signi\"ycant result) that this may not be matched in the second study. Second, it serves as a warning that apparent inconsistency in results from individual studies may be expected to be common and that one should not overreact to this phenomenon. However, I disagree with two points that he makes. First, he claims that 'the replication probability provides a means, within the frequentist framework, to separate p-values from their hypothesis test interpretation, an important \"yrst step towards understanding the concept of inferential meaning' (p. 879). I disagree with him on two grounds here: (i) it is not necessary to separate p-values from their hypothesis test interpretation; (ii) the replication probability has no direct bearing on inferential meaning. Second he claims that, 'the replication probability can be used as a frequentist counterpart of Bayesian and likelihood models to show that p-values overstate the evidence against the null-hypothesis' (p. 875, my italics). I disagree that there is such an overstatement.},
  journal = {Statistics in Medicine},
  author = {Senn, Stephen},
  year = {2002},
  pages = {2437-2444},
  file = {/Users/k/Zotero/storage/7TTX3FYE/Senn - 2002 - A comment on replication, p-values and evidence.pdf}
}

@article{Grieve2017,
  title = {Response-Adaptive Clinical Trials: Case Studies in the Medical Literature},
  volume = {16},
  issn = {15391612},
  doi = {10.1002/pst.1778},
  abstract = {The past 15 years has seen many pharmaceutical sponsors consider and implement adaptive designs (AD) across all phases of drug development. Given their arrival at the turn of the millennium, we might think that they are a recent invention. That is not the case. The earliest idea of an AD predates Bradford Hill's MRC tuberculosis study, appearing in Biometrika in 1933. In this paper, we trace the development of response-ADs, designs in which the allocation to intervention arms depends on the responses of subjects already treated. We describe some statistical details underlying the designs, but our main focus is to describe and comment on ADs from the medical research literature. Copyright \textcopyright{} 2016 John Wiley \& Sons, Ltd.},
  number = {1},
  journal = {Pharmaceutical Statistics},
  author = {Grieve, Andrew P.},
  year = {2017},
  keywords = {clinical trials,continual reassessment method,Bayesian,play-the-winner,3+3,biased coin,drug development,randomised play-the-winner,response ADs,up-and-down},
  pages = {64-86},
  file = {/Users/k/Zotero/storage/RZ9R3CQA/Grieve - 2017 - Response-adaptive clinical trials case studies in the medical literature.pdf},
  pmid = {27730735}
}

@article{Klopstock2013,
  title = {Persistence of the Treatment Effect of Idebenone in {{Leber}}'s Hereditary Optic Neuropathy},
  volume = {136},
  issn = {14602156},
  doi = {10.1093/brain/aws279},
  abstract = {There is a growing body of evidence supporting the beneficial effects of idebenone in Leber's hereditary optic neuropathy (LHON, MIM 353500), an inherited mitochondrial disease that causes rapid bilateral vision loss and lifelong legal blindness. Until recently, reports were limited to isolated case studies and small open-label case series. However, in 2011, two articles published in Brain provided additional evidence for the therapeutic use of idebenone in LHON.},
  number = {2},
  journal = {Brain},
  author = {Klopstock, T. and Metz, G. and {Yu-Wai-Man}, P. and B\"uchner, B. and Gallenm\"uller, C. and Bailie, M. and Nwali, N. and Griffiths, P. G. and Von Livonius, B. and Reznicek, L. and Rouleau, J. and Coppard, N. and Meier, T. and Chinnery, P. F.},
  year = {2013},
  keywords = {VisualAcuity},
  file = {/Users/k/Zotero/storage/9ETZUJ7F/Klopstock et al. - 2013 - Persistence of the treatment effect of idebenone in Leber's hereditary optic neuropathy.pdf},
  pmid = {23388409}
}

@article{Karanjia2016,
  title = {Correcting {{Finger Counting}} to {{Snellen Acuity}}},
  volume = {40},
  issn = {0165-8107},
  doi = {10.1080/01658107.2016.1209221},
  number = {5},
  journal = {Neuro-Ophthalmology},
  author = {Karanjia, Rustum and Jean, Tiffany and Francis, Alexander and Pouw, Andrew and Tian, Jack J},
  year = {2016},
  keywords = {VisualAcuity,count fingers,snellen,visual},
  pages = {219-221},
  file = {/Users/k/Zotero/storage/MSRY7YMR/Karanjia et al. - 2016 - Correcting Finger Counting to Snellen Acuity.pdf}
}

@article{Klopstock2011,
  title = {A Randomized Placebo-Controlled Trial of Idebenone in {{Leber}}'s Hereditary Optic Neuropathy},
  volume = {134},
  issn = {14602156},
  doi = {10.1093/brain/awr170},
  abstract = {Major advances in understanding the pathogenesis of inherited metabolic disease caused by mitochondrial DNA mutations have yet to translate into treatments of proven efficacy. Leber's hereditary optic neuropathy is the most common mitochondrial DNA disorder causing irreversible blindness in young adult life. Anecdotal reports support the use of idebenone in Leber's hereditary optic neuropathy, but this has not been evaluated in a randomized controlled trial. We conducted a 24-week multi-centre double-blind, randomized, placebo-controlled trial in 85 patients with Leber's hereditary optic neuropathy due to m.3460G$>$A, m.11778G$>$A, and m.14484T$>$C or mitochondrial DNA mutations. The active drug was idebenone 900 mg/day. The primary end-point was the best recovery in visual acuity. The main secondary end-point was the change in best visual acuity. Other secondary end-points were changes in visual acuity of the best eye at baseline and changes in visual acuity for both eyes in each patient. Colour-contrast sensitivity and retinal nerve fibre layer thickness were measured in subgroups. Idebenone was safe and well tolerated. The primary end-point did not reach statistical significance in the intention to treat population. However, post hoc interaction analysis showed a different response to idebenone in patients with discordant visual acuities at baseline; in these patients, all secondary end-points were significantly different between the idebenone and placebo groups. This first randomized controlled trial in the mitochondrial disorder, Leber's hereditary optic neuropathy, provides evidence that patients with discordant visual acuities are the most likely to benefit from idebenone treatment, which is safe and well tolerated.},
  number = {9},
  journal = {Brain},
  author = {Klopstock, Thomas and {Yu-Wai-Man}, Patrick and Dimitriadis, Konstantinos and Rouleau, Jacinthe and Heck, Suzette and Bailie, Maura and Atawan, Alaa and Chattopadhyay, Sandip and Schubert, Marion and Garip, Aylin and Kernt, Marcus and Petraki, Diana and Rummey, Christian and Leinonen, Mika and Metz, G\"unther and Griffiths, Philip G. and Meier, Thomas and Chinnery, Patrick F.},
  year = {2011},
  keywords = {VisualAcuity,idebenone,LHON,mitochondrial disease,mitochondrial DNA,mitochondrial encephalomyopathy,optic atrophy,optic neuropathy},
  pages = {2677-2686},
  file = {/Users/k/Zotero/storage/VQHL53LN/Klopstock et al. - 2011 - A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy.pdf},
  pmid = {21788663}
}

@techreport{Virgili2013,
  title = {Reading Aids for Adults with Low Vision},
  institution = {{Cochran Library}},
  author = {Virgili, G and Acosta, R and Ll, Grover and Sa, Bentley and Giacomelli, G},
  year = {2013},
  file = {/Users/k/Zotero/storage/BCG3LWFY/Virgili et al. - 2013 - Reading aids for adults with low vision.pdf},
  doi = {10.1002/14651858.CD003303.pub3.www.cochranelibrary.com},
  note = {Publication Title: Cochrane Database of Systematic Reviews}
}

@article{Mair2007,
  title = {Extended {{Rasch Modeling}}: {{The R Package eRm}}},
  volume = {20},
  abstract = {Item response theory models (IRT) are increasingly becoming established in social science research, particularly in the analysis of performance or attitudinal data in psy- chology, education, medicine, marketing and other fields where testing is relevant. We propose the R package eRm (extended Rasch modeling) for computing Rasch models and several extensions. A main characteristic of some IRT models, the Rasch model being the most prominent, concerns the separation of two kinds of parameters, one that describes qualities of the subject under investigation, and the other relates to qualities of the situation under which the response of a subject is observed. Using conditional maximum likelihood (CML) estimation both types of parameters may be estimated independently from each other. IRT models are well suited to cope with dichotomous and polytomous responses, where the response categories may be unordered as well as ordered. The incorporation of linear structures allows for modeling the effects of covariates and enables the analysis of repeated categorical measurements. The eRm package fits the following models: the Rasch model, the rating scale model (RSM), and the partial credit model (PCM) as well as linear reparameterizations through covariate structures like the linear logistic test model (LLTM), the linear rating scale model (LRSM), and the linear partial credit model (LPCM). We use an unitary, efficient CML approach to estimate the item parameters and their standard errors. Graphical and numeric tools for assessing goodness-of-fit are provided. Keywords:},
  number = {9},
  journal = {Journal of Statistical Software},
  author = {Mair, P and Hatzinger, R},
  year = {2007},
  keywords = {Likert,Rasch,Scoring,SIN Project},
  pages = {1-20},
  file = {/Users/k/Zotero/storage/BUQ6YHE7/Mair, Hatzinger - 2007 - Extended Rasch Modeling The R Package eRm.pdf}
}

@article{Norman2010,
  title = {Likert Scales, Levels of Measurement and the "Laws" of Statistics},
  volume = {15},
  issn = {13824996},
  doi = {10.1007/s10459-010-9222-y},
  abstract = {Reviewers of research reports frequently criticize the choice of statistical methods. While some of these criticisms are well-founded, frequently the use of various parametric methods such as analysis of variance, regression, correlation are faulted because: (a) the sample size is too small, (b) the data may not be normally distributed, or (c) The data are from Likert scales, which are ordinal, so parametric statistics cannot be used. In this paper, I dissect these arguments, and show that many studies, dating back to the 1930s consistently show that parametric statistics are robust with respect to violations of these assumptions. Hence, challenges like those above are unfounded, and parametric methods can be utilized without concern for "getting the wrong answer".},
  number = {5},
  journal = {Advances in Health Sciences Education},
  author = {Norman, Geoff},
  year = {2010},
  keywords = {Likert,ANOVA,Categorical,Robustness,Statistics},
  pages = {625-632},
  file = {/Users/k/Zotero/storage/TWQJH73K/Norman - 2010 - Likert scales, levels of measurement and the laws of statistics.pdf},
  pmid = {20146096}
}

@article{Senn2006a,
  title = {Change from Baseline and Analysis of Covariance Revisited},
  volume = {25},
  doi = {10.1002/sim.2682},
  abstract = {SUMMARY The case for preferring analysis of covariance (ANCOVA) to the simple analysis of change scores (SACS) has often been made. Nevertheless, claims continue to be made that analysis of covariance is biased if the groups are not equal at baseline. If the required equality were in expectation only, this would permit the use of ANCOVA in randomized clinical trials but not in observational studies. The discussion is related to Lord's paradox. In this note, it is shown, however that it is not a necessary condition for groups to be equal at baseline, not even in expectation, for ANCOVA to provide unbiased estimates of treatment effects. It is also shown that although many situations can be envisaged where ANCOVA is biased it is very difficult to imagine circumstances under which SACS would then be unbiased and a causal interpretation could be made.},
  journal = {STATISTICS IN MEDICINE Statist. Med},
  author = {Senn, Stephen},
  year = {2006},
  keywords = {ANCOVA},
  pages = {4334-4344},
  file = {/Users/k/Zotero/storage/BTRUPRSF/Senn - 2006 - Change from baseline and analysis of covariance revisited.pdf}
}

@article{Williamson2017,
  title = {The {{COMET Handbook}}: Version 1.0},
  volume = {18},
  issn = {1745-6215},
  doi = {10.1186/s13063-017-1978-4},
  abstract = {The selection of appropriate outcomes is crucial when designing clinical trials in order to compare the effects of different interventions directly. For the findings to influence policy and practice, the outcomes need to be relevant and important to key stakeholders including patients and the public, health care professionals and others making decisions about health care. It is now widely acknowledged that insufficient attention has been paid to the choice of outcomes measured in clinical trials. Researchers are increasingly addressing this issue through the development and use of a core outcome set, an agreed standardised collection of outcomes which should be measured and reported, as a minimum, in all trials for a specific clinical area. Accumulating work in this area has identified the need for guidance on the development, implementation, evaluation and updating of core outcome sets. This Handbook, developed by the COMET Initiative, brings together current thinking and methodological research regarding those issues. We recommend a four-step process to develop a core outcome set. The aim is to update the contents of the Handbook as further research is identified.},
  number = {Suppl 3},
  journal = {Trials},
  author = {Williamson, Paula R and Altman, Douglas G and Bagley, Heather and Barnes, Karen L and Blazeby, Jane M and Brookes, Sara T and Clarke, Mike and Gargon, Elizabeth and Gorst, Sarah and Harman, Nicola and Kirkham, Jamie J and McNair, Angus and Prinsen, Cecilia A C and Schmitt, Jochen and Terwee, Caroline B and Young, Bridget},
  year = {2017},
  keywords = {CoreOutcomeSets,clinical trial,1,trials,1 outcomes in clinical,background,chapter 1,clinical trials are research,comet initiative,core outcome set,patients and the public,studies undertaken with human},
  pages = {1-50},
  file = {/Users/k/Zotero/storage/CQJGBZLR/Williamson et al. - 2017 - The COMET Handbook version 1.0.pdf}
}

@article{Earl2017,
  title = {Spotlight on Landmark Oncology Trials : The Latest Evidence and Novel Trial Designs},
  volume = {15},
  doi = {10.1186/s12916-017-0884-7},
  number = {111},
  journal = {BMC Medicine},
  author = {Earl, Helena and Molica, Stefano and Rutkowski, Piotr},
  year = {2017},
  keywords = {oncology,clinical trials,cancer,Oncology,Clinical trials,Randomised trials,Cancer,randomised trials,targeted therapy,trial design},
  pages = {1-6},
  file = {/Users/k/Zotero/storage/NIYVCVFZ/Earl, Molica, Rutkowski - 2017 - Spotlight on landmark oncology trials the latest evidence and novel trial designs.pdf}
}

@article{Kemp2017,
  title = {Surrogate Endpoints in Oncology: When Are They Acceptable for Regulatory and Clinical Decisions, and Are They Currently Overused?},
  volume = {15},
  issn = {1741-7015},
  doi = {10.1186/s12916-017-0902-9},
  number = {134},
  journal = {BMC Medicine},
  author = {Kemp, Robert and Prasad, Vinay},
  year = {2017},
  keywords = {SurrogateOutcomes,Outcomes,cancer,Cancer,administration,fda,outcomes,regulation,Regulation,surrogate endpoints,Surrogate endpoints,US,us food and drug},
  file = {/Users/k/Zotero/storage/SG3JTUTV/Kemp, Prasad - 2017 - Surrogate endpoints in oncology when are they acceptable for regulatory and clinical decisions, and are they curre.pdf},
  pmid = {28728605}
}

@article{Fudge,
  title = {Fifty Years of {{J}}. {{R}}. {{Platt}}'s Strong Inference},
  volume = {217},
  doi = {10.1242/jeb.104976},
  journal = {The Journal of Experimental Biology},
  author = {{Douglas Fudge}},
  year = {2014},
  pages = {1202-4},
  file = {/Users/k/Zotero/storage/LHPB4QDZ/Douglas Fudge - 2014 - Fifty years of J. R. Platt’s strong inference.pdf}
}

@article{Brock2017a,
  title = {Implementing the {{EffTox}} Dose-Finding Design in the {{Matchpoint}} Trial},
  volume = {17},
  issn = {1471-2288},
  doi = {10.1186/s12874-017-0381-x},
  number = {1},
  journal = {BMC Medical Research Methodology},
  author = {Brock, Kristian and Billingham, Lucinda and Copland, Mhairi and Siddique, Shamyla and Sirovica, Mirjana and Yap, Christina},
  year = {2017},
  keywords = {efficacy,toxicity,dose-finding,phase i,cml,efftox,ii,MyPubs},
  pages = {112},
  file = {/Users/k/Zotero/storage/ZW5FVC29/Brock et al. - 2017 - Implementing the EffTox dose-finding design in the Matchpoint trial.pdf}
}

@article{OHagan,
  title = {Bayes {{Factors}}},
  author = {O'Hagan, Anthony},
  file = {/Users/k/Zotero/storage/XTKJEPYD/O'Hagan - Unknown - Bayes Factors.pdf}
}

@article{Altman1983,
  title = {Statistical Guidelines for Contributors to Medical Journals.},
  volume = {286},
  issn = {0267-0623},
  doi = {10.1136/bmj.286.6376.1489},
  abstract = {Most papers published in medical journals contain anlyses that have been carried out wtihout any help from a statistician. Although nearly all medical researchers have some acquaintance with basic statistics, there is no easy way for them to acquire insight into important stastical concepts and principles. There is also little help available about how to design, analyse and write up a whole project. Partly for these reasons, much that is published in medical journals is statistically poor or even worng. A high level of statistical errors has been noted in several reviews of journal articles and has caused much concern.},
  number = {6376},
  journal = {British medical journal (Clinical research ed.)},
  author = {Altman, D G and Gore, S M and Gardner, M J and Pocock, S J},
  year = {1983},
  pages = {1489-1493},
  file = {/Users/k/Zotero/storage/8K6KGSRK/Altman et al. - 1983 - Statistical guidelines for contributors to medical journals.pdf},
  pmid = {6405856}
}

@article{Gelman2017,
  archivePrefix = {arXiv},
  eprinttype = {arxiv},
  eprint = {1508.05453v1},
  title = {Beyond Subjective and Objective in Statistics},
  volume = {180},
  abstract = {Decisions in statistical data analysis are often justified, criticized, or avoided by using concepts of objectivity and subjectivity. We argue that the words `objective' and `sub- jective' in statistics discourse are used in a mostly unhelpful way, and we propose to replace each of them with broader collections of attributes, with objectivity replaced by transparency, consensus, impartiality and correspondence to observable reality , and subjectivity replaced by awareness of multiple perspectives and context dependence. Together with stability , these make up a collection of virtues that we think is helpful in discussions of statistical foundations and practice. The advantage of these reformulations is that the replacement terms do not op- pose each other and that they give more specific guidance about what statistical science strives to achieve. Instead of debating over whether a given statistical method is subjective or objective (or normatively debating the relative merits of subjectivity and objectivity in statistical practice), we can recognize desirable attributes such as transparency and acknowledgement of multiple perspectives as complementary goals.We demonstrate the implications of our proposal with recent applied examples from pharmacology, election polling and socio-economic stratification. The aim of the paper is to push users and developers of statistical methods towards more ef- fective use of diverse sources of information and more open acknowledgement of assumptions and goals.},
  number = {4},
  journal = {Journal of the Royal Statistical Society},
  author = {Gelman, Andrew and Hennig, Christian},
  year = {2017},
  pages = {1-31},
  file = {/Users/k/Zotero/storage/NKA27WW3/Gelman, Hennig - 2017 - Beyond subjective and objective in statistics.pdf}
}

@article{Senn2004,
  title = {Controversies Concerning Randomization and Additivity in Clinical Trials},
  volume = {23},
  issn = {02776715},
  doi = {10.1002/sim.2074},
  abstract = {'As ye randomise so shall ye analyse', is one way of describing Fisher's defence of randomization. Yet, when it comes to clinical trials we nearly always randomize but we rarely analyse the way we randomize and Fisher himself was no exception. Two controversies involving Fisher in the 1930s are discussed: one with Neyman concerning additivity and the other with Student concerning randomization. Their relevance today is considered, as is whether randomization inference in clinical trials is dead and whether modelling rules the day, whether minimization is an acceptable procedure and to what extent trialists confuse experiments with surveys. It will be maintained that a number of different possible purposes of clinical trials have been confused because in the case of the general linear model, under strong additivity, they can all be satisfied by a single analysis. More generally, however, this is not the case.},
  number = {24},
  journal = {Statistics in Medicine},
  author = {Senn, Stephen},
  year = {2004},
  keywords = {Additivity,Clinical trails,History of statistics,Randomisation,Senn,Unit-treatment interaction},
  pages = {3729-3753},
  file = {/Users/k/Zotero/storage/PVYYN2K4/Senn - 2004 - Controversies concerning randomization and additivity in clinical trials.pdf},
  pmid = {15580598}
}

@article{Senn2013,
  title = {Seven Myths of Randomisation in Clinical Trials},
  volume = {32},
  issn = {02776715},
  doi = {10.1002/sim.5713},
  abstract = {I consider seven misunderstandings that may be encountered about the nature, purpose and properties of randomisation in clinical trials. Some concern the practical realities of clinical research on patients. Others are to do with the value and purpose of balance. Still others are to do with a confusion about the role of conditioning in valid statistical inference. I consider a simple game of chance involving two dice to illustrate some points about inference and then consider the seven misunderstandings in turn. I conclude that although one should not make a fetish of randomisation, when proposing alternatives to randomisation in clinical trials, one should be very careful to be precise about the exact nature of the alternative being considered if one is to avoid the danger of underestimating the advantages that randomisation can offer.},
  number = {9},
  journal = {Statistics in Medicine},
  author = {Senn, Stephen},
  year = {2013},
  keywords = {Blinding,Randomisation,Senn,Conditioning,Covariates},
  pages = {1439-1450},
  file = {/Users/k/Zotero/storage/XBV8Y4FM/Senn - 2013 - Seven myths of randomisation in clinical trials.pdf},
  pmid = {23255195}
}

@article{Grieve1998,
  title = {Estimating Treatment Effects in Clinical Crossover Trials.},
  volume = {8},
  issn = {1054-3406},
  doi = {10.1080/10543409808835235},
  abstract = {Some current approaches to modeling crossover trials in two treatments are critically reviewed from the perspective of the practical requirements of the drug developer. Particular attention is paid to the AB/BA design, and the inadequacies of the once popular two-stage procedure are discussed in detail. The use of baseline data is also examined. Both frequentist and Bayesian alternatives to approaches currently advocated are considered and critically compared. It is concluded that it is crucial for the applied statistician working in this field to have an appreciation of the practical medical and pharmacological background.},
  number = {February 2015},
  journal = {Journal of biopharmaceutical statistics},
  author = {Grieve, A and Senn, S},
  year = {1998},
  keywords = {Senn},
  pages = {191-233; discussion 235-247},
  file = {/Users/k/Zotero/storage/XH4DVTWF/Grieve, Senn - 1998 - Estimating treatment effects in clinical crossover trials.pdf},
  pmid = {9598420}
}

@article{Dushay2012,
  title = {Short-{{Term Exenatide Treatment Leads}} to {{Signi}} Fi Cant {{Weight Loss}} in a {{Subset}} of {{Obese Women Without Diabetes}}},
  volume = {35},
  doi = {10.2337/dc11-0931.},
  journal = {Diabetes Care},
  author = {DUSHAY, JODY and GAO, CHUANYUN and GOPALAKRISHNAN, GOSALA S. and CRAWLEY, MEGHAN and MITTEN, EMILIE K. and WILKER, ELISSA and MULLINGTON, JANET and {MARATOS-FLIER}, ELEFTHERIA and {OBJECTIVEdTo}},
  year = {2012},
  keywords = {Exenatide,WeightLoss},
  pages = {4-11},
  file = {/Users/k/Zotero/storage/2YTZGGKB/DUSHAY et al. - 2012 - Short-Term Exenatide Treatment Leads to Signi fi cant Weight Loss in a Subset of Obese Women Without Diabetes.pdf}
}

@article{CIGTS1999,
  title = {The {{Collaborative Initial Glaucoma Treatment Study}}: Study Design, Methods, and Baseline Characteristics of Enrolled Patients.},
  volume = {106},
  issn = {0161-6420},
  doi = {10.1016/S0161-6420(99)90147-1},
  abstract = {OBJECTIVE The Collaborative Initial Glaucoma Treatment Study (CIGTS) is a randomized, controlled clinical trial designed to determine whether patients with newly diagnosed open-angle glaucoma (primary, pigmentary, or pseudoexfoliative) are better treated by initial treatment with medications or by immediate filtration surgery. DESIGN Randomized, controlled clinical trial. PARTICIPANTS A total of 607 patients with open-angle glaucoma were enrolled. INTERVENTION Patients randomized to initial medications (n=307) received a stepped regimen of medications to lower intraocular pressure. Those randomized to initial surgery (n=300) underwent trabeculectomy to lower intraocular pressure. MAIN OUTCOME MEASURES Progression in visual field loss constitutes the study's primary outcome variable. Secondary outcomes include health-related quality of life, visual acuity, and intraocular pressure. RESULTS Randomized assignment resulted in a balanced distribution between treatment groups for most demographic and clinical measures assessed at enrollment. More males than females were enrolled (55\% were males), and a substantial percentage (38.1 \%) of enrollees were blacks. Most enrollees (90.6\%) were diagnosed with primary open-angle glaucoma; the remainder had either pseudoexfoliative (4.8\%) or pigmentary (4.6\%) forms of open-angle glaucoma. CONCLUSIONS Follow-up of this well-characterized group of patients should provide well-rounded guidance, based on both traditional ophthalmic measures and patients' perspectives on their health-related quality of life, on how best to initially treat open-angle glaucoma.},
  number = {4},
  journal = {Ophthalmology},
  author = {{CIGTS}},
  year = {1999},
  keywords = {Glaucoma},
  pages = {653-62},
  file = {/Users/k/Zotero/storage/2L3MLL29/CIGTS - 1999 - The Collaborative Initial Glaucoma Treatment Study study design, methods, and baseline characteristics of enrolled patien.pdf},
  pmid = {10201583}
}

@article{Silberstein2008,
  title = {Guidelines for Controlled Trials of Prophylactic Treatment of Chronic Migraine in Adults},
  volume = {28},
  issn = {03331024},
  doi = {10.1111/j.1468-2982.2008.01555.x},
  abstract = {In 1991 the Clinical Trials Subcommittee of the International Headache Society (IHS) developed and published its first edition of the Guidelines on controlled trials of drugs in episodic migraine because only quality trials can form the basis for international collaboration on drug therapy, and these Guidelines would `improve the quality of controlled clinical trials in migraine'. With the current trend for large multinational trials, there is a need for increased awareness of methodological issues in clinical trials of drugs and other treatments for chronic migraine. These Guidelines are intended to assist in the design of well-controlled clinical trials of chronic migraine in adults, and do not apply to studies in children or adolescents.},
  number = {5},
  journal = {Cephalalgia},
  author = {Silberstein, S. and {Tfelt-Hansen}, P. and Dodick, D. W. and Limmroth, V. and Lipton, R. B. and Pascual, J. and Wang, S. J.},
  year = {2008},
  keywords = {Clinical trials,Headache,Chronic migraine,Medication-overuse headache,Prophylactic treatment},
  pages = {484-495},
  file = {/Users/k/Zotero/storage/A5UTUSBR/Silberstein et al. - 2008 - Guidelines for controlled trials of prophylactic treatment of chronic migraine in adults.pdf},
  pmid = {18294250}
}

@article{Mitsikostas2015,
  title = {New Players in the Preventive Treatment of Migraine},
  volume = {13},
  issn = {1741-7015},
  doi = {10.1186/s12916-015-0522-1},
  abstract = {Migraine is a common, chronic disorder of the brain causing much disability, as well as personal, familial and societal impact. Several oral preventive agents are available in different countries for the prevention of migraine, but none have performed better than 50\% improvement in 50\% of patients in a clinical trial. Additionally, each has various possible adverse events making their tolerability less than optimal. Recently, three monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) ligand (LY2951742, ALD403 and TEV-48125) and one targeting the CGRP receptor (AMG 334) have completed phase 2 trials, and the results have been reported. These early results show them all to be somewhat more effective than placebo, with no serious adverse events. Three have been studied for episodic migraine, and only TEV-48125 has been studied for both high frequency episodic and chronic migraine. Moreover, preliminary data suggests that neurostimulation is effective in migraine treatment, including stimulation of the sphenopalatine ganglion, transcutaneous supraorbital and supratrochlear nerve, and transcutaneous vagus nerve. In this article, these innovative therapies will be reviewed.},
  number = {1},
  journal = {BMC Medicine},
  author = {Mitsikostas, Dimos D. and Rapoport, Alan M.},
  year = {2015},
  keywords = {Headache,cgrp,cluster headache,migraine,Migraine;Cluster headache;Prevention;CGRP;Monoclon,monoclonal antibodies,neuromodulation,neurostimulation,prevention,stimulation,supraorbital and supratrochlear nerve,vagus nerve stimulation},
  pages = {279},
  file = {/Users/k/Zotero/storage/ZZDCQQST/Mitsikostas, Rapoport - 2015 - New players in the preventive treatment of migraine.pdf},
  pmid = {26555040}
}

@article{Leske1999,
  title = {Early Manifest Glaucoma Trial},
  volume = {106},
  issn = {01616420},
  doi = {10.1016/S0161-6420(99)90497-9},
  abstract = {OBJECTIVES$\backslash$nThe Early Manifest Glaucoma Trial (EMGT) will evaluate the effectiveness of reducing intraocular pressure (IOP) in early, previously untreated open-angle glaucoma. Its secondary aims are to explore factors related to glaucoma progression and to study the natural history of the disease. This article describes the EMGT design and presents baseline data. $\backslash$n$\backslash$nDESIGN$\backslash$nRandomized, clinical trial. $\backslash$n$\backslash$nPARTICIPANTS$\backslash$nNewly diagnosed patients 50 to 80 years of age with early glaucomatous visual field defects were mainly identified from a population-based screening of more than 44,000 residents of Malm\"o and Hel-singborg, Sweden. Exclusion criteria were advanced visual field loss; mean IOP greater than 30 mmHg or any IOP greater than 35 mmHg; visual acuity less than 0.5; and inability to complete follow-up protocols. $\backslash$n$\backslash$nINTERVENTIONS$\backslash$nAfter informed consent, patients were randomized to treatment or no initial treatment with close follow-up. Treated patients had laser trabeculoplasty and started receiving topical betaxolol twice daily in eligible eyes. Follow-up visits include computerized perimetry and tonometry every 3 months and fundus photography every 6 months. Decisions to change or begin treatment are made jointly with the patient when EMGT progression occurs and also later if clinically needed. $\backslash$n$\backslash$nMAIN OUTCOME MEASURES$\backslash$nThe EMGT progression is defined by sustained increases of visual field loss in three consecutive C30-2 Humphrey tests, as determined from computer-based analyses, or by optic disc changes, as determined from flicker chronoscopy and side-by-side comparisons of fundus photographs performed by masked, independent graders. $\backslash$n$\backslash$nRESULTS$\backslash$nA total of 255 patients were randomized between 1993 and 1997 and will be followed for at least 4 years. All had generally good health status; mean age was 68.1 years, and 66\% were women. At baseline, mean IOP was 20.6 mmHg and 80\% of eyes had IOP less than 25 mmHg. $\backslash$n$\backslash$nCONCLUSIONS$\backslash$nThe Early Manifest Glaucoma Trial is the first large randomized, clinical trial to evaluate the role of immediate pressure reduction, as compared to no initial reduction, in patients with early glaucoma and normal or moderately elevated IOP. Its results will have implications for: (1) the clinical management of glaucoma; (2) understanding the role of IOP and the natural history of glaucoma; and (3) evaluating the rationale for glaucoma screening.},
  number = {11},
  journal = {Ophthalmology},
  author = {Leske, M.Cristina and Heijl, Anders and Hyman, Leslie and Bengtsson, Bo},
  year = {1999},
  keywords = {Glaucoma},
  pages = {2144-2153},
  file = {/Users/k/Zotero/storage/D7HJV8W5/Leske et al. - 1999 - Early manifest glaucoma trial.pdf},
  pmid = {10571351}
}

@article{Garway-Heath2013,
  title = {The {{United Kingdom}} Glaucoma Treatment Study: {{A}} Multicenter, Randomized, Placebo-Controlled Clinical Trial: {{Design}} and Methodology},
  volume = {120},
  issn = {01616420},
  doi = {10.1016/j.ophtha.2012.07.028},
  abstract = {Objective: Elevated intraocular pressure (IOP) is a major risk factor for the deterioration of open-angle glaucoma (OAG); medical IOP reduction is the standard treatment, yet no randomized placebo-controlled study of medical IOP reduction has been undertaken previously. The United Kingdom Glaucoma Treatment Study (UKGTS) tests the hypothesis that treatment with a topical prostaglandin analog, compared with placebo, reduces the frequency of visual field (VF) deterioration events in OAG patients by 50\% over a 2-year period. Design: The UKGTS is a randomized, double-masked, placebo-controlled, multicenter treatment trial for OAG. Participants: Five hundred sixteen newly diagnosed (previously untreated) patients with OAG were recruited prospectively at 10 centers between 2007 and 2010. Methods: Patients were assigned by concealed telephone allocation to treatment with a prostaglandin analog (latanoprost 0.005\%) or placebo. The observation period was 2 years, with subjects monitored by VF testing, quantitative imaging, optic disc photography, and tonometry at 11 visits. Data were acquired according to novel protocols optimized for the analysis of deterioration velocity. The sample size was determined for a 2-sided error of $\alpha$ = 0.05 to detect the difference between 24\% and 11\% in incident deterioration over a 24-month follow-up at 90\% power and assuming a 25\% attrition rate. Main Outcome Measures: The primary outcome was time to VF deterioration within 24 months. Secondary outcomes included the deterioration velocity of VF and quantitative imaging measures and the relationship between these velocities and risk factors for deterioration. Results: The study design enabled a short trial with a 2-year observation period and provided data that can be used to assess the feasibility of further shortening trial duration with the progression velocity of VF and structural imaging measurements as outcomes. Conclusions: The UKGTS is the first randomized, placebo-controlled trial to evaluate the efficacy of medical treatment in reducing VF deterioration in OAG. The measurement of deterioration velocity and inclusion of quantitative imaging has the potential to reduce the number of patients and duration required for subsequent clinical trials. This trial also will quantify risk factors for deterioration, enabling more precise risk profiling of patients and the development of patient management protocols. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. \textcopyright{} 2013 American Academy of Ophthalmology.},
  number = {1},
  journal = {Ophthalmology},
  author = {{Garway-Heath}, David F. and Lascaratos, Gerassimos and Bunce, Catey and Crabb, David P. and Russell, Richard A. and Shah, Ameet},
  year = {2013},
  keywords = {Glaucoma},
  pages = {68-76},
  file = {/Users/k/Zotero/storage/YHUUM6DN/Garway-Heath et al. - 2013 - The United Kingdom glaucoma treatment study A multicenter, randomized, placebo-controlled clinical trial De.pdf},
  pmid = {22986112}
}

@article{Kupersmith2015,
  title = {Papilledema {{Outcomes}} from the {{Optical Coherence Tomography Substudy}} of the {{Idiopathic Intracranial Hypertension Treatment Trial}}.},
  volume = {122},
  issn = {1549-4713},
  doi = {10.1016/j.ophtha.2015.06.003},
  abstract = {PURPOSE To assess treatment efficacy using spectral-domain (SD) optical coherence tomography (OCT) measurements of papilledema in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT), which evaluated the effects of acetazolamide and weight management and of placebo and weight management in eyes with mild visual loss. DESIGN Randomized double-masked control clinical trial of acetazolamide plus weight management compared with placebo plus weight management in subjects with mild visual field loss and previously untreated idiopathic intracranial hypertension (IIH). PARTICIPANTS Eighty-nine (43 acetazolamide treated, 46 placebo treated) of 165 subjects meeting IIHTT entry criteria. METHODS Subjects underwent perimetry, papilledema grading (Fris\'en method), high- and low-contrast visual acuity, and SD OCT imaging at study entry and 3 and 6 months. Study eye results (worse perimetric mean deviation [PMD]) were used for most analyses. MAIN OUTCOME MEASURES Retinal nerve fiber layer (RNFL) thickness, total retinal thickness (TRT), optic nerve (ONH) volume, and retinal ganglion cell layer (RGCL) measurements derived using 3-dimensional segmentation. RESULTS Study entry OCT values were similar in both treatment groups. At 6 months, the acetazolamide group had greater reduction than the placebo group for RNFL thickness (175 $\mu$m vs. 89 $\mu$m; P = 0.001), TRT (220 $\mu$m vs. 113 $\mu$m; P = 0.001), and ONH volume (4.9 mm(3) vs. 2.1 mm(3); P = 0.001). The RNFL thickness (P = 0.01), TRT (P = 0.003), and ONH volume (P = 0.002) measurements also showed smaller increases in subjects who lost 6\% or more of study entry weight. The acetazolamide (3.6 $\mu$m) and placebo (2.1 $\mu$m) groups showed minor RGCL thinning (P = 0.06). The RNFL thickness, TRT, and ONH volume measurements showed moderate correlations (r = 0.48-0.59; P $\leq$ 0.0001) with Fris\'en grade. The 14 eyes with RGCL thickness less than the fifth percentile of controls had worse PMD (P = 0.001) than study eyes with RGCL in the fifth percentile or more. CONCLUSIONS In IIH, acetazolamide and weight loss effectively improve RNFL thickness, TRT, and ONH volume swelling measurements resulting from papilledema. In contrast to the strong correlation at baseline, OCT measures at 6 months show only moderate correlations with papilledema grade.},
  number = {9},
  journal = {Ophthalmology},
  author = {Kupersmith, Mark J.},
  year = {2015},
  keywords = {IIH},
  pages = {1939-45.e2},
  file = {/Users/k/Zotero/storage/XCS5VQ76/Kupersmith - 2015 - Papilledema Outcomes from the Optical Coherence Tomography Substudy of the Idiopathic Intracranial Hypertension Trea.pdf},
  pmid = {26198807}
}

@article{French2012,
  title = {Adjunctive Perampanel for Refractory Partial-Onset Seizures},
  volume = {79},
  journal = {Neurology},
  author = {French, Jacqueline A and Krauss, Gregory L and Biton, Victor and Squillacote, David and Yang, Haichen and Laurenza, Antonio and Kumar, Dinesh and Rogawski, Michael A.},
  year = {2012},
  pages = {589-596},
  file = {/Users/k/Zotero/storage/468XUYZ5/French et al. - 2012 - Adjunctive perampanel for refractory partial-onset seizures.pdf}
}

@article{Biton2014,
  title = {Brivaracetam as Adjunctive Treatment for Uncontrolled Partial Epilepsy in Adults: {{A}} Phase {{III}} Randomized, Double-Blind, Placebo-Controlled Trial},
  volume = {55},
  doi = {10.1111/epi.12433},
  number = {1},
  journal = {Epilepsia,},
  author = {Biton, Victor and Berkovic, Samuel F and {Abou-khalil}, Bassel and Sperling, Michael R and Johnson, Martin E and Lu, Sarah},
  year = {2014},
  keywords = {efficacy,Epilepsy,2010,being investigated for the,bialer,brivaracetam,brv,currently,et al,high-affinity synaptic vesicle pro-,is a pyrrolidine derivative,it is a novel,partial epilepsy,phase iii,safety,tolerability,treatment of epilepsy},
  pages = {57-66},
  file = {/Users/k/Zotero/storage/6WMHTJZN/Biton et al. - 2014 - Brivaracetam as adjunctive treatment for uncontrolled partial epilepsy in adults A phase III randomized, double-bl.pdf}
}

@article{Coeytaux2006,
  title = {Four Methods of Estimating the Minimal Important Difference Score Were Compared to Establish a Clinically Significant Change in {{Headache Impact Test}}},
  volume = {59},
  issn = {08954356},
  doi = {10.1016/j.jclinepi.2005.05.010},
  abstract = {Objective: To estimate the smallest decrease in Headache Impact Test (HIT) scores that reflects meaningful clinical change among patients with chronic daily headache (CDH). Study Design and Setting: We applied four methods of estimating the minimum important difference (MID) to data from 71 patients with CDH who participated in a clinical trial. The HIT was administered at baseline and at the 6-week follow-up assessment. Patients were considered to have experienced meaningful improvement if they reported that their headache condition was "somewhat better" or "much better" at the 6-week follow-up. Results: Mean HIT scores at baseline and 6 weeks for all patients were 64.5 (standard deviation SD = 6.0) and 62.6 (SD = 5.7), respectively. HIT scores decreased 3.7 (SD = 4.4) and 1.4 (SD = 3.6) units, respectively, among patients who reported "somewhat better" change and those who reported no change at 6 weeks. Estimates of the MID of the HIT ranged from -2.7 to -2.3. Conclusions: The method that we judge to be most valid estimated the MID of the HIT at -2.3 units (95\% confidence interval = -4.3, -0.3). This suggests that a between-group difference in HIT change scores of 2.3 units over time among patients with CDH reflects improvement in patients' headache condition that may be considered clinically significant. ?? 2006 Elsevier Inc. All rights reserved.},
  number = {4},
  journal = {Journal of Clinical Epidemiology},
  author = {Coeytaux, Remy R. and Kaufman, Jay S. and Chao, Ryon and Mann, J. Douglas and DeVellis, Robert F.},
  year = {2006},
  keywords = {Headache,Chronic daily headache,Clinical change,Headache Impact Test,Health-related quality of life,Measurement,Minimal important difference},
  pages = {374-380},
  file = {/Users/k/Zotero/storage/8CVLHGFP/Coeytaux et al. - 2006 - Four methods of estimating the minimal important difference score were compared to establish a clinically signi.pdf},
  pmid = {16549259}
}

@article{Liu2005,
  title = {The {{Analysis}} of Ordered Categorical Data: An Overview and a Survey of Recent Developments},
  volume = {14},
  issn = {1133-0686},
  doi = {10.1007/BF02595397},
  abstract = {This paper aims at assisting empirical researchers benefit from recent advances in causal inference. The paper stresses the paradigmatic shifts that must be under- taken in moving from traditional statistical analysis to causal analysis of multivari- ate data. Special emphasis is placed on the assumptions that underly all causal in- ferences, the languages used in formulating those assumptions, and the conditional nature of causal claims inferred from nonexperimental studies. These emphases are illustrated through a brief survey of recent results, including the control of confounding, the assessment of causal effects, the interpretation of counterfactuals, and a symbiosis between counterfactual and graphical methods of analysis.},
  number = {1},
  journal = {Sociedad de Estad\i{}stica e Investigacion Operativa Test},
  author = {Liu, Ivy and Agresti, Alan},
  year = {2005},
  pages = {1-73},
  file = {/Users/k/Zotero/storage/LKTZAGCQ/Liu, Agresti - 2005 - The Analysis of ordered categorical data an overview and a survey of recent developments.pdf}
}

@article{Tepper2017a,
  title = {Appendix to {{Safety}} and Efficacy of Erenumab for Preventive Treatment of Chronic Migraine: A Randomised, Double-Blind, Placebo-Controlled Phase 2 Trial},
  issn = {1533-4406},
  doi = {10.1056/NEJMoa1506699},
  journal = {The Lancet Neurology},
  author = {Tepper, Stewart and Ashina, Messoud and Reuter, Uwe and Brandes, Jan L and Dole{\v z}il, David and Silberstein, Stephen and Winner, Paul and Leonardi, Dean and Mikol, Daniel and Lenz, Robert},
  year = {2017},
  keywords = {Headache},
  file = {/Users/k/Zotero/storage/N5IC9NSR/Tepper et al. - 2017 - Appendix to Safety and efficacy of erenumab for preventive treatment of chronic migraine a randomised, double-bli.pdf},
  pmid = {22316447}
}

@article{Dodick2010,
  title = {{{OnabotulinumtoxinA}} for Treatment of Chronic Migraine: {{Pooled}} Results from the Double-Blind, Randomized, Placebo-Controlled Phases of the {{PREEMPT}} Clinical Program},
  volume = {50},
  issn = {15264610},
  doi = {10.1111/j.1526-4610.2010.01678.x},
  abstract = {(Headache 2010;50:921-936) Objective.\textemdash{} To assess the efficacy, safety, and tolerability of onabotulinumtoxinA (BOTOX\textregistered{}) as headache prophylaxis in adults with chronic migraine. Background.\textemdash{} Chronic migraine is a prevalent, disabling, and undertreated neurological disorder. Few preventive treatments have been investigated and none is specifically indicated for chronic migraine. Methods.\textemdash{} The 2 multicenter, pivotal trials in the PREEMPT: Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy clinical program each included a 24-week randomized, double-blind phase followed by a 32-week open-label phase (ClinicalTrials.gov identifiers NCT00156910, NCT00168428). Qualified patients were randomized (1:1) to onabotulinumtoxinA (155-195~U) or placebo injections every 12 weeks. Study visits occurred every 4 weeks. These studies were identical in design (eg, inclusion/exclusion criteria, randomization, visits, double-blind phase, open-label phase, safety assessments, treatment), with the only exception being the designation of the primary and secondary endpoints. Therefore, the predefined pooling of the results was justified and performed to provide a complete overview of between-group differences in efficacy, safety, and tolerability that may not have been evident in individual studies. The primary endpoint for the pooled analysis was mean change from baseline in frequency of headache days at 24 weeks. Secondary endpoints were mean change from baseline to week 24 in frequency of migraine/probable migraine days, frequency of moderate/severe headache days, total cumulative hours of headache on headache days, frequency of headache episodes, frequency of migraine/probable migraine episodes, frequency of acute headache pain medication intakes, and the proportion of patients with severe ($\geq$60) Headache Impact Test-6 score at week 24. Results of the pooled analyses of the 2 PREEMPT double-blind phases are presented. Results.\textemdash{} A total of 1384 adults were randomized to onabotulinumtoxinA (n~=~688) or placebo (n~=~696). Pooled analyses demonstrated a large mean decrease from baseline in frequency of headache days, with statistically significant between-group differences favoring onabotulinumtoxinA over placebo at week 24 (-8.4 vs -6.6; P~$<$~.001) and at all other time points. Significant differences favoring onabotulinumtoxinA were also observed for all secondary efficacy variables at all time points, with the exception of frequency of acute headache pain medication intakes. Adverse events occurred in 62.4\% of onabotulinumtoxinA patients and 51.7\% of placebo patients. Most patients reported adverse events that were mild to moderate in severity and few discontinued (onabotulinumtoxinA, 3.8\%; placebo, 1.2\%) due to adverse events. No unexpected treatment-related adverse events were identified. Conclusions.\textemdash{} The pooled PREEMPT results demonstrate that onabotulinumtoxinA is an effective prophylactic treatment for chronic migraine. OnabotulinumtoxinA resulted in significant improvements compared with placebo in multiple headache symptom measures, and significantly reduced headache-related disability and improved functioning, vitality, and overall health-related quality of life. Repeat treatments with onabotulinumtoxinA were safe and well tolerated.},
  number = {6},
  journal = {Headache},
  author = {Dodick, David W. and Turkel, Catherine C. and Degryse, Ronald E. and Aurora, Sheena K. and Silberstein, Stephen D. and Lipton, Richard B. and Diener, Hans Christoph and Brin, Mitchell F.},
  year = {2010},
  keywords = {Headache,Chronic migraine,Botulinum toxin A,Prophylaxis},
  pages = {921-936},
  file = {/Users/k/Zotero/storage/WQWZMLA8/Dodick et al. - 2010 - OnabotulinumtoxinA for treatment of chronic migraine Pooled results from the double-blind, randomized, placebo-co.pdf},
  pmid = {20487038}
}

@article{wielPackageCoin2017,
  title = {Package ` Coin '},
  author = {Wiel, Mark A Van De},
  year = {2017},
  file = {/Users/k/Zotero/storage/7DM8P9S6/Wiel - 2017 - Package ‘ coin ’.pdf}
}

@article{Wason2015,
  title = {The Power of Phase {{II}} End-Points for Different Possible Mechanisms of Action of an Experimental Treatment},
  volume = {51},
  issn = {18790852},
  doi = {10.1016/j.ejca.2015.03.002},
  abstract = {Background The high failure rate in phase III oncology trials is partly because the signal obtained from phase II trials is often weak. Several papers have considered the appropriateness of various phase II end-points for individual trials, but there has not been a systematic comparison using simulated data to determine which end-point should be used in which situation. Methods In this paper we carry out simulation studies to compare the power of several Response Evaluation Criteria in Solid Tumours (RECIST) response-based end-points for one-arm and two-arm trials, together with progression-free survival (PFS) and testing the tumour-shrinkage directly for two-arm trials. We consider six scenarios: (1) short-term cytotoxic therapy; (2) continuous cytotoxic therapy; (3 + 4) cytostatic therapy; (5 + 6) delayed tumour-shrinkage effect (seen in some immunotherapies). We also consider measurement error in the assessment of tumour size. Results Measurement error affects the type-I error rate and power of single-arm trials, and the power of two-arm trials. Generally no single end-point performed well in all scenarios. Best observed response rate, PFS and directly testing the tumour-shrinkages performed best for a number of scenarios. PFS performed very poorly when the effect of the treatment was short-lived. In scenario 6, where the delay in effect was long, no end-point performed well. Conclusions A clinician setting up a phase II trial should consider the likely mechanism of action the drug will have and choose an end-point that provides high power for that scenario. Testing the difference in tumour-shrinkage is often powerful. Alternative end-points are required for therapies with a long delayed effect.},
  number = {8},
  journal = {European Journal of Cancer},
  author = {Wason, J. M.S. and Dentamaro, A. and Eisen, T. G.},
  year = {2015},
  keywords = {RECIST,Phase II cancer trial,Measurement error,Progression-free-survival,Response},
  pages = {984-992},
  file = {/Users/k/Zotero/storage/RA8VWX8N/Wason, Dentamaro, Eisen - 2015 - The power of phase II end-points for different possible mechanisms of action of an experimental treatme.pdf},
  pmid = {25840669}
}

@article{Adams2017,
  title = {Inhibition of {{EGFR}}, {{HER2}}, and {{HER3}} Signalling in Patients with Colorectal Cancer Wild-Type for {{BRAF}}, {{PIK3CA}}, {{KRAS}} , and {{NRAS}} ({{FOCUS4}}-{{D}}): A Phase 2\textendash{}3 Randomised Trial},
  volume = {1253},
  issn = {24681253},
  doi = {10.1016/S2468-1253(17)30394-1},
  number = {17},
  journal = {The Lancet Gastroenterology \& Hepatology},
  author = {Adams, Richard and Brown, Ewan and Brown, Louise and Butler, Rachel and Falk, Stephen and Fisher, David and Kaplan, Richard and Quirke, Phil and Richman, Susan and Samuel, Leslie and Seligmann, Jenny and Seymour, Matt and Shiu, Kai Keen and Wasan, Harpreet and Wilson, Richard and Maughan, Tim},
  year = {2017},
  file = {/Users/k/Zotero/storage/854DUYGL/Adams et al. - 2017 - Inhibition of EGFR, HER2, and HER3 signalling in patients with colorectal cancer wild-type for BRAF, PIK3CA, KRA.pdf}
}

@article{Cortes2018a,
  title = {Does Evidence Support the High Expectations Placed in Precision Medicine? {{A}} Bibliographic Review},
  volume = {7},
  issn = {2046-1402},
  doi = {10.12688/f1000research.13490.1},
  number = {0},
  journal = {F1000Research},
  author = {Cort\'es, Jordi and Gonz\'alez, Jos\'e Antonio and Medina, Mar\'ia Nuncia and Vogler, Markus and Vilar\'o, Marta and Elmore, Matt and Senn, Stephen John and Campbell, Michael and Cobo, Erik},
  year = {2018},
  pages = {30},
  file = {/Users/k/Zotero/storage/VUY3TPSQ/Cortés et al. - 2018 - Does evidence support the high expectations placed in precision medicine A bibliographic review.pdf}
}

@article{Kassa,
  title = {Ten {{Simple Rules}} for {{Effective Statistical Practice}}},
  doi = {10.1371/journal.pcbi.1004961},
  author = {Kass, Robert E and Caffo, Brian S and Davidian, Marie and Meng, Xiao-Li and Yu, Bin and Reid, Nancy},
  file = {/Users/k/Zotero/storage/CIKLA3LP/Kass et al. - Unknown - Ten Simple Rules for Effective Statistical Practice.pdf}
}

@article{Deaton2017,
  title = {Understanding and Misunderstanding Randomized Controlled Trials},
  doi = {10.1016/j.socscimed.2017.12.005},
  journal = {Social Science \& Medicine},
  author = {Deaton, Angus and Cartwright, Nancy},
  year = {2017},
  file = {/Users/k/Zotero/storage/N9IMNK3H/Deaton, Cartwright - 2017 - Understanding and misunderstanding randomized controlled trials.pdf}
}

@article{Atassi2014,
  title = {The {{PRO}}-{{ACT}} Database: {{Design}}, Initial Analyses, and Predictive Features},
  volume = {83},
  issn = {0028-3878},
  doi = {10.1212/WNL.0000000000000951},
  abstract = {OBJECTIVE: To pool data from completed amyotrophic lateral sclerosis (ALS) clinical trials and create an open-access resource that enables greater understanding of the phenotype and biology of ALS.$\backslash$n$\backslash$nMETHODS: Clinical trials data were pooled from 16 completed phase II/III ALS clinical trials and one observational study. Over 8 million de-identified longitudinally collected data points from over 8,600 individuals with ALS were standardized across trials and merged to create the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. This database includes demographics, family histories, and longitudinal clinical and laboratory data. Mixed effects models were used to describe the rate of disease progression measured by the Revised ALS Functional Rating Scale (ALSFRS-R) and vital capacity (VC). Cox regression models were used to describe survival data. Implementing Bonferroni correction, the critical p value for 15 different tests was p = 0.003.$\backslash$n$\backslash$nRESULTS: The ALSFRS-R rate of decline was 1.02 ($\pm$2.3) points per month and the VC rate of decline was 2.24\% of predicted ($\pm$6.9) per month. Higher levels of uric acid at trial entry were predictive of a slower drop in ALSFRS-R (p = 0.01) and VC (p $<$ 0.0001), and longer survival (p = 0.02). Higher levels of creatinine at baseline were predictive of a slower drop in ALSFRS-R (p = 0.01) and VC (p $<$ 0.0001), and longer survival (p = 0.01). Finally, higher body mass index (BMI) at baseline was associated with longer survival (p $<$ 0.0001).$\backslash$n$\backslash$nCONCLUSION: The PRO-ACT database is the largest publicly available repository of merged ALS clinical trials data. We report that baseline levels of creatinine and uric acid, as well as baseline BMI, are strong predictors of disease progression and survival.},
  number = {19},
  journal = {Neurology},
  author = {Atassi, N. and Berry, J. and Shui, A. and Zach, N. and Sherman, A. and Sinani, E. and Walker, J. and Katsovskiy, I. and Schoenfeld, D. and Cudkowicz, M. and Leitner, M.},
  year = {2014},
  keywords = {ALS},
  pages = {1719-1725},
  file = {/Users/k/Zotero/storage/ABNDNTPP/Atassi et al. - 2014 - The PRO-ACT database Design, initial analyses, and predictive features.pdf},
  pmid = {25298304}
}

@article{Gamble2017,
  title = {Guidelines for the {{Content}} of {{Statistical Analysis Plans}} in {{Clinical Trials}}},
  volume = {318},
  issn = {0098-7484},
  doi = {10.1001/jama.2017.18556},
  number = {23},
  journal = {Jama},
  author = {Gamble, Carrol and Krishan, Ashma and Stocken, Deborah and Lewis, Steff and Juszczak, Edmund and Dor\'e, Caroline and Williamson, Paula R. and Altman, Douglas G. and Montgomery, Alan and Lim, Pilar and Berlin, Jesse and Senn, Stephen and Day, Simon and Barbachano, Yolanda and Loder, Elizabeth},
  year = {2017},
  keywords = {SAP},
  pages = {2337},
  file = {/Users/k/Zotero/storage/9426T8BH/Gamble - Unknown - Supplementary Online Content eTable 1. Identification of Existing Guidance on the Content of Statistical Analysis Pla.pdf;/Users/k/Zotero/storage/CCLU34RD/Gamble et al. - 2017 - Guidelines for the Content of Statistical Analysis Plans in Clinical Trials.pdf}
}

@article{Epton2009,
  title = {Quality of Life in Amyotrophic Lateral Sclerosis/Motor Neuron Disease: {{A}} Structured Review},
  volume = {10},
  issn = {17482968},
  doi = {10.1080/17482960802163721},
  abstract = {Amyotrophic lateral sclerosis/motor neuron disease and other related disorders are fatal progressive neurodegenerative conditions that have a substantial impact on quality of life (QoL). This systematic review examines the different methods and instruments used to assess QoL in this condition from which recommendations are made of those that evidence suggests are the most appropriate. Databases were used to survey the available literature to cover as many different approaches and papers as possible. Due to the wide variety of approaches to the measurement of QoL data across the papers, no meta-analysis was possible. The available evidence suggests that at the present time the most appropriate measures are the SF-36, a generic widely used QoL measure, and the disease specific ALSAQ-40. However, as many of the validation studies on the ALSAQ-40 were undertaken by the developers of this instrument, further independent research is desirable to confirm these conclusions.},
  number = {1},
  journal = {Amyotrophic Lateral Sclerosis},
  author = {Epton, Joanna and Harris, Robert and Jenkinson, Crispin},
  year = {2009},
  keywords = {Systematic review,ALS,ALSAQ-40,Health status measurement,MND,Patient reported outcome measures,Quality of life},
  pages = {15-26},
  file = {/Users/k/Zotero/storage/QV5TWG9G/Epton, Harris, Jenkinson - 2009 - Quality of life in amyotrophic lateral sclerosismotor neuron disease A structured review.pdf},
  pmid = {18752087}
}

@article{Jenkinson2000,
  title = {The Amyotrophic Lateral Sclerosis Assessment Questionnaire ({{ALSAQ}}-40): {{Tests}} of Data Quality, Score Reliability and Response Rate in a Survey of Patients},
  volume = {180},
  issn = {0022510X},
  doi = {10.1016/S0022-510X(00)00420-2},
  abstract = {Objectives: To evaluate response rate, data quality, and score reliability of the 40 item Amyotrophic Lateral Sclerosis Assessment Questionnaire in a survey of MND patients. Design: A survey of members of the MND Association of the UK, of which half were randomly allocated to receive a survey instrument from the MND Association and the other half allocated to receive the MND Association survey instrument and also the ALSAQ-40 questionnaire. Sample: Five hundred patients were randomly selected from the membership lists of the MND Association, of whom 250 received the MND Association Survey and the ALSAQ-40. Results: Response rate to the survey was 59.2\%. Over half of the respondents received the ALSAQ-40. Data for individual items were analysed and found to be distributed across all response categories. All items were found to be highly associated with the scales to which they contribute. Internal consistency reliability of all the five scales of the ALSAQ-40 was also found to be high. Conclusion: Inclusion of the ALSAQ-40 into the survey did not have an adverse effect upon response rates. Furthermore, the ALSAQ-40 was shown to have highly desirable psychometric properties. This paper provides further evidence of the reliability and validity of the measure. (C) 2000 Published by Elsevier Science B.V.},
  number = {1-2},
  journal = {Journal of the Neurological Sciences},
  author = {Jenkinson, Crispin and Levvy, George and Fitzpatrick, Ray and Garratt, Andrew},
  year = {2000},
  keywords = {ALS,Health status measurement,ALS Assessment Questionnaire (ALSAQ-40),Response rate},
  pages = {94-100},
  file = {/Users/k/Zotero/storage/FJR6PWYD/Jenkinson et al. - 2000 - The amyotrophic lateral sclerosis assessment questionnaire (ALSAQ-40) Tests of data quality, score reliability.pdf},
  pmid = {11090872}
}

@article{Jenkinson2003,
  title = {Interpreting Change Scores on the {{Amyotrophic Lateral Sclerosis Assessment Questionnaire}}},
  journal = {Amyotrophic Lateral Sclerosis},
  author = {Jenkinson, C and Peto, V and Jones, G and Fitzpatrick, R},
  year = {2003},
  keywords = {ALS},
  pages = {380-385},
  file = {/Users/k/Zotero/storage/CLWGIUJL/Jenkinson et al. - 2003 - Interpreting change scores on the Amyotrophic Lateral Sclerosis Assessment Questionnaire.pdf}
}

@article{Gelman2014,
  title = {Beyond {{Power Calculations}}: {{Assessing Type S}} ({{Sign}}) and {{Type M}} ({{Magnitude}}) {{Errors}}},
  volume = {9},
  doi = {10.1177/1745691614551642},
  abstract = {You have just finished running an experiment. You ana-lyze the results, and you find a significant effect. Success! But wait\textemdash{}how much information does your study really give you? How much should you trust your results? In this article, we show that when researchers use small samples and noisy measurements to study small effects\textemdash{}as they often do in psychology as well as other disciplines\textemdash{}a significant result is often surprisingly likely to be in the wrong direction and to greatly overestimate an effect. In this article, we examine some critical issues related to power analysis and the interpretation of findings aris-ing from studies with small sample sizes. We highlight the use of external information to inform estimates of true effect size and propose what we call a design anal-ysis\textemdash{}a set of statistical calculations about what could happen under hypothetical replications of a study\textemdash{}that focuses on estimates and uncertainties rather than on sta-tistical significance. As a reminder, the power of a statistical test is the probability that it correctly rejects the null hypothesis. For any experimental design, the power of a study depends on sample size, measurement variance, the number of comparisons being performed, and the size of the effects being studied. In general, the larger the effect, the higher the power; thus, power calculations are per-formed conditionally on some assumption of the size of the effect. Power calculations also depend on other assumptions, most notably the size of measurement error, but these are typically not so difficult to assess with avail-able data. It is of course not at all new to recommend the use of statistical calculations on the basis of prior guesses of effect sizes to inform the design of studies. What is new about the present article is as follows: 1. We suggest that design calculations be performed after as well as before data collection and analysis.},
  number = {6},
  journal = {Perspectives on Psychological Science},
  author = {Gelman, Andrew and Carlin, John},
  year = {2014},
  pages = {641-651},
  file = {/Users/k/Zotero/storage/QKRFRFPQ/Gelman, Carlin - 2014 - Beyond Power Calculations Assessing Type S (Sign) and Type M (Magnitude) Errors.pdf}
}

@article{Grieve2003,
  title = {The Number Needed to Treat: A Useful Clinical Measure or a Case of the {{Emperor}}'s New Clothes?},
  volume = {2},
  doi = {10.1002/pst.033},
  abstract = {The number needed to treat (NNT) was introduced into the medical literature as an easily understood and useful measure of treatment effect for clinical trials in which the main outcome variable is binary. It has been argued that it is more easily understood by practising physicians than more statistically based measures. In this paper we review the claims made for the NNT and question whether it is truly understandable to physicians, and look at issues around determining a confidence interval, or a Bayesian interval, for the NNT.},
  journal = {Pharmaceut. Statist},
  author = {Grieve, Andrew P},
  year = {2003},
  pages = {87-102},
  file = {/Users/k/Zotero/storage/68ND4GY4/Grieve - 2003 - The number needed to treat a useful clinical measure or a case of the Emperor's new clothes.pdf}
}

@article{Kushnir2010,
  title = {Liquid Chromatography-Tandem Mass Spectrometry Assay for Androstenedione, Dehydroepiandrosterone, and Testosterone with Pediatric and Adult Reference Intervals},
  volume = {56},
  issn = {00099147},
  doi = {10.1373/clinchem.2010.143222},
  abstract = {Measurement of serum androgens is important in adult, geriatric, pediatric endocrinology, and oncology patients. We developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for simultaneous measurement of androstenedione, dehydroepiandrosterone (DHEA), and testosterone in these patients.},
  number = {7},
  journal = {Clinical Chemistry},
  author = {Kushnir, Mark M. and Blamires, Takara and Rockwood, Alan L. and Roberts, William L. and Yue, Bingfang and Erdogan, Evrim and Bunker, Ashley M. and Meikle, A. Wayne},
  year = {2010},
  keywords = {DHEA},
  pages = {1138-1147},
  file = {/Users/k/Zotero/storage/4YLJ6AQM/Kushnir et al. - 2010 - Liquid chromatography-tandem mass spectrometry assay for androstenedione, dehydroepiandrosterone, and testostero.pdf},
  pmid = {20489135}
}

@article{Labrie1997,
  title = {Marked Decline in Serum Concentrations of Adrenal {{C19}} Sex Steroid Precursors and Conjugated Androgen Metabolites during Aging},
  volume = {82},
  issn = {0021972X},
  doi = {10.1210/jc.82.8.2396},
  abstract = {The present data show a dramatic decline in the circulating levels of dehydroepiandrosterone (DHEA), DHEA-sulfate (DHEA-S), androst-5-ene-3 beta,17 beta-diol (5-diol), 5-diol-sulfate, 5-diol-fatty acid esters, and androstenedione in both men and women between the ages of 20-80 yr. In the 50- to 60-yr-old group, serum DHEA decreased by 74\% and 70\% from its peak values in 20- to 30-yr-old men and women, respectively. the serum concentrations of the conjugated metabolites of dihydrotestosterone (DHT), namely androsterone (ADT)-G, androstane-3 alpha,17 beta-diol (3 alpha-diol-G), androstane-3 beta,17 beta-diol (3 beta-diol-G), and ADT-sulfate are the most reliable parameters of the total androgen pool in both men and women, whereas serum testosterone and DHT can be used as markers of testicular secretion in men and interstitial ovarian secretion in women. The serum concentration of these various conjugated androgen metabolites decreased by 40.8\% to 72.8\% between the 20- to 30-yr-old and 70- to 80-yr-old age groups in men and women, respectively, thus suggesting a parallel decrease in the total androgen pool with age. As estimated by measurement of the circulating levels of these conjugated metabolites of DHT, it is noteworthy that women produce approximately 66\% of the total androgens found in men. In women, most of these androgens originate from the transformation of DHEA and DHEA-S into testosterone and DHT in peripheral intracrine tissues, whereas in men the testes and DHEA and DHEA-S provide approximately equal amounts of androgens at the age of 50-60 yr. An additional potentially highly significant observation is that the majority of the marked decline in circulating adrenal C19 steroids and their resulting androgen metabolites takes place between the age groups of 20- to 30-yr olds and 50- to 60-yr-olds, with smaller changes are observed after the age of 60 yr.},
  number = {8},
  journal = {Journal of Clinical Endocrinology and Metabolism},
  author = {Labrie, Fernand and B\'elanger, Alain and Cusan, Lionel and Gomez, Jos\'e Luis and Candas, Bernard},
  year = {1997},
  keywords = {DHEA},
  pages = {2396-2402},
  file = {/Users/k/Zotero/storage/XIMJ2YQH/Labrie et al. - 1997 - Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites.pdf},
  pmid = {9253307}
}

@article{Senn2013a,
  title = {Statistics in {{Biopharmaceutical Research Being Efficient About Efficacy Estimation Being Efficient About Efficacy Estimation}}},
  volume = {53},
  doi = {10.1080/19466315.2012.754726},
  abstract = {I consider Bob O'Neill's important role in promoting regulatory science and, in particular, through the very influential series of lectures he gave in Basel more than 20 years ago, the effect on statistics in European regula-tion and ultimately on regulatory science in the United States. I provide a simple model of disappointment in drug development. I consider three approaches to improving efficiency in drug development and conclude that there are simple things we could be doing to reduce the cost with which information is obtained in drug development.},
  number = {10},
  journal = {Statistics in Biopharmaceutical Research},
  author = {Senn, Stephen},
  year = {2013},
  file = {/Users/k/Zotero/storage/QEPXX8IU/Senn - 2013 - Statistics in Biopharmaceutical Research Being Efficient About Efficacy Estimation Being Efficient About Efficacy Estimati.pdf}
}

@article{Senn,
  title = {Mastering Variation: Variance Components and Personalised Medicine},
  doi = {10.1002/sim.6739},
  abstract = {Various sources of variation in observed response in clinical trials and clinical practice are considered, and ways in which the corresponding components of variation might be estimated are discussed. Although the issues have been generally well-covered in the statistical literature, they seem to be poorly understood in the medical litera-ture and even the statistical literature occasionally shows some confusion. To increase understanding and commu-nication, some simple graphical approaches to illustrating issues are proposed. It is also suggested that reducing variation in medical practice might make as big a contribution to improving health outcome as personalising its delivery according to the patient. It is concluded that the common belief that there is a strong personal element in response to treatment is not based on sound statistical evidence.},
  author = {Senn, Stephen},
  file = {/Users/k/Zotero/storage/N64E5RMW/Senn - Unknown - Mastering variation variance components and personalised medicine.pdf}
}

@article{Cro,
  title = {Measuring Skin Necrosis in a Randomised Controlled Feasibility Trial of Heat Preconditioning on Wound Healing after Reconstructive Breast Surgery: Study Protocol and Statistical Analysis Plan for the {{PREHEAT}} Trial},
  doi = {10.1186/s40814-017-0223-y},
  abstract = {Background: Essential strategies are needed to help reduce the number of post-operative complications and associated costs for breast cancer patients undergoing reconstructive breast surgery. Evidence suggests that local heat preconditioning could help improve the provision of this procedure by reducing skin necrosis. Before testing the effectiveness of heat preconditioning in a definitive randomised controlled trial (RCT), we must first establish the best way to measure skin necrosis and estimate the event rate using this definition. Methods: PREHEAT is a single-blind randomised controlled feasibility trial comparing local heat preconditioning, using a hot water bottle, against standard care on skin necrosis among breast cancer patients undergoing reconstructive breast surgery. The primary objective of this study is to determine the best way to measure skin necrosis and to estimate the event rate using this definition in each trial arm. Secondary feasibility objectives include estimating recruitment and 30 day follow-up retention rates, levels of compliance with the heating protocol, length of stay in hospital and the rates of surgical versus conservative management of skin necrosis. The information from these objectives will inform the design of a larger definitive effectiveness and cost-effectiveness RCT. Discussion: This article describes the PREHEAT trial protocol and detailed statistical analysis plan, which includes the pre-specified criteria and process for establishing the best way to measure necrosis. This study will provide the evidence needed to establish the best way to measure skin necrosis, to use as the primary outcome in a future RCT to definitively test the effectiveness of local heat preconditioning. The pre-specified statistical analysis plan, developed prior to unblinded data extraction, sets out the analysis strategy and a comparative framework to support a committee evaluation of skin necrosis measurements. It will increase the transparency of the data analysis for the PREHEAT trial. Trial registration: ISRCTN ISRCTN15744669. Registered 25 February 2015},
  author = {Cro, Suzie and Mehta, Saahil and Farhadi, Jian and Coomber, Billie and Cornelius, Victoria},
  file = {/Users/k/Zotero/storage/K4NSMLV5/Cro et al. - Unknown - Measuring skin necrosis in a randomised controlled feasibility trial of heat preconditioning on wound healing aft.pdf}
}

@article{Gelmana,
  title = {Exploratory {{Data Analysis}} for {{Complex Models}}},
  doi = {10.1198/106186004X11435},
  abstract = {Exploratory " and " confirmatory " data analysis can both be viewed as methods for comparing observed data to what would be obtained under an implicit or explicit statistical model. For example, many of Tukey's methods can be interpreted as checks against hy-pothetical linear models and Poisson distributions. In more complex situations, Bayesian methods can be useful for constructing reference distributions for various plots that are useful in exploratory data analysis. This article proposes an approach to unify exploratory data analysis with more formal statistical methods based on probability models. These ideas are developed in the context of examples from fields including psychology, medicine, and social science.},
  author = {Gelman, Andrew},
  file = {/Users/k/Zotero/storage/YZMS8NG6/Gelman - Unknown - Exploratory Data Analysis for Complex Models.pdf}
}

@article{Gelmanb,
  title = {[2003] {{A Bayesian}} Formulation of Exploratory Data Analysis and Goodness-of-Fit Testing},
  author = {Gelman, Andrew},
  file = {/Users/k/Zotero/storage/G5I4KBT9/Gelman - Unknown - 2003 A Bayesian formulation of exploratory data analysis and goodness-of-fit testing.pdf}
}

@article{Fidler2016,
  title = {Degrees of {{Freedom}} in {{Planning}}, {{Running}}, {{Analyzing}}, and {{Reporting Psychological Studies}}: {{A Checklist}} to {{Avoid}} p-{{Hacking}}},
  doi = {10.3389/fpsyg.2016.01832},
  abstract = {The designing, collecting, analyzing, and reporting of psychological studies entail many choices that are often arbitrary. The opportunistic use of these so-called researcher degrees of freedom aimed at obtaining statistically significant results is problematic because it enhances the chances of false positive results and may inflate effect size estimates. In this review article, we present an extensive list of 34 degrees of freedom that researchers have in formulating hypotheses, and in designing, running, analyzing, and reporting of psychological research. The list can be used in research methods education, and as a checklist to assess the quality of preregistrations and to determine the potential for bias due to (arbitrary) choices in unregistered studies.},
  author = {Fidler, Fiona and Hoekstra, Rink and Cumming, Geoff and Wicherts, Jelte M and Veldkamp, Coosje L S and Augusteijn, Hilde E M and Bakker, Marjan and Van Aert, Robbie C M and Van Assen, Marcel A L M},
  year = {2016},
  file = {/Users/k/Zotero/storage/UXHJLD5R/Fidler et al. - 2016 - Degrees of Freedom in Planning, Running, Analyzing, and Reporting Psychological Studies A Checklist to Avoid p-Ha.pdf}
}

@article{Yao2017,
  title = {Using {{Stacking}} to {{Average Bayesian Predictive Distributions}}},
  volume = {13},
  doi = {10.1214/17-BA1091},
  abstract = {Bayesian model averaging is flawed in the M-open setting in which the true data-generating process is not one of the candidate models being fit. We take the idea of stacking from the point estimation literature and generalize to the com-bination of predictive distributions. We extend the utility function to any proper scoring rule and use Pareto smoothed importance sampling to efficiently compute the required leave-one-out posterior distributions. We compare stacking of pre-dictive distributions to several alternatives: stacking of means, Bayesian model averaging (BMA), Pseudo-BMA, and a variant of Pseudo-BMA that is stabilized using the Bayesian bootstrap. Based on simulations and real-data applications, we recommend stacking of predictive distributions, with bootstrapped-Pseudo-BMA as an approximate alternative when computation cost is an issue.},
  journal = {Bayesian Analysis},
  author = {Yao, Yuling and Vehtari, Aki and Simpson, Daniel and Gelman, Andrew},
  year = {2017},
  keywords = {_tablet,BayesCore},
  pages = {917-1007},
  file = {/Users/k/Zotero/storage/ZXFGRJSU/Yao et al_2017_Using Stacking to Average Bayesian Predictive Distributions.pdf}
}

@article{Lebozec2017,
  title = {Design, Development and Characterization of {{ACT017}}, a Humanized {{Fab}} That Blocks Platelet's Glycoprotein {{VI}} Function without Causing Bleeding Risks},
  volume = {9},
  issn = {19420870},
  doi = {10.1080/19420862.2017.1336592},
  abstract = {Glycoprotein VI is a platelet-specific collagen receptor critical for in vivo formation of arterial thrombosis. It is also considered as an attractive target for the development of anti-thrombotic drugs because blocking glycoprotein (GP)VI inhibits platelet aggregation without inducing detrimental effects on physiologic hemostasis. Here, we present data on the identification, in vitro and ex vivo pharmacology of a humanized Fab fragment designated as ACT017. ACT017 was selected out of 15 humanized variants based upon structural and functional properties. It was produced under GMP-like conditions followed by detailed physico-chemical analysis and functional characterization indicating high antigen-binding specificity and affinity. In addition, we demonstrate, in a dose-escalation study, that ACT017 has a high capacity to specifically inhibit collagen-induced platelet aggregation ex vivo after injection to the macaque without inducing thrombocytopenia, GPVI depletion or bleeding side effects as is the case for conventional anti-platelets. Therefore, ACT017 is a promising therapeutic candidate for the development of a new generation of safe and efficient anti-thrombotic drugs.},
  number = {6},
  journal = {mAbs},
  author = {Lebozec, Kristell and {Jandrot-Perrus}, Martine and Avenard, Gilles and {Favre-Bulle}, Olivier and Billiald, Philippe},
  year = {2017},
  keywords = {Cardiovascular disease,glycoprotein VI,humanization,platelet aggregation,stroke,therapeutic antibody,thrombosis},
  pages = {945-958},
  file = {/Users/k/Zotero/storage/MVCJLNB5/Lebozec et al. - 2017 - Design, development and characterization of ACT017, a humanized Fab that blocks platelet's glycoprotein VI funct.pdf},
  pmid = {28598281}
}

@article{MedicinesAgency2017,
  title = {{{ICH E9}} ({{R1}}) Addendum on Estimands and Sensitivity Analysis in Clinical Trials to the Guideline on Statistical Principles for Clinical Trials - {{Step}} 2b},
  abstract = {Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact},
  author = {Medicines Agency, European},
  year = {2017},
  file = {/Users/k/Zotero/storage/2T95ECIV/Medicines Agency - 2017 - ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical.pdf}
}

@article{Zhou2003,
  title = {Practical {{Implementation}} of {{Bayesian Dose}}-{{Escalation Procedures}}},
  volume = {37},
  issn = {21684790},
  doi = {10.1177/009286150303700108},
  number = {1},
  journal = {Therapeutic Innovation \& Regulatory Science},
  author = {Zhou, Yinghui and Whitehead, John},
  year = {2003},
  keywords = {Bayesian statistics,Computer software,Decision procedure,Dose-escalation,Phase 1 study},
  pages = {45-59},
  file = {/Users/k/Zotero/storage/LLFMPSLH/Zhou, Whitehead - 2003 - Practical Implementation of Bayesian Dose-Escalation Procedures.pdf}
}

@inproceedings{Munir2017a,
  address = {Madrid},
  title = {{{IBRUTINIB RESULTS IN REDUCTION OF PHOSPHORYLATION OF MULTIPLE KINASES IN THE B}}-{{CELL RECEPTOR PATHWAY IN CHRONIC LYMPHOCYTIC LEUKAEMIA}} ({{CLL}}): {{RESULTS OF THE BLOODWISE TAP ICICLLE STUDY}}},
  booktitle = {22nd {{Congress}} of the {{European Hematology Association}}},
  publisher = {{Haematologica}},
  author = {Munir, T. and Rawstron, A. and {Mu\~noz-Vicente}, S. and Brock, K. and Yates, F. and Bishop, R. and Dalal, S. and de Tute, R. and Fox, C.P. and Fegan, C. and McDonald, D. and Sheehy, O. and Pettitt, A. and Devereux, S. and Murray, J. and Bloor, A. and Hillmen, P.},
  editor = {Association, European Hematology},
  year = {2017},
  keywords = {CLL,MyPubs},
  pages = {229}
}

@inproceedings{Hillmen2017a,
  title = {Initial {{Results}} of {{Ibrutinib Plus Venetoclax}} in {{Relapsed}}, {{Refractory CLL}} ({{Bloodwise TAP CLARITY Study}}): {{High Rates}} of {{Overall Response}}, {{Complete Remission}} and {{MRD Eradication}} after 6 {{Months}} of {{Combination Therapy}}},
  booktitle = {59th {{ASH Abstracts}} \& {{Meeting Program}}},
  publisher = {{Blood}},
  author = {Hillmen, Peter and Munir, Talha and Rawstron, Andy and Brock, Kristian and Vicente, Samuel Munoz and Yates, Francesca and Bishop, Rebecca and Fegan, Christopher and Macdonald, Donald and McCaig, Alison and Schuh, Anna and Pettitt, Andrew and Gribben, John G. and Devereux, Stephen and Bloor, Adrian and Fox, Christopher P and Forconi, Francesco},
  editor = {{The American Society of Hematology}},
  year = {2017},
  keywords = {CLL,MyPubs},
  pages = {428}
}

@inproceedings{Cook2017,
  title = {Reduced {{Intensity Stem Cell Transplantation Followed By Adjunctive Lenalidomide Is Tolerable}} and {{Safe}} and {{Improves Complete Response Rate}} in {{Multiple Myeloma}}:A {{UK NCRI Phase}} 2 {{Feasibility Study}} ({{LenaRIC}})},
  booktitle = {59th {{ASH Abstracts}} \& {{Meeting Program}}},
  publisher = {{Blood}},
  author = {Cook, Mark and Panchal, Anesh and Brock, Kristian and McQuaker, Grant and Snowden, John A. and Crawley, Charles R and Hunter, Hannah and Cavenagh, James D and Sirovica, Mirjana and Hodgkinson, Andrea and Cook, Gordon},
  editor = {{The American Society of Hematology}},
  year = {2017},
  keywords = {MyPubs},
  pages = {3308}
}

@inproceedings{Munir2017,
  title = {The {{Bloodwise TAP Calibre Feasibility Study}} to {{Assess}} the {{Mechanism}} of {{Action}} of {{Idelalisib}} in {{B}}-{{Cell Receptor Pathway}} ({{BCR}}) {{Inhibition}} in {{Chronic Lymphocytic Leukaemia}} ({{CLL}})},
  booktitle = {59th {{ASH Abstracts}} \& {{Meeting Program}}},
  publisher = {{Blood}},
  author = {Munir, Talha and Hillmen, Peter and Rawstron, Andy and Brock, Kristian and {Munoz-Vicente}, Samuel and Yates, Francesca and Dalal, Surita and de Tute, Ruth M and Fox, Chris P and Macdonald, Donald and Fegan, Christopher and Bloor, Adrian and Schuh, Anna and Doody, Gina},
  editor = {{The American Society of Hematology}},
  year = {2017},
  keywords = {CLL,MyPubs},
  pages = {3014}
}

@inproceedings{Brock2017a,
  address = {Liverpool},
  title = {Design of a Practice-Changing Trial in the Ultra-Rare Condition of {{Wolfram Syndrome}}},
  booktitle = {Meeting Abstracts from the 4th {{International Clinical Trials Methodology Conference}} ({{ICTMC}}) and the 38th {{Annual Meeting}} of the {{Society}} for {{Clinical Trials}}},
  publisher = {{Trials}},
  author = {Brock, Kristian and Billingham, Lucinda and Nagy, Zsuzsa and Hershey, Tamara and Smith, Holly and Barton, Darren and Barrett, Timothy},
  editor = {Central, BioMed},
  year = {2017},
  keywords = {MyPubs},
  pages = {175}
}

@inproceedings{Hillmen2017,
  address = {Madrid},
  title = {The Initial Report of the Bloodwise Tap Clarity Study Combining Ibrutinib and Venetoclax in Relapsed, Refractory Cll Shows Acceptable Safety and Promising Early Indications of Efficacy},
  volume = {102},
  abstract = {Background: Ibrutinib (IBR) is an oral BTK inhibitor with high response rates in CLL. Venetoclax (VEN) is a potent, highly selective, orally bioavailable smallmolecule BCL2 inhibitor. Both IBR and VEN are approved by both the FDA and EMA as single agents for chronic lymphocytic leukaemia (CLL). IBR leads to a rapid nodal response with re-distribution of CLL into the peripheral blood whereas VEN leads to depletion of CLL cells to levels in some patients where they cannot be detected. Two of the key cellular processes that are abnormal in CLL are proliferation and apoptosis. The combination of IBR with VEN is therefore logical as biologically the two drugs would be expected to be synergistic. The eradication of minimal residual disease (MRD) from blood and bone marrow is associated with improved outcome in any treatment of CLL where it has been reported. Aims: The CLARITY trial (ISCRTN: 13751862) is a feasibility study to investigate the safety and efficacy of IBR combined with VEN in patients with relapsed/refractory CLL. Here we report for the first time the safety of the combination as well as early signs of potent synergy. Methods: After 8 weeks of IBR monotherapy (420mg/day), VEN was added initially at a dose of 10mg/day with weekly escalations to 20mg, 50mg, 100mg, 200mg to a final dose of 400mg/day. After the initial 3 patients when there was no sign of tumour lysis syndrome (TLS) the starting dose of VEN was amended to 20mg/day. The primary end-point of the trial is MRD eradication (defined as less than 1 CLL cell in 10, 000) in the bone marrow after 12 months of IBR+VEN. Key secondary end-points are MRD eradication from the bone marrow after 6 and 24 months of combined IBR and VEN as well as the safety of the combination. Important safety events that were considered critical were the incidence of laboratory and clinical TLS. All patients were given prophylactic treatment with uric acid reducing agents beginning at least 72 hours prior to their initial dose of VEN. Over the first three months of combined therapy the level of CLL in the peripheral blood was monitored weekly during VEN escalation and then monthly thereafter. 50 participants will be treated in total. Results: A total of 35 patients have been recruited between May 2016 and January 2017. To date 21 patients have completed the dose escalation period of VEN in combination with IBR. To date there has been only a single case of laboratory TLS in a patient whose phosphate (1.21 to 1.48mmol/l) and creatinine (75 to 146 umol/l) both increased when VEN was increased from 100mg to 200mg. Dosing of VEN was interrupted for 7 days (due to the logistics of clinic closure periods over the Christmas break) and IBR for 24 hours. The biochemical abnormalities resolved within 24 hours and the patient subsequently escalated to 400mg/day of VEN with no further TLS. As yet there have been a total of 5 SAEs and 22 AE's of special interest with notably lung infection (n=3) and neutropenia (n=11) occurring on more than one occasion. All SAE's resolved with appropriate management and all patients remained on therapy. No SUSAR's have been reported and no AE's have been fatal. The level of CLL in the peripheral blood increased during the 8 weeks of IBR monotherapy at 420mg/day from a median of 50 \texttimes{} 109/l (range: 0 to 330) to 55 \texttimes{} 109/l (range: 0 to 237) and then fell during the first 8 weeks of combined IBR with VEN (4 weeks dose escalation followed by 4 weeks at 400mg/day) from a median of 55 \texttimes{} 109/l to a median of 0.017 \texttimes{} 109/l (range; 0 to 3.1). The rate of fall is rapid in all patients with a median of 3 log reduction in CLL level after 8 weeks of combined therapy. Summary/Conclusions: The combination of IBR with VEN is well tolerated in relapsed, refractory CLL with to date only a single case of laboratory TLS. The rapid reduction in the peripheral blood CLL level even during the escalation phase of VEN with IBR is promising and suggests a potent synergy between the drugs. The initial bone marrow responses are expected after 6 months of combination therapy.},
  booktitle = {22nd {{Congress}} of the {{European Hematology Association}}},
  publisher = {{Haematologica}},
  author = {P., Hillmen and A., Rawstron and T., Munir and K., Brock and S., Munoz Vincente and Y., Jefferson and K., Paterson and C.P., Fox and J., Gribben and A., Bloor and A., Schuh and F., Forconi},
  editor = {{European Hematology Association}},
  year = {2017},
  keywords = {MyPubs},
  pages = {311},
  issn = {1592-8721}
}

@inproceedings{Rawstron2017,
  address = {Madrid},
  title = {Addition of {{Obinutuzumab}} to {{Ibrutinib Enhances Depletion}} of {{CLL Cells}} in the {{Peripheral Blood}} and {{Bone Marrow}} after 1 {{Month}} of {{Combination Therapy}}: {{Initial Results}} from the {{Bloodwise TAP Iciclle Extension Study}}},
  booktitle = {22nd {{Congress}} of the {{European Hematology Association}}},
  publisher = {{Haematologica}},
  author = {Rawstron, Andy C and Munir, Talha and {Mu\~noz-Vicente}, Samuel and Brock, Kristian and Yates, Francesca J and Bishop, Rebecca and Dalal, Surita and de Tute, Ruth Mary and Bloor, Adrian and Sheehy, Oonagh M and Pettitt, Andrew R. and Fox, Christopher P and Fegan, Christopher and Devereux, Stephen and Macdonald, Donald and Hillmen, Peter},
  editor = {{European Hematology Association}},
  year = {2017},
  keywords = {CLL,MyPubs},
  pages = {69}
}

@article{Urano2016a,
  title = {Wolfram {{Syndrome}}: {{Diagnosis}}, {{Management}}, and {{Treatment}}},
  volume = {16},
  issn = {15390829},
  doi = {10.1007/s11892-015-0702-6},
  abstract = {Wolfram syndrome is a rare genetic disorder characterized by juvenile-onset diabetes mellitus, diabetes insipidus, optic nerve atrophy, hearing loss, and neurodegeneration. Although there are currently no effective treatments that can delay or reverse the progression of Wolfram syndrome, the use of careful clinical monitoring and supportive care can help relieve the suffering of patients and improve their quality of life. The prognosis of this syndrome is currently poor, and many patients die prematurely with severe neurological disabilities, raising the urgency for developing novel treatments for Wolfram syndrome. In this article, we describe natural history and etiology, provide recommendations for diagnosis and clinical management, and introduce new treatments for Wolfram syndrome.},
  number = {1},
  journal = {Current Diabetes Reports},
  author = {Urano, Fumihiko},
  year = {2016},
  keywords = {Wolfram,Blindness,Deafness,Endoplasmic reticulum stress,Genetic disorder,Neurodegeneration,Type 1 diabetes,Type 2 diabetes,Wolfram syndrome,β cells},
  pages = {1-8},
  file = {/Users/k/Downloads/MendeleyWatch/11892_2015_Article_702.pdf},
  pmid = {26742931}
}

@article{Hoekel2018a,
  title = {Visual Pathway Function and Structure in {{Wolfram}} Syndrome: Patient Age, Variation and Progression},
  volume = {3},
  issn = {2397-3269},
  doi = {10.1136/bmjophth-2017-000081},
  number = {1},
  journal = {BMJ Open Ophthalmology},
  author = {Hoekel, James and Narayanan, Anagha and Rutlin, Jerrel and Lugar, Heather and {Al-Lozi}, Amal and Hershey, Tamara and Tychsen, Lawrence},
  year = {2018},
  keywords = {Wolfram},
  pages = {e000081},
  file = {/Users/k/Downloads/MendeleyWatch/e000081.full.pdf}
}

@article{Doty2017a,
  title = {The Effects of Disease-Related Symptoms on Daily Function in {{Wolfram Syndrome}}},
  volume = {2},
  issn = {22146490},
  doi = {10.3233/TRD-170012},
  abstract = {OBJECTIVE: To investigate daily function among individuals with Wolfram Syndrome (WFS) and examine whether any limitations are related to disease-related symptoms. METHODS: WFS (n = 31), Type 1 diabetic (T1DM; n = 25), and healthy control (HC; n = 29) participants completed the Pediatric Quality of Life Questionnaire (PEDSQL) Self and Parent Report. PEDSQL domain scores were compared among these groups and between WFS patients with and without specific disease-related symptoms. Relationships between PEDSQL scores and symptom severity as assessed by the Wolfram Unified Rating Scale (WURS) Physical Scale were also examined. RESULTS: Across most domains, the WFS group had lower PEDSQL Self and Parent Report scores than the T1DM and HC groups. WFS participants with urinary, sleep, and temperature regulation problems had lower PEDSQL scores than those without. The WURS Physical Scale correlated with Self and Parent Report PEDSQL domains. WFS group Self and Parent Reports correlated with each other. CONCLUSIONS: The WFS group reported lower daily function compared to T1DM and HC groups. Within WFS, worse symptom severity and the specific symptoms of sleep, temperature regulation, and urinary problems were associated with poorer daily function. These findings provide rationale for an increased emphasis on identifying, treating and understanding these less well-known symptoms of WFS.},
  number = {1-2},
  journal = {Translational Science of Rare Diseases},
  author = {Doty, Tasha and Foster, Erin R. and Marshall, Bess and Ranck, Samantha and Hershey, Tamara},
  year = {2017},
  keywords = {Wolfram,daily function,diabetes mellitus,inventory,pediatric quality of life,wolfram syndrome},
  pages = {89-100},
  file = {/Users/k/Downloads/MendeleyWatch/trd-2-trd012.pdf}
}

@article{Popovtzer2014,
  title = {Phase i Trial of Radiotherapy Concurrent with Twice-Weekly Gemcitabine for Head and Neck Cancer: {{Translation}} from Preclinical Investigations Aiming to Improve the Therapeutic Ratio},
  volume = {7},
  issn = {19365233},
  doi = {10.1016/j.tranon.2014.04.016},
  abstract = {BACKGROUND: Once-weekly gemcitabine concurrent with radiotherapy was highly effective in the treatment of head and neck cancer (HNC) but limited by high mucosal toxicity. Pre-clinical investigations suggested that delivering gemcitabine at substantially lower doses twice weekly during radiotherapy improved the therapeutic ratio. We sought to translated these preclinical findings to a phase I trial. METHODS: Twenty-five patients with non-resectable HNC were scheduled to receive gemcitabine twice weekly during the last 2 weeks (total 5 infusions) of hyperfractionated radiotherapy delivering 1.2 Gy twice daily to total 76.8 Gy. Tumor biopsies to measure active intracellular (phosphorylated) gemcitabine were planned after the first drug delivery. Patients were assigned to escalating dose cohorts using the Continuous Reassessment Method. RESULTS: Twenty-one patients evaluable for toxicity were divided into cohorts receiving twice weekly treatment with 10, 20, 33, or 50 mg/m2gemcitabine. Dose-limiting toxicity was grade 3-4 confluent mucositis/pharyngitis, and the maximally tolerated dose (MTD) was 20 mg/m2. Median survival was 20 months, with no difference between cohorts receiving lower (10, 20 mg/m2) or higher (33, 50 mg/m2) gemcitabine doses. Tumor biopsies after the first drug delivery showed only a minority of tumor cells in the specimens. CONCLUSION: These findings validate preclinical models that show that gemcitabine is radiation sensitizer at doses far below those used for systemic chemotherapy. However, the improvement in the therapeutic ratio predicted from the preclinical study did not translate into a substantial relative increase in the MTD of the drug in the clinical phase I trial. \textcopyright{} 2014 The Authors. Published by Elsevier Inc. on behalf ofNeoplasia Press, Inc.},
  number = {4},
  journal = {Translational Oncology},
  author = {Popovtzer, Aron and Normolle, Daniel and Worden, Francis P. and Prince, Mark E. and Chepeha, Douglas B. and Wolf, Gregory T. and Bradford, Carol R. and Lawrence, Theodore S. and Eisbruch, Avraham},
  year = {2014},
  keywords = {Chiuzan},
  pages = {479-483},
  file = {/Users/k/Zotero/storage/GHFZRNB2/Popovtzer et al. - 2014 - Phase i trial of radiotherapy concurrent with twice-weekly gemcitabine for head and neck cancer Translation fr.pdf},
  pmid = {25171890}
}

@article{Sleight2000,
  title = {Debate: {{Subgroup}} Analyses in Clinical Trials \textemdash{} Fun to Look at, but Don't Believe Them!},
  volume = {1},
  abstract = {Analysis of subgroup results in a clinical trial is surprisingly unreliable, even in a large trial. This is the result of a combination of reduced statistical power, increased variance and the play of chance. Reliance on such analyses is likely to be more erroneous, and hence harmful, than application of the overall proportional (or relative) result in the whole trial to the estimate of absolute risk in that subgroup. Plausible explanations can usually be found for effects that are, in reality, simply due to the play of chance. When clinicians believe such subgroup analyses, there is a real danger of harm to the individual patient. (Print ISSN 1468-6708; Online 1468-6694) MI = myocardial infarction; t-PA = tissue plasminogen activator.},
  journal = {Curr Control Trials Cardiovasc Med},
  author = {Sleight, Peter},
  year = {2000},
  keywords = {Subgroups},
  pages = {25-27},
  file = {/Users/k/Zotero/storage/KMZKA5C6/Sleight - 2000 - Debate Subgroup analyses in clinical trials — fun to look at, but don't believe them!.pdf}
}

@article{Sharma2014,
  title = {Safety, Pharmacokinetics, and Pharmacodynamics of the {{DR5}} Antibody {{LBY135}} Alone and in Combination with Capecitabine in Patients with Advanced Solid Tumors},
  volume = {32},
  issn = {15730646},
  doi = {10.1007/s10637-013-9952-9},
  abstract = {PURPOSE: We evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, biologic activity, and antitumor efficacy of the DR5 antibody, LBY135 +/- capecitabine., EXPERIMENTAL DESIGN: Escalating LBY135 was administered every 21 days, alone (Arm1) or with capecitabine (Arm2), to patients with advanced solid tumors., RESULTS: In Arm1 (n=40), LBY135 (0.3-40 mg/kg) resulted in no dose-limiting toxicities (DLTs); adverse events (AEs) included fatigue, hypotension, abdominal pain, dyspnea, and nausea. Stable disease (SD) was observed in 21/38 (55.3 \%) patients. In Arm2 (n=33), LBY135 (1-40 mg/kg) plus capecitabine resulted in 3 DLTs (each grade 3): dehydration and mucosal inflammation (1 mg/kg), colitis (20 mg/kg), and diarrhea (40 mg/kg). AEs included fatigue, nausea, dyspnea, and vomiting. Partial response was observed in 2 patients (rectal and breast cancer) and SD in 12/27 (44.4 \%) patients. Mean elimination half-life of LBY135 +/- capecitabine at saturation of clearance ($>$10 mg/kg) ranged between 146 h and 492 h. Immunogenicity was detected in 16/73 (22 \%) patients, of which 6 patients experienced reduced LBY135 exposure with repeat dosing. M30/M65 levels were not predictive for LBY135 response. FDG-PET responses were not consistently associated with RECIST responses., CONCLUSIONS: LBY135 was well tolerated up to 40 mg/kg, the maximal dose administered; no MTD for LBY135 +/- capecitabine was defined. Clearance was saturated at doses $>$10 mg/kg.},
  number = {1},
  journal = {Investigational New Drugs},
  author = {Sharma, Sunil and De Vries, Elisabeth G. and Infante, Jeffrey R. and Oldenhuis, Corina N. and Gietema, Jourik A. and Yang, Lin and Bilic, Sanela and Parker, Katie and Goldbrunner, Michael and Scott, Jeffrey W. and Burris, Howard A.},
  year = {2014},
  keywords = {Dose escalation,Chiuzan,Capecitabine,DR5 death receptor,LBY135,TNF-related apoptosis-inducing ligand},
  pages = {135-144},
  file = {/Users/k/Zotero/storage/752Q87V6/Sharma et al. - 2014 - Safety, pharmacokinetics, and pharmacodynamics of the DR5 antibody LBY135 alone and in combination with capecitab.pdf},
  pmid = {23589214}
}

@article{Macaulay2016a,
  title = {Phase {{I}} Dose-Escalation Study of Linsitinib ({{OSI}}-906) and Erlotinib in Patients with Advanced Solid Tumors},
  volume = {22},
  issn = {15573265},
  doi = {10.1158/1078-0432.CCR-15-2218},
  abstract = {Purpose: Cross-talk between type I IGF receptor (IGF1R), insulin receptor (INSR), and epidermal growth factor receptor (EGFR) mediates resistance to individual receptor blockade. This study aimed to determine the MTD, safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of linsitinib, a potent oral IGF1R/INSR inhibitor, with EGFR inhibitor erlotinib.Experimental Design: This open-label, dose-escalation study investigated linsitinib schedules S1: once daily intermittent (days 1\textendash{}3 weekly); S2, once daily continuous; S3, twice-daily continuous; each with erlotinib 100\textendash{}150 mg once daily; and a non\textendash{}small cell lung cancer (NSCLC) expansion cohort.Results: Ninety-five patients were enrolled (S1, 44; S2, 24; S3, 12; expansion cohort, 15) and 91 treated. Seven experienced dose-limiting toxicities: QTc prolongation (3), abnormal liver function (2), hyperglycemia (1), and anorexia (1). Common adverse events included drug eruption (84\%), diarrhea (73\%), fatigue (68\%), nausea (58\%), vomiting (40\%). MTDs for linsitinib/erlotinib were 450/150 mg (S1), 400/100 mg (S2). On the basis of prior monotherapy data, S3 dosing at 150 mg twice daily/150 mg once daily was the recommended phase II dose for the expansion cohort. There was no evidence of drug\textendash{}drug interaction. Pharmacodynamic data showed IGF-1 elevation and reduced IGF1R/INSR phosphorylation, suggesting pathway inhibition. Across schedules, 5/75 (7\%) evaluable patients experienced partial responses: spinal chordoma (268+ weeks), rectal cancer (36 weeks), three NSCLCs including 2 adenocarcinomas (16, 72 weeks), 1 squamous wild-type EGFR NSCLC (36 weeks). Disease control (CR+PR+SD) occurred in 38 of 75 (51\%), and 28 of 91 (31\%) patients were on study \&amp;gt;12 weeks.Conclusions: The linsitinib/erlotinib combination was tolerable with preliminary evidence of activity, including durable responses in cases unlikely to respond to erlotinib monotherapy. Clin Cancer Res; 22(12); 2897\textendash{}907. \textcopyright{}2016 AACR.},
  number = {12},
  journal = {Clinical Cancer Research},
  author = {Macaulay, Valentine M. and Middleton, Mark R. and Eckhardt, S. Gail and Rudin, Charles M. and Juergens, Rosalyn A. and Gedrich, Richard and Gogov, Sven and McCarthy, Sean and Poondru, Srinivasu and Stephens, Andrew W. and Gadgeel, Shirish M.},
  year = {2016},
  keywords = {AdamAkhtar},
  pages = {2897-2907},
  file = {/Users/k/Zotero/storage/PGRSXDX9/Macaulay et al. - 2016 - Phase I dose-escalation study of linsitinib (OSI-906) and erlotinib in patients with advanced solid tumors.pdf}
}

@article{Abayomi2008,
  title = {Diagnostics for Multivariate Imputations},
  volume = {57},
  abstract = {We consider three sorts of diagnostics for random imputations: displays of the com-pleted data, which are intended to reveal unusual patterns that might suggest problems with the imputations, comparisons of the distributions of observed and imputed data values and checks of the fit of observed data to the model that is used to create the imputations. We formulate these methods in terms of sequential regression multivariate imputation, which is an iterative procedure in which the missing values of each variable are randomly imputed conditionally on all the other variables in the completed data matrix. We also consider a recalibration procedure for sequential regression imputations. We apply these methods to the 2002 environmental sus-tainability index, which is a linear aggregation of 64 environmental variables on 142 countries.},
  number = {3},
  author = {Abayomi, Kobi and Gelman, Andrew and Levy, Marc},
  year = {2008},
  pages = {273-291},
  file = {/Users/k/Zotero/storage/SVFRECMN/Abayomi, Gelman, Levy - 2008 - Diagnostics for multivariate imputations.pdf}
}

@article{Piironen2017,
  archivePrefix = {arXiv},
  eprinttype = {arxiv},
  eprint = {1503.08650v1},
  title = {Comparison of {{Bayesian}} Predictive Methods for Model Selection},
  volume = {27},
  issn = {15731375},
  doi = {10.1007/s11222-016-9649-y},
  abstract = {The goal of this paper is to compare several widely used Bayesian model selection methods in practical model selection problems, highlight their differences and give recommendations about the preferred approaches. We focus on the variable subset selection for regression and classification and perform several numerical experiments using both simulated and real world data. The results show that the optimization of a utility estimate such as the cross-validation score is liable to finding overfitted models due to relatively high variance in the utility estimates when the data is scarce. Better and much less varying results are obtained by incorporating all the uncertainties into a full encompassing model and projecting this information onto the submodels. The reference model projection appears to outperform also the maximum a posteriori model and the selection of the most probable variables. The study also demonstrates that the model selection can greatly benefit from using cross-validation outside the searching process both for guiding the model size selection and assessing the predictive performance of the finally selected model.},
  number = {3},
  journal = {Statistics and Computing},
  author = {Piironen, Juho and Vehtari, Aki},
  year = {2017},
  keywords = {Cross-validation,BayesCore,Bayesian model selection,Projection,Reference model,Selection bias},
  pages = {711-735},
  file = {/Users/k/Zotero/storage/WCH4BY8R/Piironen, Vehtari - 2017 - Comparison of Bayesian predictive methods for model selection.pdf}
}

@article{Paoletti,
  title = {Title: {{Phase}} 1-2 Trial Designs: How Early Should Efficacy Guide the Dose Recommendation Process? {{Running}} Head: {{Using}} Efficacy to Guide Dose Recommendation in Phase 1-2 Trials?},
  doi = {10.1093/annonc/mdy044/4838339},
  abstract = {Oncology has the highest number of drug development failures, which calls for improvement in drug development methodology [1]. Following the two therapeutic revolutions of targeted agents and immune therapies, several drug development paradigms have been challenged, including the systematic recommendation of the maximum tolerable dose (MTD) as recommended phase 2 dose (RP2D) [2]. More and more trials seek to determine the " optimal biological dose " (dose associated with the most desirable effect on a pre-specified biomarker). Further, although determination of safety profile of a new agent remains the primary endpoint of phase 1 trials, efficacy is more and more often brought forward as a co-primary endpoint. This has resulted in significant transformations over the last few years, with phase 1 samples sizes and number of expansion cohorts being multiplied [3]. Such expansion cohorts are sometimes disguised single arm phase 2 studies, resulting in a two-step design made of a dose-escalation phase, based on toxicity only, followed by a " signal-searching " expansion phase with stopping rules for futility [4]. In this context, should we take into account efficacy to guide dose-escalation and dose-recommendation? In this issue of Annals of Oncology, Yan and colleagues [5] illustrate, using clear examples, that responses at doses other than the RP2D are not integrated in the overall efficacy evaluation, and propose the phase 1-2 EffTox model-based design, which utilizes both toxicity and efficacy data to guide dose-recommendation. Doses are escalated if the agent is safe and if more activity is expected; doses are de-escalated if lower doses appear almost equally active but less toxic; agents without sufficient activity at any safe dose are halted early. Dose that allows reaching the optimal efficacy-toxicity trade-off is further selected.},
  author = {Paoletti, Xavier},
  file = {/Users/k/Zotero/storage/UVYTTK4A/Paoletti - Unknown - Title Phase 1-2 trial designs how early should efficacy guide the dose recommendation process Running head Using ef.pdf}
}

@article{Kobayashi2014,
  title = {Phase {{I}} Study of Adjuvant Gemcitabine or {{S}}-1 in Patients with Biliary Tract Cancers Undergoing Major Hepatectomy: {{KHBO1003}} Study},
  volume = {74},
  issn = {14320843},
  doi = {10.1007/s00280-014-2543-4},
  abstract = {BACKGROUND: Standardized adjuvant therapy is not performed after major hepatectomy for biliary tract cancer (BTC) because of frequent adverse events, which may be caused by insufficient liver function. Therefore, the aim of this multicenter study (KHBO1003) was to determine the safety protocol for adjuvant chemotherapy after major hepatectomy.$\backslash$n$\backslash$nMETHODS: Within 12 weeks of R0 or R1 major hepatectomy (hemihepatectomy or trisectionectomy) for BTC, the following adjuvant chemotherapy was performed for 6 months: 800-1,000 mg/m(2) gemcitabine on days 1, 8, and 15 and then every 3-4 weeks or 40-80 mg/m(2)/day S-1 on days 1-28 and every 3-6 weeks. Major dose-limited toxicity (DLT) was defined as grade 4 hematotoxicity, grade 3/4 febrile neutropenia, grade 3/4 non-hematotoxicity, skipped gemcitabine on days 8 and 15, or halting the course at or after 14 days. Dose-escalation and de-escalation decisions were based on the continual reassessment method. Every three patients were alternately assigned to each arm.$\backslash$n$\backslash$nRESULTS: Thirty-three patients (14 intrahepatic bile duct, 1 gall bladder, 18 extrahepatic bile duct) were enrolled in this study from February 2011 to July 2012 (n = 18 gemcitabine, n = 15 S-1). At 10\% of DLT, the recommended dose was 1,000 mg/m(2) gemcitabine biweekly and 80 mg/m(2)/day S-1 on days 1-28 and every 6 weeks. Major DLT and adverse drug reactions were neutropenia. No grade 3 or 4 non-hematological adverse events were noted.$\backslash$n$\backslash$nCONCLUSION: We determined RDs for gemcitabine and S-1 adjuvant chemotherapy after major hepatectomy with a DLT that does not exceed 10\%.},
  number = {4},
  journal = {Cancer Chemotherapy and Pharmacology},
  author = {Kobayashi, Shogo and Nagano, Hiroaki and Sakai, Daisuke and Eguchi, Hidetoshi and Hatano, Etsuro and Kanai, Masashi and Seo, Satoru and Taura, Kojiro and Fujiwara, Yutaka and Ajiki, Tetsuo and Takemura, Shigekazu and Kubo, Shoji and Yanagimoto, Hiroaki and Toyokawa, Hideyoshi and Tsuji, Akihito and Terajima, Hiroaki and Morita, Satoshi and Ioka, Tatsuya},
  year = {2014},
  keywords = {Chiuzan,Adjuvant chemotherapy,Biliary tract cancer,Gemcitabine,Major hepatectomy,S-1},
  pages = {699-709},
  file = {/Users/k/Downloads/MendeleyWatch/kobayashi2014.pdf},
  pmid = {25074036}
}

@article{Villers2017,
  title = {Robot-Assisted Partial Prostatectomy for Anterior Prostate Cancer: A Step-by-Step Guide},
  volume = {119},
  issn = {1464410X},
  doi = {10.1111/bju.13785},
  abstract = {Objective: To describe a step-by-step guide to robot-assisted anterior partial prostatectomy (RA-APP) for isolated magnetic resonance imaging (MRI)-detected anterior prostate cancer (APC). Patients and Methods: After Institutional Review Board approval, over an 8-year period (2008\textendash{}2015), 17 consenting patients were enrolled in a prospective, single-arm, single-centre, Idea, Development, Evaluation, Assessment and Long-term evaluation of innovative surgery (IDEAL) phase 2a study. The inclusion criteria comprised pre-urethral, low\textendash{}intermediate risk APC diagnosed by MRI and targeted biopsies. Patient position and port placement were identical to the transperitoneal RA radical prostatectomy procedure. Three steps of dissection were identified in the following order: (i) retrograde apical, after dorsal venous plexus division, transition zone (TZ) enucleation, and distal peripheral zone (PZ) sectioning; (ii) antegrade, at the bladder neck (BN) after anterior BN sectioning, TZ enucleation up to the verumontanum; and (iii) lateral dissections, including anterolateral PZ sectioning without incision of the endopelvic fascia. We report the incidence of perioperative complications. The RA completion of prostatectomy in four cases with cancer recurrence was performed at 0.3, 2.5, 2 and 2~years, respectively. Results: The RA-APP comprised en bloc excision of the anterior part of the prostate comprising of the anterior fibromuscular stroma, BN, prostate adenoma (TZ and median lobe) along with the proximal prostate urethra, PZ apical anterior horns, anterior aspect of the distal (sub-montanal) urethra, and anterior BN. The posterolateral parts of the PZ and distal (sub-montanal) urethra and peri-prostatic tissues were preserved intact. The bladder opening was sutured to the anterior sphincteric urethra wall and PZ lateral edges. The technique was feasible in all cases with no conversion to an open procedure. Perioperative complications were only Clavien\textendash{}Dindo grade II. RA completion of prostatectomy was feasible in the four cases with cancer recurrence. Conclusion: PZ prostate-sparing RA-APP for isolated APC is feasible and safe, and represents an option for highly selected men with APCs as an alternative to other focal ablative therapy.},
  number = {6},
  journal = {BJU International},
  author = {Villers, Arnauld and Flamand, Vincent and Arqu\'imedes, Rodr\'iguez Carlin and Puech, Philippe and Haber, Georges Pascal and Desai, Mihir M. and Crouzet, Sebastien and Ouzzane, Adil and Gill, Inderbir S.},
  year = {2017},
  keywords = {\#PCSM,\#ProstateCancer,focal therapy,prostate MRI,robot-assisted surgery},
  pages = {968-974},
  file = {/Users/k/Zotero/storage/28LAV3PI/Villers et al. - 2017 - Robot-assisted partial prostatectomy for anterior prostate cancer a step-by-step guide.pdf},
  pmid = {28111893}
}

@article{Khouri2014,
  title = {{{BFR}} (Bendamustine, Fludarabine, and Rituximab) Allogeneic Conditioning for Chronic Lymphocytic Leukemia/Lymphoma: {{Reduced}} Myelosuppression and {{GVHD}}},
  volume = {124},
  issn = {15280020},
  doi = {10.1182/blood-2014-07-587519},
  abstract = {Myelosuppression, graft-versus-host disease (GVHD), and relapse remain major causes of morbidity after stem cell transplantation for relapsed lymphoma. In this phase 1/2 study, we tested the safety and efficacy of escalating doses of bendamustine (70, 90, 110, and 130 mg/m2 per day for 3 days), coupled with our historical fixed doses of fludarabine and rituximab (BFR), as a nonmyeloablative allogeneic conditioning regimen for patients with relapsed lymphoma (n = 41) and chronic lymphocytic leukemia (CLL) (n = 15). Ten patients entered the phase 1 study; none experienced a dose-limiting toxicity. Forty-six additional patients were then treated in the phase 2 study at the maximum dose of 130 mg/m2 per day for 3 days. The proportions of transplants from matched siblings or unrelated donors were 54\% and 46\%. Remarkably, 55\% of patients did not experience severe neutropenia. Forty-nine patients (88\%) did not require platelet transfusion. The incidence of acute grade II-IV GVHD was 11\%. The 2-year rate of extensive chronic GVHD was 26\%. After a median follow-up duration of 26 months (range, 6-50 months), the 2-year overall and progression-free survival rates were 90\% and 75\%. In conclusion, our new BFR regimen is safe and effective for relapsed CLL and lymphoma patients.},
  number = {14},
  journal = {Blood},
  author = {Khouri, Issa F. and Wei, Wei and Korbling, Martin and Turturro, Francesco and Ahmed, Sairah and Alousi, Amin and Anderlini, Paolo and Ciurea, Stefan and Jabbour, Elias and Oran, Betul and Popat, Uday R. and Rondon, Gabriela and Bassett, Roland L. and Gulbis, Alison},
  year = {2014},
  keywords = {Chiuzan},
  pages = {2306-2312},
  file = {/Users/k/Dropbox/Research/ChiuzanReview/Manuscripts/2014 Khouri.pdf},
  pmid = {25145344}
}

@article{Ando2014,
  archivePrefix = {arXiv},
  eprinttype = {arxiv},
  eprint = {1011.1669v3},
  title = {Phase {{I}} Dose-Escalation Study of Buparlisib ({{BKM120}}), an Oral Pan-Class {{I PI3K}} Inhibitor, in {{Japanese}} Patients with Advanced Solid Tumors},
  volume = {105},
  issn = {13497006},
  doi = {10.1111/cas.12350},
  abstract = {Buparlisib (BKM120) is an oral pan-phosphatidylinositol 3-kinase inhibitor, targeting all four isoforms of class I PI3K ($\alpha$, $\beta$, $\gamma$ and $\delta$). This open-label Phase I dose-escalation study was conducted to determine the maximum tolerated dose of continuous daily buparlisib in Japanese patients with advanced solid tumors. Secondary objectives included safety and tolerability, pharmacokinetics, antitumor activity and pharmacodynamic marker changes. Fifteen patients were treated at 25 mg/day (n = 3), 50 mg/day (n = 3) and 100 mg/day (n = 9) dose levels. One dose-limiting toxicity of Grade 4 abnormal liver function occurred at 100 mg/day. Considering the safety profile and the maximum tolerated dose in the first-in-man study of buparlisib in non-Japanese patients, further dose escalation was stopped and 100 mg/day was declared the recommended dose. The most common treatment-related adverse events were rash, abnormal hepatic function (including increased transaminase levels), increased blood insulin levels and increased eosinophil count. Hyperglycemia was experienced by two patients, one Grade 1 and one Grade 4, and mood alterations were experienced by three patients, two Grade 1 and one Grade 2. Pharmacokinetic results showed that buparlisib was rapidly absorbed in a dose-proportional manner. Best overall response was stable disease for six patients, including one unconfirmed partial response. In these Japanese patients with advanced solid tumors, buparlisib had a manageable safety profile, with similar pharmacokinetics to non-Japanese patients. The recommended dose of 100 mg/day will be used in future studies of buparlisib in Japanese patients.},
  number = {3},
  journal = {Cancer Science},
  author = {Ando, Yuichi and {Inada-Inoue}, Megumi and Mitsuma, Ayako and Yoshino, Takayuki and Ohtsu, Atsushi and Suenaga, Naoko and Sato, Masahiko and Kakizume, Tomoyuki and Robson, Matthew and Quadt, Cornelia and Doi, Toshihiko},
  year = {2014},
  keywords = {Chiuzan,BKM120,Buparlisib,Japanese patients},
  pages = {347-353},
  file = {/Users/k/Zotero/storage/VBM9BFQN/Ando et al. - 2014 - Phase I dose-escalation study of buparlisib (BKM120), an oral pan-class I PI3K inhibitor, in Japanese patients with.pdf},
  pmid = {24405565}
}

@article{Shaw2014,
  title = {Ceritinib in {{ALK}} -{{Rearranged Non}}\textendash{{Small}}-{{Cell Lung Cancer}}},
  volume = {370},
  issn = {0028-4793},
  doi = {10.1056/NEJMoa1311107},
  abstract = {BackgroundNon\textendash{}small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies. MethodsIn this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib. ResultsA total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-l...},
  number = {13},
  journal = {New England Journal of Medicine},
  author = {Shaw, Alice T. and Kim, Dong-Wan and Mehra, Ranee and Tan, Daniel S.W. and Felip, Enriqueta and Chow, Laura Q.M. and Camidge, D. Ross and Vansteenkiste, Johan and Sharma, Sunil and De Pas, Tommaso and Riely, Gregory J. and Solomon, Benjamin J. and Wolf, Juergen and Thomas, Michael and Schuler, Martin and Liu, Geoffrey and Santoro, Armando and Lau, Yvonne Y. and Goldwasser, Meredith and Boral, Anthony L. and Engelman, Jeffrey A.},
  year = {2014},
  keywords = {Chiuzan},
  pages = {1189-1197},
  file = {/Users/k/Zotero/storage/RNWCNLWH/Shaw et al. - 2014 - Ceritinib in ALK -Rearranged Non–Small-Cell Lung Cancer - Supplement.pdf;/Users/k/Zotero/storage/YDSKKVV2/Shaw et al. - 2014 - Ceritinib in ALK -Rearranged Non–Small-Cell Lung Cancer.pdf},
  pmid = {24670165}
}

@article{Spiegelhalter1986,
  title = {{{PROBABILISTIC PREDICTION IN PATIENT MANAGEMENT A N D CLINICAL TRIALS}}},
  volume = {5},
  abstract = {SUMMARY It is argued that the provision of accurate and useful probabilistic assessments of future events should be a fundamental task for biostatisticians collaborating in clinical or experimental medicine, and we explore two aspects of obtaining and evaluating such predictions. When covariate information on patients is available, logistic regression and other multivariate techniques are often used to select prognostic factors and create predictive models. An example shows how the explicit aim of prediction needs to be taken into account in such modelling, and how predictive performance may be assessed by decomposition of a scoring rule. Secondly, results from a program that provides pretrial and interim predictions in clinical trials are displayed, bringing together the use of subjective opinion, Bayesian methodology and techniques for evaluating and criticizing predictions.},
  journal = {STATISTICS IN MEDICINE},
  author = {Spiegelhalter, D J},
  year = {1986},
  file = {/Users/k/Zotero/storage/KSAGMGF8/Spiegelhalter - 1986 - PROBABILISTIC PREDICTION IN PATIENT MANAGEMENT A N D CLINICAL TRIALS.pdf}
}

@article{Barr2013,
  title = {Random Effects Structure for Confirmatory Hypothesis Testing: {{Keep}} It Maximal},
  volume = {68},
  doi = {10.1016/j.jml.2012.11.001},
  abstract = {a b s t r a c t Linear mixed-effects models (LMEMs) have become increasingly prominent in psycholin-guistics and related areas. However, many researchers do not seem to appreciate how ran-dom effects structures affect the generalizability of an analysis. Here, we argue that researchers using LMEMs for confirmatory hypothesis testing should minimally adhere to the standards that have been in place for many decades. Through theoretical arguments and Monte Carlo simulation, we show that LMEMs generalize best when they include the maximal random effects structure justified by the design. The generalization performance of LMEMs including data-driven random effects structures strongly depends upon modeling criteria and sample size, yielding reasonable results on moderately-sized samples when conservative criteria are used, but with little or no power advantage over maximal models. Finally, random-intercepts-only LMEMs used on within-subjects and/or within-items data from populations where subjects and/or items vary in their sensitivity to experimental manipulations always generalize worse than separate F 1 and F 2 tests, and in many cases, even worse than F 1 alone. Maximal LMEMs should be the 'gold standard' for confirmatory hypothesis testing in psycholinguistics and beyond.},
  journal = {Journal of Memory and Language},
  author = {Barr, Dale J and Levy, Roger and Scheepers, Christoph and Tily, Harry J},
  year = {2013},
  pages = {255-278},
  file = {/Users/k/Zotero/storage/RDZB9X97/Barr et al. - 2013 - Random effects structure for confirmatory hypothesis testing Keep it maximal.pdf}
}

@article{Baayen2017,
  title = {The Cave of Shadows: {{Addressing}} the Human Factor with Generalized Additive Mixed Models},
  doi = {10.1016/j.jml.2016.11.006},
  abstract = {a b s t r a c t Generalized additive mixed models are introduced as an extension of the generalized linear mixed model which makes it possible to deal with temporal autocorrelational structure in experimental data. This autocorrelational structure is likely to be a consequence of learn-ing, fatigue, or the ebb and flow of attention within an experiment (the 'human factor'). Unlike molecules or plots of barley, subjects in psycholinguistic experiments are intelligent beings that depend for their survival on constant adaptation to their environment, includ-ing the environment of an experiment. Three data sets illustrate that the human factor may interact with predictors of interest, both factorial and metric. We also show that, especially within the framework of the generalized additive model, in the nonlinear world, fitting maximally complex models that take every possible contingency into account is ill-advised as a modeling strategy. Alternative modeling strategies are discussed for both con-firmatory and exploratory data analysis.},
  author = {Baayen, Harald and Vasishth, Shravan and Kliegl, Reinhold and Bates, Douglas},
  year = {2017},
  file = {/Users/k/Zotero/storage/45XHYLIL/Baayen et al. - 2017 - The cave of shadows Addressing the human factor with generalized additive mixed models.pdf}
}

@article{Saura2014,
  title = {Phase Lb Study of Buparlisib plus Trastuzumab in Patients with {{HER2}}-Positive Advanced or Metastatic Breast Cancer That Has Progressed on Trastuzumab-Based Therapy},
  volume = {20},
  issn = {15573265},
  doi = {10.1158/1078-0432.CCR-13-1070},
  abstract = {PURPOSE: Phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway activation in patients with HER2-positive (HER2(+)) breast cancer has been implicated in de novo and acquired trastuzumab resistance. The purpose of this study was to determine the clinical activity of the PI3K inhibitor buparlisib (BKM120) in patients with HER2(+) advanced/metastatic breast cancer resistant to trastuzumab-based therapy.$\backslash$n$\backslash$nEXPERIMENTAL DESIGN: In the dose-escalation portion of this phase I/II study, patients with trastuzumab-resistant locally advanced or metastatic HER2(+) breast cancer were treated with daily oral doses of buparlisib and weekly intravenous trastuzumab (2 mg/kg). Dose escalation was guided by a Bayesian logistic regression model with overdose control.$\backslash$n$\backslash$nRESULTS: Of 18 enrolled patients, 17 received buparlisib. One dose-limiting toxicity of grade 3 general weakness was reported at the 100-mg/day dose level (the single-agent maximum tolerated dose) and this dose level was declared the recommended phase II dose (RP2D) of buparlisib in combination with trastuzumab. Common ($>$25\%) adverse events included rash (39\%), hyperglycemia (33\%), and diarrhea (28\%). The pharmacokinetic profile of buparlisib was not affected by its combination with trastuzumab. At the RP2D, there were two (17\%) partial responses, 7 (58\%) patients had stable disease ($\geq$6 weeks), and the disease control rate was 75\%. Pharmacodynamic studies showed inhibition of the PI3K/AKT/mTOR and RAS/MEK/ERK pathways.$\backslash$n$\backslash$nCONCLUSIONS: In this patient population, the combination of buparlisib and trastuzumab was well tolerated, and preliminary signs of clinical activity were observed. The phase II portion of this study will further explore the safety and efficacy of this combination at the RP2D. Clin Cancer Res; 20(7); 1935-45. \textcopyright{}2014 AACR.},
  number = {7},
  journal = {Clinical Cancer Research},
  author = {Saura, Cristina and Bendell, Johanna and Jerusalem, Guy and Su, Shaun and Ru, Qinhua and De Buck, Stefan and Mills, David and Ruquet, Sophie and Bosch, Ana and Urruticoechea, Ander and Beck, Joseph T. and Di Tomaso, Emmanuelle and Sternberg, David W. and Massacesi, Cristian and Hirawat, Samit and Dirix, Luc and Baselga, Jose},
  year = {2014},
  keywords = {Chiuzan},
  pages = {1935-1945},
  file = {/Users/k/Dropbox/Research/ChiuzanReview/Manuscripts/2014 Saura.pdf},
  pmid = {24470511}
}

@article{Rodon2014,
  title = {A Phase {{I}}, Multicenter, Open-Label, First-in-Human, Dose-Escalation Study of the Oral Smoothened Inhibitor Sonidegib ({{LDE225}}) in Patients with Advanced Solid Tumors},
  volume = {20},
  issn = {15573265},
  doi = {10.1158/1078-0432.CCR-13-1710},
  abstract = {PURPOSE: This phase I trial was undertaken to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the novel smoothened inhibitor sonidegib (LDE225), a potent inhibitor of hedgehog signaling, in patients with advanced solid tumors.$\backslash$n$\backslash$nEXPERIMENTAL DESIGN: Oral sonidegib was administered to 103 patients with advanced solid tumors, including medulloblastoma and basal cell carcinoma (BCC), at doses ranging from 100 to 3,000 mg daily and 250 to 750 mg twice daily, continuously, with a single-dose pharmacokinetics run-in period. Dose escalations were guided by a Bayesian logistic regression model. Safety, tolerability, efficacy, pharmacokinetics, and biomarkers in skin and tumor biopsies were assessed.$\backslash$n$\backslash$nRESULTS: The MTDs of sonidegib were 800 mg daily and 250 mg twice daily. The main DLT of reversible grade 3/4 elevated serum creatine kinase (18\% of patients) was observed at doses $\geq$ the MTD in an exposure-dependent manner. Common grade 1/2 adverse events included muscle spasm, myalgia, gastrointestinal toxicities, increased liver enzymes, fatigue, dysgeusia, and alopecia. Sonidegib exposure increased dose proportionally up to 400 mg daily, and displayed nonlinear pharmacokinetics at higher doses. Sonidegib exhibited exposure-dependent reduction in GLI1 mRNA expression. Tumor responses observed in patients with medulloblastoma and BCC were associated with evidence of hedgehog pathway activation.$\backslash$n$\backslash$nCONCLUSIONS: Sonidegib has an acceptable safety profile in patients with advanced solid tumors and exhibits antitumor activity in advanced BCC and relapsed medulloblastoma, both of which are strongly associated with activated hedgehog pathway, as determined by gene expression.},
  number = {7},
  journal = {Clinical Cancer Research},
  author = {Rodon, Jordi and Tawbi, Hussein A. and Thomas, Anne L. and Stoller, Ronald G. and Turtschi, Christian P. and Baselga, Jose and Sarantopoulos, John and Mahalingam, Devalingam and Shou, Yaping and Moles, Melissa A. and Yang, Lin and Granvil, Camille and Hurh, Eunju and Rose, Kristine L. and Amakye, Dereck D. and Dummer, Reinhard and Mita, Alain C.},
  year = {2014},
  keywords = {Chiuzan},
  pages = {1900-1909},
  file = {/Users/k/Dropbox/Research/ChiuzanReview/Manuscripts/2014 Rodon (1).pdf},
  pmid = {24523439}
}

@article{Rodon,
  title = {No {{Title}}},
  author = {Rodon, Jordi and Tawbi, Hussein and Thomas, Anne and Stoller, Ronald and Turtschi, Christian P and Sarantopoulos, John and Mahalingam, Devalingam and Shou, Yaping and Moles, Melissa and Yang, Lin and Granvil, Camille and Hurh, Eunju and Rose, Kristine and Amakye, Dereck and Mita, Alain},
  keywords = {Chiuzan},
  file = {/Users/k/Dropbox/Research/ChiuzanReview/Manuscripts/2014 Rodon (1)_suppl.pdf}
}

@article{Hundeshagen2017,
  title = {A {{Prospective}}, {{Randomized}}, {{Controlled Trial Comparing}} the {{Outpatient Treatment}} of {{Pediatric}} and {{Adult Partial}}-{{Thickness Burns}} with {{Suprathel}} or {{Mepilex Ag}}},
  issn = {15590488},
  doi = {10.1097/BCR.0000000000000584},
  abstract = {Modern treatment of partial thickness burns follow the paradigm of less frequent dressing changes to allow for undisturbed reepithelialization of the burn wound. We compared Mepilex Ag (M), a silver-impregnated foam dressing, and Suprathel (S), a DL-lactid acid polymer, in the outpatient treatment of partial thickness burns in pediatric and adult patients. Patients were enrolled in a randomized controlled prospective clinical trial. We monitored time to reepithelialization, wound pain, discomfort during dressing changes, and treatment cost. Objective scar characteristics (elasticity, transepidermal water loss, hydration, and pigmentation) and subjective assessments (Patient and Observer Scar Assessment Scale) were measured at 1-month post burn. Data are presented as mean +/- SEM and significance accepted at P $<$ 0.05. Sixty-two patients (S n = 32; M n = 30) were enrolled; age, sex, and burn size were comparable between the groups. Time to reepithelialization was not different between the groups (12 days; P = 0.75). Pain ratings were significantly reduced during the first 5 days after burn in the Suprathel group in all patients (P = 0.03) and a pediatric subgroup (P $<$ 0.001). Viscolelasticity of burned skin was elevated compared with unburned skin in the Mepilex Ag group at 1-month post burn. Patients treated with Suprathel reported better overall scar quality (S: 2; M: 4.5; P $<$ 0.001). The cost of treatment per square centimeter for Mepilex Ag was considerably lower than Suprathel. Both dressings are feasible and efficacious for the outpatient treatment of minor and selected moderate partial thickness burns. Reduced pain, especially in a pediatric patient population, may be advantageous, despite increased treatment cost.},
  number = {March},
  journal = {Journal of Burn Care and Research},
  author = {Hundeshagen, Gabriel and Collins, Vanessa N. and Wurzer, Paul and Sherman, William and Voigt, Charles D. and {Cambiaso-Daniel}, Janos and {Nunez-Lopez}, Omar and Sheaffer, Jason and Herndon, David N. and Finnerty, Celeste C. and Branski, Ludwik K.},
  year = {2017},
  pages = {261-267},
  file = {/Users/k/Downloads/MendeleyWatch/bcr.0000000000000584.pdf}
}

@article{Yap2017,
  title = {Dose Transition Pathways: {{The}} Missing Link between Complex Dose-Finding Designs and Simple Decision-Making},
  volume = {23},
  issn = {15573265},
  doi = {10.1158/1078-0432.CCR-17-0582},
  number = {24},
  journal = {Clinical Cancer Research},
  author = {Yap, Christina and Billingham, Lucinda J. and Cheung, Ying Kuen and Craddock, Charlie and O'Quigley, John},
  year = {2017},
  keywords = {continual reassessment,model-based designs,phase i dose-finding,rule-based designs},
  pages = {7440-7447},
  file = {/Users/k/Downloads/MendeleyWatch/1078-0432.CCR-17-0582.full.pdf;/Users/k/Downloads/MendeleyWatch/yap2017.pdf}
}

@article{Rothman,
  title = {Six {{Persistent Research Misconceptions}}},
  doi = {10.1007/s11606-013-2755-z},
  author = {Rothman, Kenneth J},
  file = {/Users/k/Zotero/storage/6JI93IKQ/Rothman - Unknown - Six Persistent Research Misconceptions.pdf}
}

@article{Doi2014,
  title = {Phase {{I}} Dose-Escalation Study of the {{HSP90}} Inhibitor {{AUY922}} in {{Japanese}} Patients with Advanced Solid Tumors},
  volume = {74},
  issn = {14320843},
  doi = {10.1007/s00280-014-2521-x},
  abstract = {PURPOSE: AUY922 is a potent non-geldanamycin inhibitor of heat-shock protein 90. This study was carried out in Japanese patients to determine the maximum tolerated dose (MTD), and to characterize safety, tolerability and pharmacokinetics of single-agent AUY922. METHODS: Japanese patients with advanced solid tumors whose disease had progressed on at least one line of standard therapy, or for whom no standard therapy existed, were treated with AUY922 (intravenous, once-weekly, 28-day cycle, starting dose 8 mg/m(2)). RESULTS: Thirty-one patients were treated. Two DLTs were reported in one patient of the 54 mg/m(2) cohort; fatigue and decreased appetite (both Grade 3, resolving to Grade 1 within 8 days). No MTD was determined, and the dose recommended for Phase II studies was determined to be 70 mg/m(2) once-weekly. Most common drug-related toxicities were diarrhea, night blindness and nausea. Grade 1 and 2 visual toxicities at high AUY922 doses $>$/=22 mg/m(2) were observed. Ten patients (32 \%) achieved a best overall response of stable disease, and one patient (3 \%) achieved a confirmed partial response. CONCLUSION: Overall, AUY922 exhibited acceptable toxicities and demonstrated potential clinical activity in Japanese patients, with similar safety and pharmacokinetic profiles to those reported in a preceding global Phase I study in Western patients (CAUY922A2101).},
  number = {3},
  journal = {Cancer Chemotherapy and Pharmacology},
  author = {Doi, Toshihiko and Onozawa, Yusuke and Fuse, Nozomu and Yoshino, Takayuki and Yamazaki, Kentaro and Watanabe, Junichiro and Akimov, Mikhail and Robson, Matthew and Boku, Narikazu and Ohtsu, Atsushi},
  year = {2014},
  keywords = {Clinical trial,Phase I,Chiuzan,AUY922,HSP90,Japanese},
  pages = {629-636},
  file = {/Users/k/Zotero/storage/CZCD3AZH/Doi et al. - 2014 - Phase I dose-escalation study of the HSP90 inhibitor AUY922 in Japanese patients with advanced solid tumors.pdf},
  pmid = {25059319}
}

@article{Rodon2014a,
  title = {Phase {{I}} Dose-Escalation and -Expansion Study of Buparlisib ({{BKM120}}), an Oral Pan-{{Class I PI3K}} Inhibitor, in Patients with Advanced Solid Tumors},
  volume = {32},
  issn = {15730646},
  doi = {10.1007/s10637-014-0082-9},
  abstract = {Purpose The pan-Class I PI3K inhibitor buparlisib (BKM120) has shown activity in a range of preclinical cancer models. This first-in-man study was initiated to identify the maximum tolerated dose (MTD) of buparlisib (100 mg/day) and to assess safety and preliminary efficacy. Methods Patients with advanced solid tumors (N = 83) enrolled in a Phase I dose-escalation and -expansion study of single-agent buparlisib. Patients in the dose-expansion arm (n = 43) had tumor samples with PIK3CA and/or PTEN alterations. Results The most common cancers were colorectal (n = 31) and breast cancer (n = 21). Median number of prior antineoplastic regimens was four (range: 1\textendash{}12). Grade 3/4 adverse events (AEs) included asthenia (12.0 \%) and performance status decrease (9.6 \%). Treatment-related AEs (all grades) included decreased appetite, diarrhea, nausea (each in 33 \% of patients), hyperglycemia (31 \%) and rash (29 \%). One confirmed partial response (PR; triple-negative breast cancer) and three unconfirmed PRs (parotid gland carcinoma, epithelioid hemangiothelioma, ER + breast cancer) were reported. Tumor molecular status did not predict clinical benefit in the full study cohort, or among the colorectal or breast cancer subpopulations. Pharmacodynamic biomarkers (18F-FDG-PET, C-peptide, pS6) demonstrated dose-dependent changes; however, tumor heterogeneity precluded a clear correlation with clinical benefit. Conclusion Buparlisib was well tolerated up to the 100 mg/day dose and showed preliminary activity in patients with advanced cancers. Future studies in more homogeneous patient populations will evaluate buparlisib in combination with other agents and further investigate the use of predictive biomarkers.},
  number = {4},
  journal = {Investigational New Drugs},
  author = {Rodon, Jordi and Bra\~na, Irene and Siu, Lillian L. and De Jonge, Maja J. and Homji, Natasha and Mills, David and Di Tomaso, Emmanuelle and Sarr, Celine and Trandafir, Lucia and Massacesi, Cristian and Eskens, Ferry and Bendell, Johanna C.},
  year = {2014},
  keywords = {Oncology,Chiuzan,BKM120,Buparlisib,PI3K inhibitor,Solid tumors,Targeted therapy},
  pages = {670-681},
  file = {/Users/k/Zotero/storage/6YCLZDVG/Rodon et al. - 2014 - Phase I dose-escalation and -expansion study of buparlisib (BKM120), an oral pan-Class I PI3K inhibitor, in patien.pdf},
  pmid = {24652201}
}

@article{Cornfield1969,
  title = {{{THE BAYESIAN OUTLOOK AND ITS APPLICATION}}},
  volume = {25},
  abstract = {JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range of content in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new forms of scholarship. For more information about JSTOR, please contact support@jstor.org. SUMMARY This is a review of the general argument which says that the Bayesian formulation is necessary and sufficient to avoid certain logical inconsistencies. These inconsistencies relate both to the generation of recognizable subsets, examples of which are given in sections 2-4, and of mutually inconsistent confidence intervals. The argument that Bayesian probability assignments are necessary and sufficient to avoid such inconsistencies is sketched out in sec-tion 5 and given in full detail for finite sample and parameter spaces in section 6. A related formalization for estimation is reviewed in section 7. Section 8 considers in detail the problem of extending proofs from finite to infinite spaces, and section 9 considers likelihoods without priors. Section 10 reviews an application of Bayesian methods to a clinical trial now in progress, with special emphasis on the assignment of prior probabilities and the sensitivity of the analysis to such assignment.},
  number = {4},
  journal = {Biometrics},
  author = {Cornfield, Jerome},
  year = {1969},
  pages = {617-657},
  file = {/Users/k/Zotero/storage/WGR3CV8M/Cornfield - 1969 - THE BAYESIAN OUTLOOK AND ITS APPLICATION.pdf}
}

@article{Faderl2014,
  title = {Phase {{I}} and {{Extension Study}} of {{Clofarabine Plus Cyclophosphamide}} in {{Patients With Relapsed}} / {{Refractory Acute Lymphoblastic Leukemia}}},
  volume = {14},
  issn = {2152-2650},
  doi = {10.1016/j.clml.2013.12.001},
  number = {3},
  journal = {Clinical Lymphoma, Myeloma and Leukemia},
  author = {Faderl, Stefan and Balakrishnan, Kumudha and Thomas, Deborah A and Ravandi, Farhad and Borthakur, Gautam and Burger, Jan and Ferrajoli, Alessandra and Cortes, Jorge and Brien, Susan O and Kadia, Tapan and Feliu, Jennie and Plunkett, William and Gandhi, Varsha and Kantarjian, Hagop M},
  year = {2014},
  keywords = {Chiuzan,all,clofarabine,department of experimental therapeutics,division of leukemia,hackensack,hackensack university medical center,nj,salvage chemotherapy},
  pages = {231-238},
  file = {/Users/k/Dropbox/Research/ChiuzanReview/Manuscripts/2014 Faderl.pdf}
}

@article{Boulin2014,
  title = {Idarubicin-Loaded Beads for Chemoembolisation of Hepatocellular Carcinoma: {{Results}} of the {{IDASPHERE}} Phase i Trial},
  volume = {39},
  issn = {13652036},
  doi = {10.1111/apt.12746},
  abstract = {Background A phase I dose-escalation trial of transarterial chemoembolisation (TACE) with idarubicin-loaded beads was performed in cirrhotic patients with hepatocellular carcinoma (HCC). Aim To estimate the maximum-tolerated dose (MTD) and to assess safety, efficacy, pharmacokinetics and quality of life. Methods Patients received a single TACE session with injection of 2 mL drug-eluting beads (DEBs; DC Bead 300-500 mum) loaded with idarubicin. The idarubicin dose was escalated according to a modified continuous reassessment method. MTD was defined as the dose level closest to that causing dose-limiting toxicity (DLT) in 20\% of patients. Results Twenty-one patients were enrolled, including nine patients at 5 mg, six patients at 10 mg, and six patients at 15 mg. One patient at each dose level experienced DLT (acute myocardial infarction, hyperbilirubinaemia and elevated aspartate aminotransferase (AST) at 5-, 10- and 15-mg, respectively). The calculated MTD of idarubicin was 10 mg. The most frequent grade $>$3 adverse events were pain, elevated AST, elevated gamma-glutamyltranspeptidase and thrombocytopenia. At 2 months, the objective response rate was 52\% (complete response, 28\%, and partial response, 24\%) by modified Response Evaluation Criteria in Solid Tumours. The median time to progression was 12.1 months (95\% CI 7.4 months - not reached); the median overall survival was 24.5 months (95\% CI 14.7 months - not reached). Pharmacokinetic analysis demonstrated the ability of DEBs to release idarubicin slowly. Conclusions Using drug-eluting beads, the maximum-tolerated dose of idarubicin was 10 mg per TACE session. Encouraging responses and median time to progression were observed. Further clinical investigations are warranted (NCT01040559). \textcopyright{} 2014 John Wiley \& Sons Ltd.},
  number = {11},
  journal = {Alimentary Pharmacology and Therapeutics},
  author = {Boulin, M. and Hillon, P. and Cercueil, J. P. and Bonnetain, F. and Dabakuyo, S. and Minello, A. and Jouve, J. L. and Lepage, C. and Bardou, M. and Wendremaire, M. and Guerard, P. and Denys, A. and Grandvuillemin, A. and Chauffert, B. and Bedenne, L. and Guiu, B.},
  year = {2014},
  keywords = {Chiuzan},
  pages = {1301-1313},
  file = {/Users/k/Dropbox/Research/ChiuzanReview/Manuscripts/2014 Boulin.pdf},
  pmid = {24738629}
}

@article{Infante2014,
  title = {Phase {{I Dose}}-{{Escalation Study}} of {{LCL161}}, an {{Oral Inhibitor}} of {{Apoptosis Proteins Inhibitor}}, in {{Patients With Advanced Solid Tumors}}},
  volume = {32},
  issn = {0732-183X},
  doi = {10.1200/JCO.2013.52.3993},
  abstract = {PURPOSE: LCL161 antagonizes the function of inhibitor of apoptosis proteins (IAPs), thereby promoting cancer cell death. This first-in-human dose-escalation study assessed the maximum-tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of LCL161 in patients with advanced solid tumors. A second part of the study assessed the relative bioavailability of a tablet versus solution formulation.$\backslash$n$\backslash$nPATIENTS AND METHODS: LCL161 was administered orally, once weekly, on a 21-day cycle to adult patients with advanced solid tumors by using an adaptive Bayesian logistic regression model with overdose control-guided dose escalation.$\backslash$n$\backslash$nRESULTS: Fifty-three patients received at least one dose of LCL161 (dose range, 10 to 3,000 mg). LCL161 was well tolerated at doses up to 1,800 mg. Cytokine release syndrome (CRS) was the only dose-limiting toxicity (in three [6\%] of 53 patients) and was the most common grades 3 to 4 event (in five [9\%] of 53 patients). Vomiting, nausea, asthenia/fatigue, and anorexia were common but not severe. Although the MTD was not formally determined, an 1,800-mg dose was selected in compliance with the protocol for additional study, given the dose-limiting CRS at higher doses and pharmacodynamic activity at lower doses. LCL161 was rapidly absorbed, and exposure was generally increased with dose. The tablet formulation of LCL161 was better tolerated than the solution; tablet and solution formulations had similar exposures, and the solution was discontinued. No patient had an objective response. LCL161 induced degradation of cellular IAP1 protein in the blood, skin, and tumor and increased circulating cytokine levels.$\backslash$n$\backslash$nCONCLUSION: The 1,800-mg dose of LCL161, administered as a single agent once weekly, in tablet formulation is the recommended dose for additional study. This combined dose and formulation was well tolerated and had significant pharmacodynamic activity, which warrants additional investigation.},
  number = {28},
  journal = {Journal of Clinical Oncology},
  author = {Infante, Jeffrey R. and Dees, E. Claire and Olszanski, Anthony J. and Dhuria, Shyeilla V. and Sen, Suman and Cameron, Scott and Cohen, Roger B.},
  year = {2014},
  keywords = {Chiuzan},
  pages = {3103-3110},
  file = {/Users/k/Dropbox/Research/ChiuzanReview/Manuscripts/2014 Infante.pdf},
  pmid = {25113756}
}

@article{Brana2014,
  title = {A Parallel-Arm Phase {{I}} Trial of the Humanised Anti-{{IGF}}-{{1R}} Antibody Dalotuzumab in Combination with the {{AKT}} Inhibitor {{MK}}-2206, the {{mTOR}} Inhibitor Ridaforolimus, or the {{NOTCH}} Inhibitor {{MK}}-0752, in Patients with Advanced Solid Tumours},
  volume = {111},
  issn = {15321827},
  doi = {10.1038/bjc.2014.497},
  abstract = {Background:Two strategies to interrogate the insulin growth factor 1 receptor (IGF-1R) pathway were investigated: vertical inhibition with dalotuzumab and MK-2206 or ridaforolimus to potentiate PI3K pathway targeting and horizontal cross-talk inhibition with dalotuzumab and MK-0752 to exert effects against cellular proliferation, angiogenesis, and stem cell propagation.Methods:A phase I, multi-cohort dose escalation study was conducted in patients with advanced solid tumours. Patients received dalotuzumab (10\,mg\,kg(-1)) and escalating doses of MK-2206 (90-200\,mg) or escalating doses of dalotuzumab (7.5-10\,mg\,kg(-1)) and MK-0752 (1800\,mg) weekly. Upon maximum tolerated dose determination, patients with low-RAS signature, high-IGF1 expression ovarian cancer were randomised to dalotuzumab/MK-2206 versus dalotuzumab/ridaforolimus, whereas patients with high IGF1/low IGF2 expression colorectal cancer received dalotuzumab/MK-0752.Results:A total of 47 patients were enrolled: 29 in part A (18 in the dalotuzumab/MK-2206 arm and 11 in the dalotuzumab/MK-0752 arm) and 18 in part B (6 in each arm). Dose-limiting toxicities (DLTs) for dalotuzumab/MK-2206 included grade 4 neutropenia and grade 3 serum sickness-like reaction, maculopapular rash, and gastrointestinal inflammation. For dalotuzumab/MK-0752, DLTs included grade 3 dehydration, rash, and diarrhoea. Seven patients remained on study for $>$4 cycles.Conclusions:Dalotuzumab/MK-2206 and dalotuzumab/MK-0752 combinations were tolerable. Further developments of prospectively validated predictive biomarkers to aid in patient selection for anti-IGF-1R therapies are needed.British Journal of Cancer advance online publication, 7 October 2014; doi:10.1038/bjc.2014.497 www.bjcancer.com.},
  number = {10},
  journal = {British Journal of Cancer},
  author = {Brana, I. and Berger, R. and Golan, T. and Haluska, P. and Edenfield, J. and Fiorica, J. and Stephenson, J. and Martin, L. P. and Westin, S. and Hanjani, P. and Jones, M. B. and Almhanna, K. and Wenham, R. M. and Sullivan, D. M. and Dalton, W. S. and Gunchenko, A. and Cheng, J. D. and Siu, L. L. and Gray, J. E.},
  year = {2014},
  keywords = {colorectal cancer,Chiuzan,dalotuzumab,MK-0752,MK-2206,ovarian cancer,ridaforolimus},
  pages = {1932-1944},
  file = {/Users/k/Dropbox/Research/ChiuzanReview/Manuscripts/2014 Brana.pdf},
  pmid = {25290091}
}

@article{Iyer2014,
  title = {A {{Phase IB}} Multicentre Dose-Determination Study of {{BHQ880}} in Combination with Anti-Myeloma Therapy and Zoledronic Acid in Patients with Relapsed or Refractory Multiple Myeloma and Prior Skeletal-Related Events},
  volume = {167},
  issn = {13652141},
  doi = {10.1111/bjh.13056},
  abstract = {Dickkopf-1 (DKK1), expressed by myeloma cells, suppresses osteoblast function and plays a key role in bone disease in multiple myeloma. BHQ880, a human neutralizing IgG1 anti-DKK1 monoclonal antibody, is being investigated for its impact on multiple myeloma-related bone disease and as an agent with potential anti-myeloma activity. The primary objectives of this Phase IB study were to determine the maximum tolerated dose (MTD) of BHQ880 and to characterize the dose-limiting toxicity (DLT) of escalating doses in combination with anti-myeloma therapy and zoledronic acid. Twenty-eight patients were enrolled and received BHQ880 at doses of 3-40 mg/kg. No DLTs were reported, therefore, the MTD was not determined. The recommended Phase II dose was declared as 10 mg/kg, based mainly on saturation data. There was a general trend towards increased bone mineral density (BMD) observed over time; specific increases in spine BMD from Cycle 12 onwards irrespective of new skeletal-related events on study were observed, and increases in bone strength at the spine and hip were also demonstrated in some patients. BHQ880 in combination with zoledronic acid and anti-myeloma therapy was well tolerated and demonstrated potential clinical activity in patients with relapsed or refractory multiple myeloma.},
  number = {3},
  journal = {British Journal of Haematology},
  author = {Iyer, Swaminathan P. and Beck, Joseph Taddeus and Stewart, A. Keith and Shah, Jatin and Kelly, Kevin R. and Isaacs, Randi and Bilic, Sanela and Sen, Suman and Munshi, Nikhil C.},
  year = {2014},
  keywords = {Phase I,Chiuzan,BHQ880,Multiple myeloma,Skeletal-related event},
  pages = {366-375},
  file = {/Users/k/Zotero/storage/XT9MQVHR/Iyer et al. - 2014 - A Phase IB multicentre dose-determination study of BHQ880 in combination with anti-myeloma therapy and zoledronic a.pdf},
  pmid = {25139740}
}

@article{Tsimberidou2014,
  title = {A Phase i Study of Fludarabine, Cytarabine, and Oxaliplatin Therapy in Patients with Relapsed or Refractory Acute Myeloid Leukemia},
  volume = {14},
  issn = {21522669},
  doi = {10.1016/j.clml.2014.01.009},
  abstract = {We conducted a phase I study combining oxaliplatin with cytarabine and fludarabine for patients with relapsed or refractory AML. Oxaliplatin 30 mg/m2/d on days 1 to 4, fludarabine 30 mg/m2, and cytarabine 500 mg/ m2on days 2 to 6 was the MTD. Of 27 patients who were treated, 3 had a complete remission and 2 patients had complete remission without platelet recovery.
Purpose: The combination of cytarabine and fludarabine was associated with superior clinical outcomes compared with those of high-dose cytarabine in relapse acute myeloid leukemia (AML). We conducted a phase I study combining oxaliplatin with cytarabine and fludarabine therapy for patients with relapsed or refractory AML.
Patients and Methods: Between January 2008 and November 2009, 27 patients were registered in the study. Patients had histologically confirmed disease, performance status 0 to 2, and adequate organ function. The treatment regimen consisted of increasing doses of oxaliplatin (25, 30, or 35 mg/ m2/d) on days 1 to 4 (escalation phase), and fludarabine (30 mg/m2) and cytarabine (500 mg/m2) on days 2 to 6, every 28 days for $\leq$ 6 cycles. The dose-limiting toxicity was defined as any symptomatic grade $\geq$ nonhematologic toxicity lasting $\geq$3 days and involving a major organ system.
Results: Of 27 patients, 12 were treated in the dose-escalation phase and 15 at the maximum tolerated dose for oxaliplatin (30 mg/m2; expansion phase). All patients were evaluable for toxicity and response. Only 1 patient received the second cycle; the remaining patients received no further study treatment, owing to slow recovery from toxicities or physician decision. Grade 3-4 drug-related toxicities included diarrhea (grade 4) and elevated levels of bilirubin (grade 3) and aspartate transaminase (grade 3). In all, 3 patients had a complete remission and 2 patients complete response without platelet recovery.
Conclusion: Oxaliplatin, cytarabine, and fludarabine therapy had antileukemic activity in patients with poor-risk AML, but it was associated with toxicity. Different schedules and doses may be better tolerated.},
  number = {5},
  journal = {Clinical Lymphoma, Myeloma and Leukemia},
  author = {Tsimberidou, Apostolia Maria and Keating, Michael J. and Jabbour, Elias J. and {Ravandi-Kashani}, Farhad and O'Brien, Susan and Estey, Elihu and Bekele, Neby and Plunkett, William K. and Kantarjian, Hagop and Borthakur, Gautam},
  year = {2014},
  keywords = {Toxicity,Chiuzan,Response,DLT,High-risk MDS,Poor-risk},
  pages = {395-400.e1},
  file = {/Users/k/Dropbox/Research/ChiuzanReview/Manuscripts/2014 Tsimberidou.pdf}
}

@article{Ho2007,
  title = {Matching as {{Nonparametric Preprocessing}} for {{Reducing Model Dependence}} in {{Parametric Causal Inference}}},
  volume = {15},
  doi = {10.1093/pan/mpl013},
  abstract = {Although published works rarely include causal estimates from more than a few model specifications, authors usually choose the presented estimates from numerous trial runs readers never see. Given the often large variation in estimates across choices of control variables, functional forms, and other modeling assumptions, how can researchers ensure that the few estimates presented are accurate or representative? How do readers know that publications are not merely demonstrations that it is possible to find a specification that fits the author's favorite hypothesis? And how do we evaluate or even define statistical prop-erties like unbiasedness or mean squared error when no unique model or estimator even exists? Matching methods, which offer the promise of causal inference with fewer assump-tions, constitute one possible way forward, but crucial results in this fast-growing method-ological literature are often grossly misinterpreted. We explain how to avoid these},
  journal = {Political Analysis},
  author = {Ho, Daniel E and Imai, Kosuke and King, Gary and Stuart, Elizabeth A and Abadie, Alberto and Beck, Neal and Cook, Sam and Diamond, Alexis and Hansen, Ben and Imbens, Guido and Lau, Olivia and Lenz, Gabe and Rosenbaum, Paul and Rubin, Don},
  year = {2007},
  keywords = {CausalInference},
  pages = {199-236},
  file = {/Users/k/Zotero/storage/FYLKCCBU/Ho et al. - Unknown - Matching as Nonparametric Preprocessing for Reducing Model Dependence in Parametric Causal Inference.pdf}
}

@article{Konopleva,
  title = {Supplement to {{Phase I}}/{{II}} Study of the Hypoxia-Activated Prodrug {{PR104}} in Refractory/Relapsed Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia},
  issn = {10709878},
  doi = {10.1109/TDEI.2009.5211872},
  author = {Konopleva, Marina},
  pmid = {24335434}
}

@article{Pocock2002,
  title = {Subgroup Analysis, Covariate Adjustment and Baseline Comparisons in Clinical Trial Reporting: Current Practice and Problems},
  volume = {21},
  doi = {10.1002/sim.1296},
  abstract = {SUMMARY Clinical trial investigators often record a great deal of baseline data on each patient at randomiza-tion. When reporting the trial's \"yndings such baseline data can be used for (i) subgroup analyses which explore whether there is evidence that the treatment diierence depends on certain patient char-acteristics, (ii) covariate-adjusted analyses which aim to re\"yne the analysis of the overall treatment diierence by taking account of the fact that some baseline characteristics are related to outcome and may be unbalanced between treatment groups, and (iii) baseline comparisons which compare the base-line characteristics of patients in each treatment group for any possible (unlucky) diierences. This paper examines how these issues are currently tackled in the medical journals, based on a recent survey of 50 trial reports in four major journals. The statistical rami\"ycations are explored, major problems are highlighted and recommendations for future practice are proposed. Key issues include: the overuse and overinterpretation of subgroup analyses; the underuse of appropriate statistical tests for interaction; inconsistencies in the use of covariate-adjustment; the lack of clear guidelines on covariate selection; the overuse of baseline comparisons in some studies; the misuses of signi\"ycance tests for baseline comparability, and the need for trials to have a prede\"yned statistical analysis plan for all these uses of baseline data.},
  journal = {STATISTICS IN MEDICINE Statist. Med},
  author = {Pocock, Stuart J and Assmann, Susan E and Enos, Laura E and Kasten, Linda E},
  year = {2002},
  keywords = {Subgroups},
  pages = {2917-2930},
  file = {/Users/k/Zotero/storage/TKFRBTUA/Pocock et al. - 2002 - Subgroup analysis, covariate adjustment and baseline comparisons in clinical trial reporting current practice and.pdf}
}

@article{Vass2007,
  title = {Medical Interventions for Primary Open Angle Glaucoma and Ocular Hypertension ({{Review}})},
  doi = {10.1002/14651858.CD003167.pub3.www.cochranelibrary.com},
  number = {4},
  journal = {Cochrane Database of Syst Rev},
  author = {Vass, C and Hirn, C and Sycha, T and Findl, O and Sacu, S and Bauer, P and Schmetterer, L},
  year = {2007},
  keywords = {Glaucoma},
  pages = {CD003167},
  file = {/Users/k/Downloads/MendeleyWatch/Vass_et_al-2007-.sup-2.pdf}
}

@article{Garway-Heath2015,
  title = {Latanoprost for Open-Angle Glaucoma ({{UKGTS}}): {{A}} Randomised, Multicentre, Placebo-Controlled Trial},
  volume = {385},
  issn = {1474547X},
  doi = {10.1016/S0140-6736(14)62111-5},
  abstract = {Background Treatments for open-angle glaucoma aim to prevent vision loss through lowering of intraocular pressure, but to our knowledge no placebo-controlled trials have assessed visual function preservation, and the observation periods of previous (unmasked) trials have typically been at least 5 years. We assessed vision preservation in patients given latanoprost compared with those given placebo. Methods In this randomised, triple-masked, placebo-controlled trial, we enrolled patients with newly diagnosed open-angle glaucoma at ten UK centres (tertiary referral centres, teaching hospitals, and district general hospitals). Eligible patients were randomly allocated (1:1) with a website-generated randomisation schedule, stratified by centre and with a permuted block design, to receive either latanoprost 0$\cdot$005\% (intervention group) or placebo (control group) eye drops. Drops were administered from identical bottles, once a day, to both eyes. The primary outcome was time to visual field deterioration within 24 months. Analyses were done in all individuals with follow-up data. The Data and Safety Monitoring Committee (DSMC) recommended stopping the trial on Jan 6, 2011 (last patient visit July, 2011), after an interim analysis, and suggested a change in primary outcome from the difference in proportions of patients with incident progression between groups to time to visual field deterioration within 24 months. This trial is registered, number ISRCTN96423140. Findings We enrolled 516 individuals between Dec 1, 2006, and March 16, 2010. Baseline mean intraocular pressure was 19$\cdot$6 mm Hg (SD 4$\cdot$6) in 258 patients in the latanoprost group and 20$\cdot$1 mm Hg (4$\cdot$8) in 258 controls. At 24 months, mean reduction in intraocular pressure was 3$\cdot$8 mm Hg (4$\cdot$0) in 231 patients assessed in the latanoprost group and 0$\cdot$9 mm Hg (3$\cdot$8) in 230 patients assessed in the placebo group. Visual field preservation was significantly longer in the latanoprost group than in the placebo group: adjusted hazard ratio (HR) 0$\cdot$44 (95\% CI 0$\cdot$28-0$\cdot$69; p=0$\cdot$0003). We noted 18 serious adverse events, none attributable to the study drug. Interpretation This is the first randomised placebo-controlled trial to show preservation of the visual field with an intraocular-pressure-lowering drug in patients with open-angle glaucoma. The study design enabled significant differences in vision to be assessed in a relatively short observation period. Funding Pfizer, UK National Institute for Health Research Biomedical Research Centre.},
  number = {9975},
  journal = {The Lancet},
  author = {{Garway-Heath}, David F. and Crabb, David P. and Bunce, Catey and Lascaratos, Gerassimos and Amalfitano, Francesca and Anand, Nitin and {Azuara-Blanco}, Augusto and Bourne, Rupert R. and Broadway, David C. and Cunliffe, Ian A. and Diamond, Jeremy P. and Fraser, Scott G. and Ho, Tuan A. and Martin, Keith R. and McNaught, Andrew I. and Negi, Anil and Patel, Krishna and Russell, Richard A. and Shah, Ameet and Spry, Paul G. and Suzuki, Katsuyoshi and White, Edward T. and Wormald, Richard P. and Xing, Wen and Zeyen, Thierry G.},
  year = {2015},
  keywords = {Glaucoma},
  pages = {1295-1304},
  file = {/Users/k/Downloads/MendeleyWatch/PIIS0140673614621115.pdf},
  pmid = {25533656}
}

@article{Wasserstein2016,
  title = {The {{ASA}} ' s {{Statement}} on p-{{Values}} : {{Context}} , {{Process}} , and {{Purpose}}},
  volume = {70},
  issn = {0003-1305},
  doi = {10.1080/00031305.2016.1154108},
  number = {2},
  journal = {The American Statistician},
  author = {Wasserstein, Ronald L and Lazar, Nicole A and Wasserstein, Ronald L and Lazar, Nicole A and Asa, The},
  year = {2016},
  pages = {129-133},
  file = {/Users/k/Downloads/MendeleyWatch/The ASA s Statement on p Values Context Process and Purpose.pdf}
}

@article{Assmann2000,
  title = {Subgroup Analysis and Other ( Mis ) Uses of Baseline Data in Clinical Trials},
  volume = {355},
  doi = {10.1016/S0140-6736(00)02039-0},
  number = {9209},
  journal = {The Lancet},
  author = {Assmann, Susan F and Pocock, Stuart J and Enos, Laura E and Kasten, Linda E},
  year = {2000},
  keywords = {Subgroups},
  pages = {1064-1069},
  file = {/Users/k/Downloads/MendeleyWatch/assmann2000.pdf}
}

@article{Smyth2017,
  title = {Mismatch Repair Deficiency, Microsatellite Instability, and Survival: {{An}} Exploratory Analysis of the {{Medical Research Council Adjuvant Gastric Infusional Chemotherapy}} ({{MAGIC}}) Trial},
  volume = {3},
  issn = {23742445},
  doi = {10.1001/jamaoncol.2016.6762},
  abstract = {Importance Mismatch repair (MMR) deficiency (MMRD) and microsatellite instability (MSI) are prognostic for survival in many cancers and for resistance to fluoropyrimidines in early colon cancer. However, the effect of MMRD and MSI in curatively resected gastric cancer treated with perioperative chemotherapy is unknown. Objective To examine the association among MMRD, MSI, and survival in patients with resectable gastroesophageal cancer randomized to surgery alone or perioperative epirubicin, cisplatin, and fluorouracil chemotherapy in the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial. Design, Setting, and Participants This secondary post hoc analysis of the MAGIC trial included participants who were treated with surgery alone or perioperative chemotherapy plus surgery for operable gastroesophageal cancer from July 1, 1994, through April 30, 2002. Tumor sections were assessed for expression of the MMR proteins mutL homologue 1, mutS homologue 2, mutS homologue 6, and PMS1 homologue 2. The association among MSI, MMRD, and survival was assessed. Main Outcomes and Measures Interaction between MMRD and MSI status and overall survival (OS). Results Of the 503 study participants, MSI results were available for 303 patients (283 with microsatellite stability or low MSI [median age, 62 years; 219 males (77.4\%)] and 20 with high MSI [median age, 66 years; 14 males (70.0\%)]). A total of 254 patients had MSI and MMR results available. Patients treated with surgery alone who had high MSI or MMRD had a median OS that was not reached (95\% CI, 11.5 months to not reached) compared with a median OS among those who had neither high MSI nor MMRD of 20.5 months (95\% CI, 16.7-27.8 months; hazard ratio, 0.42; 95\% CI, 0.15-1.15; P = .09). In contrast, patients treated with chemotherapy plus surgery who had either high MSI or MMRD had a median OS of 9.6 months (95\% CI, 0.1-22.5 months) compared with a median OS among those who were neither high MSI nor MMRD of 19.5 months (95\% CI, 15.4-35.2 months; hazard ratio, 2.18; 95\% CI, 1.08-4.42; P = .03). Conclusions and Relevance In the MAGIC trial, MMRD and high MSI were associated with a positive prognostic effect in patients treated with surgery alone and a differentially negative prognostic effect in patients treated with chemotherapy. If independently validated, MSI or MMRD determined by preoperative biopsies could be used to select patients for perioperative chemotherapy.},
  number = {9},
  journal = {JAMA Oncology},
  author = {Smyth, Elizabeth C. and Wotherspoon, Andrew and Peckitt, Clare and Gonzalez, David and {Hulkki-Wilson}, Sanna and Eltahir, Zakaria and Fassan, Matteo and Rugge, Massimo and Valeri, Nicola and Okines, Alicia and Hewish, Madeleine and Allum, William and Stenning, Sally and Nankivell, Matthew and Langley, Ruth and Cunningham, David},
  year = {2017},
  keywords = {DigestiveCancer,Subgroups},
  pages = {1197-1203},
  file = {/Users/k/Zotero/storage/UA4NENP6/Smyth et al. - 2017 - Mismatch repair deficiency, microsatellite instability, and survival An exploratory analysis of the Medical Resear.pdf},
  pmid = {28241187}
}

@article{Baraniskin2017,
  title = {Clinical Relevance of Molecular Diagnostics in Gastrointestinal ({{GI}}) Cancer: {{European Society}} of {{Digestive Oncology}} ({{ESDO}}) Expert Discussion and Recommendations from the 17th {{European Society}} for {{Medical Oncology}} ({{ESMO}})/{{World Congress}} on {{Gastrointestinal}}},
  volume = {86},
  issn = {18790852},
  doi = {10.1016/j.ejca.2017.09.021},
  abstract = {Background and scope In the epoch of precision medicine and personalised oncology, which aims to deliver the right treatment to the right patient, molecular genetic biomarkers are a topic of growing interest. The aim of this expert discussion and position paper is to review the current status of various molecular tests for gastrointestinal (GI) cancers and especially considering their significance for the clinical routine use. Methodology Opinion leaders and experts from diverse nationalities selected on scientific merit were asked to answer to a prepared set of questions about the current status of molecular diagnostics in different GI cancers. All answers were then discussed during a plenary session and reported here in providing a well-balanced reflection of both clinical expertise and updated evidence-based medicine. Results Preselected molecular genetic biomarkers that are described and disputed in the current medical literature in different GI cancers were debated, and recommendations for clinical routine practice were made whenever possible. Furthermore, the preanalytical variations were commented and proposals for quality controls of biospecimens were made. Conclusion The current article summarises the recommendations of the expert committee regarding prognostic and predictive molecular genetic biomarkers in different entities of GI cancers. The briefly and comprehensively formulated guidelines should assist clinicians in the process of decision making in daily clinical practice.},
  journal = {European Journal of Cancer},
  author = {Baraniskin, Alexander and Van Laethem, Jean Luc and Wyrwicz, Lucjan and Guller, Ulrich and Wasan, Harpreet S. and {Matysiak-Budnik}, Tamara and Gruenberger, Thomas and Ducreux, Michel and Carneiro, Fatima and Van Cutsem, Eric and Seufferlein, Thomas and Schmiegel, Wolff},
  year = {2017},
  keywords = {DigestiveCancer,Clinical relevance,ESDO expert discussion,GI cancer,Molecular diagnostics},
  pages = {305-317},
  file = {/Users/k/Zotero/storage/LKQR29F3/Baraniskin et al. - 2017 - Clinical relevance of molecular diagnostics in gastrointestinal (GI) cancer European Society of Digestive Onc.pdf},
  pmid = {29065378}
}

@article{Jones2011,
  title = {Bayesian Models for Subgroup Analysis in Clinical Trials},
  volume = {8},
  issn = {17407745},
  doi = {10.1177/1740774510396933},
  abstract = {BACKGROUND: In a pharmaceutical drug development setting, possible interactions between the treatment and particular baseline clinical or demographic factors are often of interest. However, the subgroup analysis required to investigate such associations remains controversial. Concerns with classical hypothesis testing approaches to the problem include low power, multiple testing, and the possibility of data dredging. PURPOSE: As an alternative to hypothesis testing, the use of shrinkage estimation techniques is investigated in the context of an exploratory post hoc subgroup analysis. A range of models that have been suggested in the literature are reviewed. Building on this, we explore a general modeling strategy, considering various options for shrinkage of effect estimates. This is applied to a case-study, in which evidence was available from seven-phase II-III clinical trials examining a novel therapy, and also to two artificial datasets with the same structure. METHODS: Emphasis is placed on hierarchical modeling techniques, adopted within a Bayesian framework using freely available software. A range of possible subgroup model structures are applied, each incorporating shrinkage estimation techniques. RESULTS: The investigation of the case-study showed little evidence of subgroup effects. Because inferences appeared to be consistent across a range of well-supported models, and model diagnostic checks showed no obvious problems, it seemed this conclusion was robust. It is reassuring that the structured shrinkage techniques appeared to work well in a situation where deeper inspection of the data suggested little evidence of subgroup effects. LIMITATIONS: The post hoc examination of subgroups should be seen as an exploratory analysis, used to help make better informed decisions regarding potential future studies examining specific subgroups. To a certain extent, the degree of understanding provided by such assessments will be limited by the quality and quantity of available data. CONCLUSIONS: In light of recent interest by health authorities into the use of subgroup analysis in the context of drug development, it appears that Bayesian approaches involving shrinkage techniques could play an important role in this area. Hopefully, the developments outlined here provide useful methodology for tackling such a problem, in-turn leading to better informed decisions regarding subgroups.},
  number = {2},
  journal = {Clinical Trials},
  author = {Jones, Hayley E. and Ohlssen, David I. and Neuenschwander, Beat and Racine, Amy and Branson, Michael},
  year = {2011},
  keywords = {Subgroups},
  pages = {129-143},
  file = {/Users/k/Zotero/storage/LG6S8NC6/Jones et al. - 2011 - Bayesian models for subgroup analysis in clinical trials.pdf},
  pmid = {21282293}
}

@article{Hsu2017,
  title = {Hierarchical {{Bayes}} Approach for Subgroup Analysis},
  issn = {0962-2802},
  doi = {10.1177/0962280217721782},
  journal = {Statistical Methods in Medical Research},
  author = {Hsu, Yu-Yi and Zalkikar, Jyoti and Tiwari, Ram C},
  year = {2017},
  keywords = {hierarchical model,Subgroups,bayes factor,consistency,half-cauchy distribution,parameters,prior distributions for variance},
  pages = {096228021772178},
  file = {/Users/k/Zotero/storage/C53XDUHX/Hsu, Zalkikar, Tiwari - 2017 - Hierarchical Bayes approach for subgroup analysis.pdf}
}

@article{Chu2018,
  title = {A {{Bayesian}} Basket Trial Design Using a Calibrated {{Bayesian}} Hierarchical Model},
  volume = {15},
  issn = {1740-7745},
  doi = {10.1177/1740774518755122},
  abstract = {Background:The basket trial evaluates the treatment effect of a targeted therapy in patients with the same genetic or molecular aberration, regardless of their cancer types. Bayesian hierarchical modeling has been proposed to adaptively borrow information across cancer types to improve the statistical power of basket trials. Although conceptually attractive, research has shown that Bayesian hierarchical models cannot appropriately determine the degree of information borrowing and may lead to substantially inflated type I error rates.Methods:We propose a novel calibrated Bayesian hierarchical model approach to evaluate the treatment effect in basket trials. In our approach, the shrinkage parameter that controls information borrowing is not regarded as an unknown parameter. Instead, it is defined as a function of a similarity measure of the treatment effect across tumor subgroups. The key is that the function is calibrated using simulation such that information is strongly borrowed across subgroups if their treatment effects are similar and barely borrowed if the treatment effects are heterogeneous.Results:The simulation study shows that our method has substantially better controlled type I error rates than the Bayesian hierarchical model. In some scenarios, for example, when the true response rate is between the null and alternative, the type I error rate of the proposed method can be inflated from 10\% up to 20\%, but is still better than that of the Bayesian hierarchical model.Limitation:The proposed design assumes a binary endpoint. Extension of the proposed design to ordinal and time-to-event endpoints is worthy of further investigation.Conclusion:The calibrated Bayesian hierarchical model provides a practical approach to design basket trials with more flexibility and better controlled type I error rates than the Bayesian hierarchical model. The software for implementing the proposed design is available at http://odin.mdacc.tmc.edu/\textasciitilde{}yyuan/index\_code.html},
  number = {2},
  journal = {Clinical Trials},
  author = {Chu, Yiyi and Yuan, Ying},
  year = {2018},
  keywords = {adaptive borrowing,basket trials,bayesian adaptive trial design,bayesian hierarchical model,borrow information},
  pages = {174077451875512},
  file = {/Users/k/Zotero/storage/KGRMMYHN/Chu, Yuan - 2018 - A Bayesian basket trial design using a calibrated Bayesian hierarchical model.pdf}
}

@article{Fisher2017,
  title = {Meta-Analytical Methods to Identify Who Benefits Most from Treatments: {{Daft}}, Deluded, or Deft Approach?},
  volume = {356},
  issn = {17561833},
  doi = {10.1136/bmj.j573},
  abstract = {Identifying which individuals benefit most from particular treatments or other interventions underpins so-called personalised or stratified medicine. However, single trials are typically underpowered for exploring whether participant characteristics, such as age or disease severity, determine an individual's response to treatment. A meta-analysis of multiple trials, particularly one where individual participant data (IPD) are available, provides greater power to investigate interactions between participant characteristics (covariates) and treatment effects. We use a published IPD meta-analysis to illustrate three broad approaches used for testing such interactions. Based on another systematic review of recently published IPD meta-analyses, we also show that all three approaches can be applied to aggregate data as well as IPD. We also summarise which methods of analysing and presenting interactions are in current use, and describe their advantages and disadvantages. We recommend that testing for interactions using within-trials information alone (the deft approach) becomes standard practice, alongside graphical presentation that directly visualises this. Meta-analysis of participant level treatment-covariate interactions raises additional complications that do not affect either standard meta-analysis or single trial interaction analysis alone. These complications are often overlooked by reviewers. The issues are independent of other aspects of meta-analysis, such as the choice of one stage or two stage model fitting, or whether aggregate data or individual participant data (IPD)1 is used. The three titular approaches discussed in this paper are derived from two independent quantities referred to in recent IPD literature as across-trial and within-trial interactions.23 We have used three descriptive terms to be memorable and to avoid ambiguity. ``Daft'' (meaning absurd or preposterous) refers to estimation of the across-trial interaction alone. ``Deluded'' (meaning misleading or deceiving) refers to an estimation of both the across-trial and within-trial interactions combined. ``Deft'' (demonstrating skill or cleverness) refers to estimation of the within-trial interaction alone. As their \ldots{}},
  journal = {BMJ (Online)},
  author = {Fisher, David J. and Carpenter, James R. and Morris, Tim P. and Freeman, Suzanne C. and Tierney, Jayne F.},
  year = {2017},
  keywords = {Subgroups},
  pages = {1-6},
  file = {/Users/k/Downloads/MendeleyWatch/bmj.j573.full.pdf},
  pmid = {28258124}
}

@article{Gelman2000,
  archivePrefix = {arXiv},
  eprinttype = {arxiv},
  eprint = {1011.1669v3},
  title = {Type {{S}} Error Rates for Classical and {{Bayesian}} Single and Multiple Comparison Procedures},
  volume = {15},
  issn = {09434062},
  doi = {10.1007/s001800000040},
  abstract = {$<$br$>$Gelman, A., and F. Tuerlinckx. 2000. Type S error rates for classical and Bayesian single and multiple comparison procedures. Computational Statistics 15: 373-390},
  number = {3},
  journal = {Computational Statistics},
  author = {Gelman, Andrew and Tuerlinckx, Francis},
  year = {2000},
  pages = {373-390},
  file = {/Users/k/Downloads/MendeleyWatch/francis8.pdf},
  pmid = {25246403}
}

@article{Costa2018,
  title = {Bayesian Joint Modelling of Benefit and Risk in Drug Development},
  issn = {15391604},
  doi = {10.1002/pst.1852},
  number = {March 2017},
  journal = {Pharmaceutical Statistics},
  author = {Costa, Maria J. and Drury, Thomas},
  year = {2018},
  keywords = {uk,bayesian inference,benefit,copula,decision,generalised linear mixed models,integral statistics limited,joint,london,making,modelling,risk,uncertainty},
  pages = {1-16},
  file = {/Users/k/Zotero/storage/5Y4DHX37/Costa, Drury - 2018 - Bayesian joint modelling of benefit and risk in drug development.pdf}
}

@article{Spears2017,
  title = {'{{Thursday}}'s Child Has Far to Go'-Interpreting Subgroups and the {{STAMPEDE}} Trial},
  volume = {28},
  issn = {15698041},
  doi = {10.1093/annonc/mdx410},
  number = {10},
  journal = {Annals of Oncology},
  author = {Spears, M. R. and James, N. D. and Sydes, M. R.},
  year = {2017},
  keywords = {Subgroups},
  pages = {2327-2330},
  file = {/Users/k/Downloads/MendeleyWatch/mdx410.pdf}
}

@article{Gelman2005,
  archivePrefix = {arXiv},
  eprinttype = {arxiv},
  eprint = {math/0508530v1},
  title = {Discussion Paper Analysis of Variance - {{Why}} It Is More Important than Ever},
  volume = {33},
  issn = {00905364},
  doi = {10.1214/009053604000001048},
  abstract = {Analysis of variance (ANOVA) is an extremely important method in exploratory and confirmatory data analysis. Unfortunately, in complex problems (e.g., split-plot designs), it is not always easy to set up an appropriate ANOVA. We propose a hierarchical analysis that automatically gives the correct ANOVA comparisons even in complex scenarios. The inferences for all means and variances are performed under a model with a separate batch of effects for each row of the ANOVA table. We connect to classical ANOVA by working with finite-sample variance components: fixed and random effects models are characterized by inferences about existing levels of a factor and new levels, respectively. We also introduce a new graphical display showing inferences about the standard deviations of each batch of effects. We illustrate with two examples from our applied data analysis, first illustrating the usefulness of our hierarchical computations and displays, and second showing how the ideas of ANOVA are helpful in understanding a previously fit hierarchical model.},
  number = {1},
  journal = {Annals of Statistics},
  author = {Gelman, Andrew and Tjur, Tue and McCullagh, Peter and Hox, Joop and Hoijtink, Herbert and Zaslavsky, Alan M.},
  year = {2005},
  keywords = {Bayesian inference,ANOVA,Fixed effects,Hierarchical model,Linear regression,Multilevel model,Random effects,Variance components},
  pages = {1-53},
  file = {/Users/k/Zotero/storage/R4L9VALB/Gelman et al. - 2005 - Discussion paper analysis of variance - Why it is more important than ever.pdf}
}

@article{Borm2007,
  title = {A Simple Sample Size Formula for Analysis of Covariance in Randomized Clinical Trials},
  volume = {60},
  issn = {08954356},
  doi = {10.1016/j.jclinepi.2007.02.006},
  abstract = {Objective: Randomized clinical trials that compare two treatments on a continuous outcome can be analyzed using analysis of covariance (ANCOVA) or a t-test approach. We present a method for the sample size calculation when ANCOVA is used. Study Design and Setting: We derived an approximate sample size formula. Simulations were used to verify the accuracy of the formula and to improve the approximation for small trials. The sample size calculations are illustrated in a clinical trial in rheumatoid arthritis. Results: If the correlation between the outcome measured at baseline and at follow-up is $\rho$, ANCOVA comparing groups of (1 - $\rho$2)n subjects has the same power as t-test comparing groups of n subjects. When on the same data, ANCOVA is used instead of t-test, the precision of the treatment estimate is increased, and the length of the confidence interval is reduced by a factor sqrt(1 - $\rho$2). Conclusion: ANCOVA may considerably reduce the number of patients required for a trial. \textcopyright{} 2007 Elsevier Inc. All rights reserved.},
  number = {12},
  journal = {Journal of Clinical Epidemiology},
  author = {Borm, George F. and Fransen, Jaap and Lemmens, Wim A J G},
  year = {2007},
  keywords = {Power,Clinical trial,Sample size,ANCOVA,Precision,Analysis of covariance,Statistical test},
  pages = {1234-1238},
  file = {/Users/k/Zotero/storage/HW85UBR2/Borm, Fransen, Lemmens - 2007 - A simple sample size formula for analysis of covariance in randomized clinical trials.pdf},
  pmid = {17998077}
}

@article{Gelman2017b,
  title = {The Failure of Null Hypothesis Significance Testing When Studying Incremental Changes, and What to Do about It *},
  abstract = {A standard mode of inference in social and behavioral science is to establish stylized facts using statistical significance in quantitative studies. However, in a world in which measure-ments are noisy and effects are small, this will not work: selection on statistical significance leads to effect sizes which are overestimated and often in the wrong direction. After a brief discussion of two examples, one in economics and one in social psychology, we consider the procedural solution of open post-publication review, the design solution of devoting more effort to accurate measurements and within-person comparisons, and the statistical analysis solution of multilevel modeling and reporting all results rather than selection on significance. We argue that the current replication crisis in science arises in part from the ill effects of null hypothesis significance testing being used to study small effects with noisy data. In such settings, apparent success comes easy but truly replicable results require a more serious connection between theory, measurement, and data.},
  author = {Gelman, Andrew},
  year = {2017},
  file = {/Users/k/Zotero/storage/LS8ECII9/Gelman - 2017 - The failure of null hypothesis significance testing when studying incremental changes, and what to do about it.pdf}
}

@article{Binnewies,
  title = {Understanding the Tumor Immune Microenvironment ({{TIME}}) for Effective Therapy},
  doi = {10.1038/s41591-018-0014-x},
  abstract = {T he past decade has seen a revolution in cancer treatments by moving away from drugs that target tumors broadly (for example, chemotherapy and radiation) and toward the use of antibody-based immunotherapies that modulate immune responses against tumors. The first generation of antibody-based immuno-therapy, so-called immune-checkpoint blockade (ICB), works by blocking the receptor and/or ligand interactions of molecules, such as CTLA-4 and PD-1, that are involved in dulling T cell activation or function 1 . ICB therapies have shown significant clinical ben-efit for a minority of patients, who demonstrate durable responses. Unfortunately, there is still an unmet clinical need for the majority of patients, who do not respond to ICB. Retrospective analyses of patient populations treated with ICB have revealed that there are classes of TIME that are associated with those tumors more prone to ICB responsiveness. Deeper analysis of complexity within the TIME is likely to reveal advanced biomarkers that will prove fruitful in identifying patient populations responsive to current ICB therapy and will benefit the search for novel targets for therapeutic modulation. Past efforts to characterize the TIME have provided a foundation for future efforts in which recent technological advances in techniques such as high-resolution single-cell RNA sequencing, flow cytometry and imaging are expected to provide an unprecedented view of the composition, function and location of immune cells within the TIME. In this Review, we provide a summary of the current knowledge centered around classes of TIME, focusing on the use of new technologies to study the TIME with increased granularity and the roles of systemic immune-and nonimmune-related factors in influencing TIME char-acter and quality, and hence how tumors respond to immunotherapy.},
  journal = {Nature Medicine},
  author = {Binnewies, Mikhail and Roberts, Edward W and Kersten, Kelly and Chan, Vincent and Fearon, Douglas F and Merad, Miriam and Coussens, Lisa M and Gabrilovich, Dmitry I and {Ostrand-Rosenberg}, Suzanne and Hedrick, Catherine C and Vonderheide, Robert H and Pittet, Mikael J and Jain, Rakesh K and Zou, Weiping and Kevin Howcroft, T and Woodhouse, Elisa C and Weinberg, Robert A and Krummel, Matthew F},
  file = {/Users/k/Zotero/storage/CBNL7BMB/Binnewies et al. - Unknown - Understanding the tumor immune microenvironment (TIME) for effective therapy.pdf}
}

@article{Burkner2017b,
  archivePrefix = {arXiv},
  eprinttype = {arxiv},
  eprint = {1705.11123},
  title = {Advanced {{Bayesian Multilevel Modeling}} with the {{R Package}} Brms},
  abstract = {The brms package allows R users to easily specify a wide range of Bayesian single-level and multilevel models, which are fitted with the probabilistic programming language Stan behind the scenes. Several response distributions are supported, of which all parameters (e.g., location, scale, and shape) can be predicted at the same time thus allowing for distributional regression. Non-linear relationships may be specified using non-linear predictor terms or semi-parametric approaches such as splines or Gaussian processes. To make all of these modeling options possible in a multilevel framework, brms provides an intuitive and powerful formula syntax, which extends the well known formula syntax of lme4. The purpose of the present paper is to introduce this syntax in detail and to demonstrate its usefulness with four examples, each showing other relevant aspects of the syntax.},
  author = {B\"urkner, Paul-Christian},
  year = {2017},
  keywords = {BayesCore},
  pages = {1-18},
  file = {/Users/k/Zotero/storage/VCTXFRZM/Bürkner - 2017 - Advanced Bayesian Multilevel Modeling with the R Package brms.pdf}
}

@article{Harrella,
  title = {Biostatistics for {{Biomedical Research}}},
  author = {Harrell, Frank E and Slaughter, James C},
  file = {/Users/k/Zotero/storage/7RNFH46G/Harrell, Slaughter - Unknown - Biostatistics for Biomedical Research.pdf}
}

@article{Freedman1989a,
  title = {Comparison of {{Bayesian}} with Group Sequential Methods for Monitoring Clinical Trials},
  volume = {10},
  issn = {01972456},
  doi = {10.1016/0197-2456(89)90001-9},
  abstract = {We describe some problems with applying methods based on classical sequential analysis to monitoring clinical trials. A Bayesian method is developed and the boundaries are compared with frequentist schemes. For the examples chosen, the Bayesian boundaries can be quite similar to those obtained from Pocock and O'Brien and Fleming (OBF) rules, depending on the choice of prior distribution. They converge less rapidly than OBF's but more rapidly than Pocock's. In general the Bayesian methods provide the same desirable features as frequentist methods, without sacrificing flexibility and simplicity of interpretation.},
  number = {1989},
  journal = {Controlled Clinical Trials},
  author = {Freedman, L. S. and Spiegelhalter, D. J.},
  year = {1989},
  keywords = {clinical trials,Bayesian methods,GroupSequential,sequential methods,Stopping,stopping rules},
  pages = {357-367},
  file = {/Users/k/Zotero/storage/CMGZZZEX/Freedman, Spiegelhalter - 1989 - Comparison of Bayesian with group sequential methods for monitoring clinical trials.pdf},
  pmid = {2691203}
}

@article{Greenland2016,
  title = {Statistical Tests, {{P}} Values, Confidence Intervals, and Power: A Guide to Misinterpretations},
  volume = {31},
  doi = {10.1007/s10654-016-0149-3},
  abstract = {Misinterpretation and abuse of statistical tests, confidence intervals, and statistical power have been decried for decades, yet remain rampant. A key problem is that there are no interpretations of these concepts that are at once simple, intuitive, correct, and foolproof. Instead, correct use and interpretation of these statistics requires an attention to detail which seems to tax the patience of working scientists. This high cognitive demand has led to an epidemic of shortcut definitions and interpretations that are simply wrong, sometimes disastrously so\textemdash{}and yet these misinterpretations dominate much of the scientific literature. In light of this problem, we provide definitions and a discussion of basic statistics that are more general and critical than typically found in traditional introductory expositions. Our goal is to provide a resource for instruc-tors, researchers, and consumers of statistics whose knowledge of statistical theory and technique may be limited but who wish to avoid and spot misinterpretations. We emphasize how violation of often unstated analysis protocols (such as selecting analyses for presentation based on the P values they produce) can lead to small P values even if the declared test hypothesis is correct, and can lead to large P values even if that hypothesis is incorrect. We then provide an explanatory list of 25 misinterpretations of P values, confidence intervals, and power. We conclude with guidelines for improving statistical interpretation and reporting. Editor's note This article has been published online as supplementary material with an article of Wasserstein RL, Lazar NA. The ASA's statement on p-values: context, process and purpose. The American Statistician 2016.},
  journal = {European Journal of Epidemiology},
  author = {Greenland, Sander and Stephen Senn, Bullet J and Kenneth Rothman, Bullet J and John Carlin, Bullet B and Charles Poole, Bullet and Steven Goodman, Bullet N and Douglas Altman, Bullet G},
  year = {2016},
  file = {/Users/k/Zotero/storage/39JAR6DG/Greenland et al. - 2016 - Statistical tests, P values, confidence intervals, and power a guide to misinterpretations.pdf}
}

@article{Austin2017a,
  title = {A {{Tutorial}} on {{Multilevel Survival Analysis}}: {{Methods}}, {{Models}} and {{Applications}}},
  volume = {85},
  doi = {10.1111/insr.12214},
  abstract = {Data that have a multilevel structure occur frequently across a range of disciplines, including epidemiology, health services research, public health, education and sociology. We describe three families of regression models for the analysis of multilevel survival data. First, Cox proportional hazards models with mixed effects incorporate cluster-specific random effects that modify the baseline hazard function. Second, piecewise exponential survival models partition the duration of follow-up into mutually exclusive intervals and fit a model that assumes that the hazard function is constant within each interval. This is equivalent to a Poisson regression model that incorporates the duration of exposure within each interval. By incorporating cluster-specific random effects, generalised linear mixed models can be used to analyse these data. Third, after partitioning the duration of follow-up into mutually exclusive intervals, one can use discrete time survival models that use a complementary log\textendash{}log generalised linear model to model the occurrence of the outcome of interest within each interval. Random effects can be incorporated to account for within-cluster homogeneity in outcomes. We illustrate the application of these methods using data consisting of patients hospitalised with a heart attack. We illustrate the application of these methods using three statistical programming languages (R, SAS and Stata).},
  number = {2},
  journal = {International Statistical Review},
  author = {Austin, Peter C},
  year = {2017},
  pages = {185-203},
  file = {/Users/k/Zotero/storage/7AJL3MGK/Austin - 2017 - A Tutorial on Multilevel Survival Analysis Methods, Models and Applications.pdf}
}

@article{AHern2001,
  title = {Sample Size Tables for Exact Single-Stage Phase {{II}} Designs},
  volume = {20},
  issn = {02776715},
  doi = {10.1002/sim.721},
  abstract = {Tables for single-phase II trials based on the exact binomial distribution are presented. These are preferable to those generated using Fleming's design, which are based on the normal approximation and can give rise to anomalous results. For example, if the upper success rate is accepted, the lower success rate, which the trial is designed to reject, may be included in the final confidence interval for the proportion being estimated.},
  number = {6},
  journal = {Statistics in Medicine},
  author = {A'Hern, R. P.},
  year = {2001},
  pages = {859-866},
  file = {/Users/k/Zotero/storage/R7H6S73N/A'Hern - 2001 - Sample size tables for exact single-stage phase II designs.pdf},
  pmid = {11252008}
}

@article{ISISstudygroup1988,
  title = {Randomized Trial of Intravenous Streptokinase, Oral Aspirin, Both, or Neither among 17,187 Cases of Suspected Acute Myocardial Infarction: {{ISIS}}-2.{{ISIS}}-2 ({{Second International Study}} of {{Infarct Survival}}) {{Collaborative Group}}.},
  volume = {12},
  issn = {0735-1097},
  doi = {10.1016/S0140-6736(88)92833-4},
  abstract = {17,187 patients entering 417 hospitals up to 24 h (median 5 h) after the onset of suspected acute myocardial infarction were randomized, with placebo control, between i) a 1 h intravenous infusion of 1.5 million units of streptokinase; ii) 1 month of 160 mg/day enteric-coated aspirin; iii) both active treatments; or iv) neither. Streptokinase alone and aspirin alone each produced a highly significant reduction in 5 week vascular mortality: 791/8592 (9.2\%) vascular deaths among patients allocated streptokinase infusion versus 1029/8595 (12.0\%) among those allocated placebo infusion (odds reduction: 25\% +/- 4; 2p less than 0.00001); 804/8587 (9.4\%) vascular deaths among patients allocated aspirin tablets versus 1016/8600 (11.8\%) among those allocated placebo tablets (odds reduction: 23\% +/- 4; 2p less than 0.00001). The combination of streptokinase and aspirin was significantly (2p less than 0.0001) better than either agent alone. Their separate effects on vascular death appeared to be additive: 343/4292 (8.0\%) among patients allocated both active agents versus 568/4300 (13.2\%) among those allocated neither (odds reduction: 42\% +/- 5; 95\% confidence limits 34\% to 50\%). There was evidence of benefit rom each agent even for patients treated late after pain onset (odds reduction at 0-4, 5-12, and 13-24 h: 35\% +/- 6, 16\% +/- 7 and 21\% +/- 12 for streptokinase alone; 25\% +/- 7,21\% +/- 7 and 21\% +/- 12 for aspirin alone; and 53\% +/- 8,32\% +/- 9 and 38\% +/- 15 for the combination of streptokinase and aspirin). Streptokinase was associated with an excess of bleeds requiring transfusion (0.5\% versus 0.2\%) and of confirmed cerebral hemorrhage (0.1\% versus 0.0\%), but with fewer other strokes (0.6\% versus 0.8\%). These "other" strokes may have included a few undiagnosed cerebral hemorrhages, but still there was no increase in total strokes (0.7\% streptokinase versus 0.8\% placebo infusion). Aspirin significantly reduced nonfatal reinfarction (1.0\% versus 2.0\%) and nonfatal stroke (0.3\% versus 0.6\%), and was not associated with any significant increase in cerebral hemorrhage or in bleeds requiring transfusion. An excess of nonfatal reinfarction was reported when streptokinase was used alone, but this appeared to be entirely avoided by the addition of aspirin. Those allocated the combination of streptokinase and aspirin had significantly fewer reinfarctions (1.8\% versus 2.9\%), strokes (0.6\% versus 1.1\%), and deaths (8.0\% versus 13.2\%) than those allocated neither.},
  number = {August},
  journal = {Journal of the American College of Cardiology},
  author = {{ISIS study group}},
  year = {1988},
  keywords = {Subgroups},
  pages = {3A-13A},
  file = {/Users/k/Zotero/storage/IJBLVS5H/ISIS study group - 1988 - Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected.pdf},
  pmid = {2903874}
}

@article{betancourtHamiltonianMonteCarlo2013,
  archivePrefix = {arXiv},
  eprinttype = {arxiv},
  eprint = {1312.0906},
  title = {Hamiltonian {{Monte Carlo}} for {{Hierarchical Models}}},
  doi = {10.1201/b18502-5},
  abstract = {Hierarchical modeling provides a framework for modeling the complex interactions typical of problems in applied statistics. By capturing these relationships, however, hierarchical models also introduce distinctive pathologies that quickly limit the efficiency of most common methods of in- ference. In this paper we explore the use of Hamiltonian Monte Carlo for hierarchical models and demonstrate how the algorithm can overcome those pathologies in practical applications.},
  author = {Betancourt, M. J. and Girolami, Mark},
  year = {2013},
  keywords = {BayesCore},
  file = {/Users/k/Zotero/storage/IPFU697G/Betancourt, Girolami - 2013 - Hamiltonian Monte Carlo for Hierarchical Models.pdf}
}

@article{gelmanPriorDistributionsVariance2006,
  title = {Prior Distributions for Variance Parameters in Hierarchical Models},
  volume = {1},
  abstract = {Various noninformative prior distributions have been suggested for scale parameters in hierarchical models. We construct a new folded-noncentral-t family of conditionally conjugate priors for hierarchical standard deviation pa-rameters, and then consider noninformative and weakly informative priors in this family. We use an example to illustrate serious problems with the inverse-gamma family of " noninformative " prior distributions. We suggest instead to use a uni-form prior on the hierarchical standard deviation, using the half-t family when the number of groups is small and in other settings where a weakly informative prior is desired. We also illustrate the use of the half-t family for hierarchical modeling of multiple variance parameters such as arise in the analysis of variance.},
  number = {3},
  journal = {Bayesian Analysis},
  author = {Gelman, Andrew},
  year = {2006},
  keywords = {Bayesian inference,hierarchical model,BayesCore,conditional conjugacy,folded-noncentral-t distri-bution,half-t distribution,multilevel model,noninformative prior distribution,weakly informative prior distribution},
  pages = {515-533},
  file = {/Users/k/Zotero/storage/G7QWIE59/Gelman - 2006 - Prior distributions for variance parameters in hierarchical models.pdf}
}

@article{Betancourt2017,
  archivePrefix = {arXiv},
  eprinttype = {arxiv},
  eprint = {1701.02434v1},
  title = {A {{Conceptual Introduction}} to {{Hamiltonian Monte Carlo}}},
  abstract = {Hamiltonian Monte Carlo has proven a remarkable empirical success, but only recently have we begun to develop a rigorous under-standing of why it performs so well on difficult problems and how it is best applied in practice. Unfortunately, that understanding is con-fined within the mathematics of differential geometry which has limited its dissemination, especially to the applied communities for which it is particularly important. In this review I provide a comprehensive conceptual account of these theoretical foundations, focusing on developing a principled intuition behind the method and its optimal implementations rather of any ex-haustive rigor. Whether a practitioner or a statistician, the dedicated reader will acquire a solid grasp of how Hamiltonian Monte Carlo works, when it succeeds, and, perhaps most importantly, when it fails.},
  author = {Betancourt, Michael},
  year = {2017},
  keywords = {BayesCore},
  file = {/Users/k/Zotero/storage/ZA9P5HSW/Betancourt - 2017 - A Conceptual Introduction to Hamiltonian Monte Carlo.pdf}
}

@article{Ungerer2011,
  title = {Novel Antiplatelet Drug Revacept (Dimeric Glycoprotein {{VI}}-{{Fc}}) Specifically and Efficiently Inhibited Collagen-Induced Platelet Aggregation without Affecting General Hemostasis in Humans},
  volume = {123},
  issn = {15244539},
  doi = {10.1161/CIRCULATIONAHA.110.980623},
  abstract = {Blocking of glycoprotein VI-dependent pathways by interfering in vascular collagen sites is commonly seen as an attractive target for an antiplatelet therapy of acute atherosclerotic diseases such as myocardial infarction or stroke. Revacept (soluble dimeric glycoprotein VI-Fc fusion protein) has been shown to reduce platelet adhesion by blocking vascular collagen in plaques or erosion and to be safe in preclinical studies. A dose-escalating clinical phase I study was performed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of Revacept in humans.},
  number = {17},
  journal = {Circulation},
  author = {Ungerer, Martin and Rosport, Kai and B\"ultmann, Andreas and Piechatzek, Richard and Uhland, Kerstin and Schlieper, Peter and Gawaz, Meinrad and M\"unch, G\"otz},
  year = {2011},
  keywords = {glycoprotein VI,platelet aggregation,stroke,platelet adhesion,platelet aggregation inhibitors},
  pages = {1891-1899},
  file = {/Users/k/Zotero/storage/4HGEE2EQ/Ungerer et al. - 2011 - Novel antiplatelet drug revacept (dimeric glycoprotein VI-Fc) specifically and efficiently inhibited collagen-in.pdf},
  pmid = {21502572}
}

@article{Berry,
  title = {Bayesian Hierarchical Modeling of Patient Subpopulations: {{Efficient}} Designs of {{Phase II}} Oncology Clinical Trials},
  doi = {10.1177/1740774513497539},
  abstract = {Background\textemdash{}In oncology, the treatment paradigm is shifting toward personalized medicine, where the goal is to match patients to the treatments most likely to deliver benefit. Treatment effects in various subpopulations may provide some information about treatment effects in other subpopulations.},
  author = {Berry, Scott M and Broglio, Kristine R and Groshen, Susan and Berry, Donald A},
  file = {/Users/k/Zotero/storage/UU9EPYQ2/Berry et al. - Unknown - Bayesian hierarchical modeling of patient subpopulations Efficient designs of Phase II oncology clinical trials.pdf}
}

@article{piironenSparsityInformationRegularization2017,
  archivePrefix = {arXiv},
  eprinttype = {arxiv},
  eprint = {1707.01694},
  title = {Sparsity Information and Regularization in the Horseshoe and Other Shrinkage Priors},
  issn = {19357524},
  doi = {10.1214/17-EJS1337SI},
  abstract = {The horseshoe prior has proven to be a noteworthy alternative for sparse Bayesian estimation, but has previously suffered from two problems. First, there has been no systematic way of specifying a prior for the global shrinkage hyperparameter based on the prior information about the degree of sparsity in the parameter vector. Second, the horseshoe prior has the undesired property that there is no possibility of specifying separately information about sparsity and the amount of regularization for the largest coefficients, which can be problematic with weakly identified parameters, such as the logistic regression coefficients in the case of data separation. This paper proposes solutions to both of these problems. We introduce a concept of effective number of nonzero parameters, show an intuitive way of formulating the prior for the global hyperparameter based on the sparsity assumptions, and argue that the previous default choices are dubious based on their tendency to favor solutions with more unshrunk parameters than we typically expect a priori. Moreover, we introduce a generalization to the horseshoe prior, called the regularized horseshoe, that allows us to specify a minimum level of regularization to the largest values. We show that the new prior can be considered as the continuous counterpart of the spike-and-slab prior with a finite slab width, whereas the original horseshoe resembles the spike-and-slab with an infinitely wide slab. Numerical experiments on synthetic and real world data illustrate the benefit of both of these theoretical advances.},
  journal = {Electronic Journal of Statistics},
  author = {Piironen, Juho and Vehtari, Aki},
  year = {2017},
  keywords = {Bayesian inference,BayesCore,Horseshoe prior,Shrinkage priors,Sparse estimation},
  file = {/Users/k/Zotero/storage/6AMGX2MF/Piironen, Vehtari - 2017 - Sparsity information and regularization in the horseshoe and other shrinkage priors.pdf}
}

@article{Talts,
  title = {Validating {{Bayesian Inference Algorithms}} with {{Simulation}}-{{Based Calibration}}},
  abstract = {Verifying the correctness of Bayesian computation is challeng-ing. This is especially true for complex models that are common in prac-tice, as these require sophisticated model implementations and algo-rithms. In this paper we introduce simulation-based calibration (SBC), a general procedure for validating inferences from Bayesian algorithms capable of generating posterior samples. This procedure not only iden-tifies inaccurate computation and inconsistencies in model implemen-tations but also provides graphical summaries that can indicate the nature of the problems that arise. We argue that SBC is a critical part of a robust Bayesian workflow, as well as being a useful tool for those developing computational algorithms and statistical software.},
  author = {Talts, Sean and Betancourt, Michael and Simpson, Daniel and Vehtari, Aki and Gelman, Andrew},
  keywords = {BayesCore,_tablet_modified},
  file = {/Users/k/Zotero/storage/MPPH92YK/Talts et al_Validating Bayesian Inference Algorithms with Simulation-Based Calibration.pdf}
}

@article{Muth2018,
  title = {User-Friendly {{Bayesian}} Regression Modeling: {{A}} Tutorial with Rstanarm and Shinystan},
  volume = {14},
  doi = {10.20982/tqmp.14.2.p099},
  abstract = {This tutorial provides a pragmatic introduction to specifying, estimating and interpret-ing single-level and hierarchical linear regression models in the Bayesian framework. We start by summarizing why one should consider the Bayesian approach to the most common forms of regres-sion. Next we introduce the R package rstanarm for Bayesian applied regression modeling. An overview of rstanarm fundamentals accompanies step-by-step guidance for fitting a single-level regression model with the stan\_glm function, and fitting hierarchical regression models with the stan\_lmer function, illustrated with data from an experience sampling study on changes in af-fective states. Exploration of the results is facilitated by the intuitive and user-friendly shinystan package. Data and scripts are available on the Open Science Framework page of the project. For readers unfamiliar with R, this tutorial is self-contained to enable all researchers who apply regres-sion techniques to try these methods with their own data. Regression modeling with the functions in the rstanarm package will be a straightforward transition for researchers familiar with their frequentist counterparts, lm (or glm) and lmer.},
  number = {2},
  author = {Muth, Chelsea and Oravecz, Zita and Gabry, Jonah},
  year = {2018},
  keywords = {BayesTutorials},
  file = {/Users/k/Zotero/storage/LSI45RDE/Muth, Oravecz, Gabry - 2018 - User-friendly Bayesian regression modeling A tutorial with rstanarm and shinystan.pdf}
}

@article{Gelmanc,
  title = {Parameterization and {{Bayesian Modeling}}},
  doi = {10.1198/016214504000000458},
  abstract = {Progress in statistical computation often leads to advances in statistical modeling. For example, it is surprisingly common that an existing model is reparameterized, solely for computational purposes, but then this new conn guration motivates a new family of models that is useful in applied statistics. One reason why this phenomenon may not have been noticed in statistics is that reparameterizations do not change the likelihood. In a Bayesian framework, however, a transformation of parameters typically suggests a new family of prior distributions. We discuss examples in censored and truncated data, mixture modeling, multivariate imputation, stochastic processes, and multilevel models.},
  author = {Gelman, Andrew},
  file = {/Users/k/Zotero/storage/SPVMH3ZQ/Gelman - Unknown - Parameterization and Bayesian Modeling.pdf}
}

@article{Karanevich2018,
  title = {Using an Onset-Anchored {{Bayesian}} Hierarchical Model to Improve Predictions for Amyotrophic Lateral Sclerosis Disease Progression},
  author = {Karanevich, Alex G and Statland, Jeffrey M and Gajewski, Byron J and He, Jianghua},
  year = {2018},
  keywords = {Prediction,correspondence,prediction,ALS,als,akaranevich,alsfrs,ALSFRS,edu,hierarchical modelling,Hierarchical modelling,kumc,onset-anchor,Pro-a,pro-act},
  pages = {1-13},
  file = {/Users/k/Downloads/MendeleyWatch/s12874-018-0479-9.pdf}
}

@article{Curran1998,
  title = {Identifying the Types of Missingness in Quality of Life Data from Clinical Trials},
  volume = {17},
  issn = {0277-6715},
  doi = {10.1002/(SICI)1097-0258(19980315/15)17:5/7<739::AID-SIM818>3.0.CO;2-M},
  abstract = {This paper discusses methods of identifying the types of missingness in quality of life (QOL) data in cancer clinical trials. The first approach involves collecting information on why the QOL questionnaires were not completed. Based on the reasons provided one may be able to distinguish the mechanisms causing missing data. The second approach is to model the missing data mechanism and perform hypothesis testing to determine the missing data processes. Two methods of testing if missing data are missing completely at random (MCAR) are presented and applied to incomplete longitudinal QOL data obtained from international multi-centre cancer clinical trials. The first method (Ridout, 1991) is based on a logistic regression and the second method (Park and Davis, 1993) is based on an adaptation of weighted least squares. In one application (advanced breast cancer) missing data was not likely to be MCAR. In the second application (adjuvant breast cancer) the missing mechanism was dependent on the QOL scale under study. MCAR and missing at random (MAR) have distinct consequences for data analysis. Therefore it is relevant to distinguish between them. However, if either MCAR or MAR hold, likelihood or Bayesian inferences can be based solely on the observed data, although for MAR, depending on the research question, modelling the dropout mechanism may still be necessary. Distinguishing between MAR and missing not at random (MNAR) is not trivial and relies on fundamentally untestable assumptions. \textcopyright{} 1998 John Wiley \& Sons, Ltd.},
  number = {5-7},
  journal = {Statistics in medicine},
  author = {Curran, D and Bacchi, M and Schmitz, S F Hsu and Molenberghs, G and Sylvester, R J},
  year = {1998},
  pages = {739-756},
  file = {/Users/k/Downloads/MendeleyWatch/curran1998.pdf;/Users/k/Zotero/storage/353PFVSC/Barraclough, Simms, Govindan - 2011 - Biostatistics primer What a clinician ought to know Hazard ratios(2).pdf},
  pmid = {9549820}
}

@article{Brilleman,
  title = {Joint Longitudinal and Time-to-Event Models for Multilevel Hierarchical Data},
  author = {Brilleman, Samuel L and Crowther, Michael J and {Moreno-Betancur}, Margarita and Novik, Jacqueline Buros and Dunyak, James and {Al-Huniti}, Nidal and Fox, Robert and Hammerbacher, Jeff and Wolfe, Rory},
  file = {/Users/k/Zotero/storage/DHX3WQEI/Brilleman et al. - Unknown - Joint longitudinal and time-to-event models for multilevel hierarchical data.pdf}
}

@misc{RLang,
  address = {Vienna, Austria},
  title = {R: {{A Language}} and {{Enviroment}} for {{Statistical Computing}}},
  author = {{R Development Core Team}},
  year = {2017}
}

@misc{SoetaertManual,
  title = {{{rootSolve}}: {{Non}}-Linear Root Finding, Equilibrium and Steady-State Analysis of Ordinary Differential Equations},
  author = {Soetaert, Karline},
  year = {2009}
}

@article{Greenwald1996,
  title = {Effect Sizes and p Values: {{What}} Should Be Reported and What Should Be Replicated?},
  volume = {33},
  abstract = {Despite publication of many well-argued critiques of null hypothesis testing (NHT), behavioral science research-ers continue to rely heavily on this set of practices. Although we agree with most critics' catalogs of NHT's flaws, this article also takes the unusual stance of identifying virtues that may explain why NHT continues to be so exten-sively used. These virtues include providing results in the form of a dichotomous (yesho) hypothesis evaluation and providing an index (p value) that has a justifiable mapping onto confidence in repeatability of a null hypoth-esis rejection. The most-criticized flaws of NHT can be avoided when the importance of a hypothesis, rather than t h e p value of its test, is used to determine that a finding is worthy of report, and whenp z .05 is treated as},
  journal = {Psychophysiology},
  author = {Greenwald, Anthony G and Gonzalez, Richard and Harris, Richard J and Guthrie ', Donald},
  year = {1996},
  pages = {175-183},
  file = {/Users/k/Zotero/storage/4IXU9444/Greenwald et al. - 1996 - Effect sizes and p values What should be reported and what should be replicated.pdf}
}

@article{Sweeting2013,
  title = {Bcrm : {{Bayesian Continual Reassessment Method Designs}} for {{Phase I Dose}}-{{Finding Trials}}},
  volume = {54},
  issn = {1548-7660},
  doi = {10.18637/jss.v054.i13},
  abstract = {This paper presents the R package bcrm for conducting and assessing Bayesian continual reassessment method (CRM) designs in Phase I dose-escalation trials. CRM designsare a class of adaptive design that select the dose to be given to the next recruited patient based on accumulating toxicity data from patients already recruited into the trial, often using Bayesian methodology. Despite the original CRM design being proposed in 1990, the methodology is still not widely implemented within oncology Phase I trials. The aim of this paper is to demonstrate, through example of the bcrm package, how a variety of possible designs can be easily implemented within the R statistical software, and how properties of the designs can be communicated to trial investigators using simple textual and graphical output obtained from the package. This in turn should facilitate an iterative process to allow a design to be chosen that is suitable to the needs of the investigator. Our bcrm package is the first to offer a large comprehensive choice of CRM designs, priors and escalation procedures, which can be easily compared and contrasted within the package through the assessment of operating characteristics.},
  number = {13},
  journal = {Journal of Statistical Software},
  author = {Sweeting, Michael and Mander, Adrian and Sabin, Tony},
  year = {2013},
  keywords = {phase i,dose escalation,continual reassessment method,dose finding,r,bayesian adaptive designs},
  pages = {1-26},
  file = {/Users/k/Downloads/MendeleyWatch/bcrm_Bayesian_Continual_Reassessment_Method_Designs_for_Phase_I_Dose-Finding_Trials.pdf}
}

@article{Johnson2009a,
  title = {Bayesian {{Design}} of {{Single}}-{{Arm Phase II Clinical Trials}} with {{Continuous Monitoring}}},
  volume = {6},
  journal = {Clinical Trials},
  author = {Johnson, V E and Cook., J D},
  year = {2009},
  pages = {217:226},
  file = {/Users/k/Zotero/storage/I93WVKFW/Johnson, Cook. - 2009 - Bayesian Design of Single-Arm Phase II Clinical Trials with Continuous Monitoring.pdf}
}

@book{GelmanHill,
  title = {Data {{Analysis Using Regression}} and {{Multilevel}} / {{Hierarchical Models}}},
  isbn = {978-0-521-68689-1},
  publisher = {{Cambridge University Press}},
  author = {Gelman, Andrew and Hill, Jennifer},
  year = {2007}
}

@article{hickeyJoineRMLJointModel2018,
  title = {{{joineRML}}: A Joint Model and Software Package for Time-to-Event and Multivariate Longitudinal Outcomes},
  volume = {18},
  issn = {1471-2288},
  shorttitle = {{{joineRML}}},
  doi = {10.1186/s12874-018-0502-1},
  abstract = {Background: Joint modelling of longitudinal and time-to-event outcomes has received considerable attention over recent years. Commensurate with this has been a rise in statistical software options for fitting these models. However, these tools have generally been limited to a single longitudinal outcome. Here, we describe the classical joint model to the case of multiple longitudinal outcomes, propose a practical algorithm for fitting the models, and demonstrate how to fit the models using a new package for the statistical software platform R, joineRML.
Results: A multivariate linear mixed sub-model is specified for the longitudinal outcomes, and a Cox proportional hazards regression model with time-varying covariates is specified for the event time sub-model. The association between models is captured through a zero-mean multivariate latent Gaussian process. The models are fitted using a Monte Carlo Expectation-Maximisation algorithm, and inferences are based on approximate standard errors from the empirical profile information matrix, which are contrasted to an alternative bootstrap estimation approach. We illustrate the model and software on a real data example for patients with primary biliary cirrhosis with three repeatedly measured biomarkers.
Conclusions: An open-source software package capable of fitting multivariate joint models is available. The underlying algorithm and source code makes use of several methods to increase computational speed.},
  language = {en},
  number = {1},
  journal = {BMC Medical Research Methodology},
  author = {Hickey, Graeme L. and Philipson, Pete and Jorgensen, Andrea and {Kolamunnage-Dona}, Ruwanthi},
  month = dec,
  year = {2018},
  file = {/Users/k/Zotero/storage/D5AH5G2M/Hickey et al. - 2018 - joineRML a joint model and software package for t.pdf}
}

@article{zoharContinualReassessmentMethod2001,
  title = {The Continual Reassessment Method: Comparison of {{Bayesian}} Stopping Rules for Dose-Ranging Studies},
  volume = {20},
  issn = {0277-6715, 1097-0258},
  shorttitle = {The Continual Reassessment Method},
  doi = {10.1002/sim.920},
  abstract = {The continual reassessment method (CRM) provides a Bayesian estimation of the maximum tolerated dose (MTD) in phase I clinical trials and is also used to estimate the minimal e cacy dose (MED) in phase II clinical trials. In this paper we propose Bayesian stopping rules for the CRM, based on either posterior or predictive probability distributions that can be applied sequentially during the trial. These rules aim at early detection of either the mis-choice of dose range or a pre\"yxed gain in the point estimate or accuracy of estimated probability of response associated with the MTD (or MED). They were compared through a simulation study under six situations that could represent the underlying unknown dose\textendash{}response (either toxicity or failure) relationship, in terms of sample size, probability of correct selection and bias of the response probability associated to the MTD (or MED). Our results show that the stopping rules act correctly, with early stopping by using the two \"yrst rules based on the posterior distribution when the actual underlying dose\textendash{}response relationship is far from that initially supposed, while the rules based on predictive gain functions provide a discontinuation of inclusions whatever the actual dose\textendash{}response curve after 20 patients on average, that is, depending mostly on the accumulated data. The stopping rules were then applied to a data set from a dose-ranging phase II clinical trial aiming at estimating the MED dose of midazolam in the sedation of infants during cardiac catheterization. All these \"yndings suggest the early use of the two \"yrst rules to detect a mis-choice of dose range, while they con\"yrm the requirement of including at least 20 patients at the same dose to reach an accurate estimate of MTD (MED). A two-stage design is under study. Copyright ? 2001 John Wiley \& Sons, Ltd.},
  language = {en},
  number = {19},
  journal = {Statistics in Medicine},
  author = {Zohar, Sarah and Chevret, Sylvie},
  month = oct,
  year = {2001},
  pages = {2827-2843},
  file = {/Users/k/Zotero/storage/3IBTJURN/Zohar and Chevret - 2001 - The continual reassessment method comparison of B.pdf}
}

@article{barracloughBiostatisticsPrimerWhat2010,
  title = {Biostatistics {{Primer}}: {{What}} a {{Clinician Ought}} to {{Know}}: {{Subgroup Analyses}}},
  volume = {5},
  issn = {15560864},
  shorttitle = {Biostatistics {{Primer}}},
  doi = {10.1097/JTO.0b013e3181d9009e},
  abstract = {Large randomized phase III prospective studies continue to redefine the standard of therapy in medical practice. Often when studies do not meet the primary endpoint, it is common to explore possible benefits in specific subgroups of patients. In addition, these analyses may also be done, even in the case of a positive trial to find subsets of patients where the therapy is especially effective or ineffective. These unplanned subgroup analyses are justified to maximize the information that can be obtained from a study and to generate new hypotheses. Unfortunately, however, they are too often overinterpreted or misused in the hope of resurrecting a failed study. It is important to distinguish these overinterpreted, misused, and unplanned subgroup analyses from those prespecified and well-designed subgroup analyses. This overview provides a practical guide to the interpretation of subgroup analyses.},
  language = {en},
  number = {5},
  journal = {Journal of Thoracic Oncology},
  author = {Barraclough, Helen and Govindan, Ramaswamy},
  month = may,
  year = {2010},
  pages = {741-746},
  file = {/Users/k/Zotero/storage/NZTD957W/Barraclough and Govindan - 2010 - Biostatistics Primer What a Clinician Ought to Kn.pdf}
}

@article{gandrudSimPHPackageShowing,
  title = {{{simPH}}: {{An R Package}} for {{Showing Estimates}} from {{Cox Proportional Hazard Models}} Including for {{Interactive}} and {{Nonlinear Effects}}},
  abstract = {The R package simPH provides tools for effectively communicating results from Cox Proportional Hazard (PH) models, including models with interactive and nonlinear effects. The Cox Proportional Hazard model is a popular tool for examining event data. However, previously available computational tools have not made it easy to explore and communicate quantities of interest and associated uncertainty estimated from these models. This is especially true when the effects are from interactions or nonlinear transformations of continuous variables. These transformation are especially useful with Cox PH models because they can be employed to correctly specifying models that would otherwise violate the nonproportional hazards assumption. simPH makes it easy to simulate and then plot quantities of interest for a variety of effects estimated from Cox PH models including interactive effects, nonlinear effects, as well as `vanilla' linear effects. simPH employs visual weighting in order to effectively communicate estimation uncertainty. The user also has the option of showing either the standard central interval of the simulation's distribution or the shortest probability interval\textendash{}which can be useful for asymmetrically distributed estimates. This paper uses hypothetical and empirical examples to illustrate simPH's syntax and capabilities.},
  language = {en},
  author = {Gandrud, Christopher},
  pages = {21},
  file = {/Users/k/Zotero/storage/BA4W7C8T/Gandrud - simPH An R Package for Showing Estimates from Cox.pdf}
}

@article{uschnerRandomizeRPackageAssessment2018,
  title = {{{{\textbf{randomizeR}}}} : {{An}} {{{\emph{R}}}} {{Package}} for the {{Assessment}} and {{Implementation}} of {{Randomization}} in {{Clinical Trials}}},
  volume = {85},
  issn = {1548-7660},
  shorttitle = {{{{\textbf{randomizeR}}}}},
  doi = {10.18637/jss.v085.i08},
  abstract = {Randomization in clinical trials is the key design technique to ensure the comparability of treatment groups. Although there exist a large number of software products which assist the researcher to implement randomization, no tool which would cover a wide range of procedures and allow the comparative evaluation of the procedures under practical restrictions has been proposed in the literature so far.},
  language = {en},
  number = {8},
  journal = {Journal of Statistical Software},
  author = {Uschner, Diane and Schindler, David and Hilgers, Ralf-Dieter and Heussen, Nicole},
  year = {2018},
  file = {/Users/k/Zotero/storage/EZFN2AS3/Uschner et al. - 2018 - brandomizeRb  An iRi Package for the As.pdf}
}

@article{poschAdaptiveTwoStage1999,
  title = {Adaptive {{Two Stage Designs}} and the {{Conditional Error Function}}},
  volume = {41},
  issn = {0323-3847, 1521-4036},
  doi = {10.1002/(SICI)1521-4036(199910)41:6<689::AID-BIMJ689>3.0.CO;2-P},
  abstract = {Proschan and Hunsberger (1995) suggest the use of a conditional error function to construct a two stage test that meets the a level and allows a very flexible reassessment of the sample size after the interim analysis. In this note we show that several adaptive designs can be formulated in terms of such an error function. The conditional power function defined similarly provides a simple method for sample size reassessment in adaptive two stage designs.},
  language = {en},
  number = {6},
  journal = {Biometrical Journal},
  author = {Posch, Martin and Bauer, Peter},
  month = oct,
  year = {1999},
  pages = {689-696},
  file = {/Users/k/Zotero/storage/JEKH2CSD/Posch and Bauer - 1999 - Adaptive Two Stage Designs and the Conditional Err.pdf}
}

@article{neuenschwanderSummarizingHistoricalInformation2010,
  title = {Summarizing Historical Information on Controls in Clinical Trials},
  volume = {7},
  issn = {1740-7745, 1740-7753},
  doi = {10.1177/1740774509356002},
  abstract = {Background Historical information is always relevant when designing clinical trials, but it might also be incorporated in the analysis. It seems appropriate to exploit past information on comparable control groups.
Purpose Phase IV and proof-of-concept trials are used to discuss aspects of summarizing historical control data as prior information in a new trial. The importance of a fair assessment of the similarity of control parameters is emphasized.
Methods The methodology is meta-analytic-predictive. Heterogeneity of control parameters is expressed via the between-trial variation, which is the key parameter determining the prior effective sample size and its upper bound (prior maximum sample size).
Results For a Phase IV trial (930 control patients in 11 historical trials) between-trial heterogeneity was fairly small, resulting in a prior effective sample size of approximately 90 patients. For a proof-of-concept trial (363 patients in four historical trials) heterogeneity was moderate to substantial, resulting in a prior effective sample size of approximately 20. For another proof-of-concept trial (14 patients in one historical trial), assuming substantial heterogeneity implied a prior effective sample size of 7. The prior effective sample size can only be large if the amount of historical data is large and between-trial heterogeneity is small. The prior effective sample size is bounded by the prior maximum sample size (ratio of within- to between-trial variance), irrespective of the amount of historical data. Limitations The meta-analytic-predictive approach assumes exchangeability of control parameters across trials. Due to the difficulty to quantify between-trial variability, sensitivity of conclusions regarding assumptions and type of inference should be assessed.
Conclusions The use of historical control information is a valuable option and may lead to more efficient clinical trials. The proposed approach is attractive for nonconfirmatory trials, but under certain circumstances extensions to the confirmatory setting could be envisaged as well. Clinical Trials 2010; 7: 5\textendash{}18. http://ctj.sagepub.com},
  language = {en},
  number = {1},
  journal = {Clinical Trials: Journal of the Society for Clinical Trials},
  author = {Neuenschwander, Beat and {Capkun-Niggli}, Gorana and Branson, Michael and Spiegelhalter, David J},
  month = feb,
  year = {2010},
  pages = {5-18},
  file = {/Users/k/Zotero/storage/83JKIZLU/Neuenschwander et al. - 2010 - Summarizing historical information on controls in .pdf}
}

@article{schmidliRobustMetaanalyticpredictivePriors2014,
  title = {Robust Meta-Analytic-Predictive Priors in Clinical Trials with Historical Control Information: {{Robust Meta}}-{{Analytic}}-{{Predictive Priors}}},
  volume = {70},
  issn = {0006341X},
  shorttitle = {Robust Meta-Analytic-Predictive Priors in Clinical Trials with Historical Control Information},
  doi = {10.1111/biom.12242},
  abstract = {Historical information is always relevant for clinical trial design. Additionally, if incorporated in the analysis of a new trial, historical data allow to reduce the number of subjects. This decreases costs and trial duration, facilitates recruitment, and may be more ethical. Yet, under prior-data conflict, a too optimistic use of historical data may be inappropriate. We address this challenge by deriving a Bayesian meta-analytic-predictive prior from historical data, which is then combined with the new data. This prospective approach is equivalent to a meta-analytic-combined analysis of historical and new data if parameters are exchangeable across trials. The prospective Bayesian version requires a good approximation of the metaanalytic-predictive prior, which is not available analytically. We propose two- or three-component mixtures of standard priors, which allow for good approximations and, for the one-parameter exponential family, straightforward posterior calculations. Moreover, since one of the mixture components is usually vague, mixture priors will often be heavy-tailed and therefore robust. Further robustness and a more rapid reaction to prior-data conflicts can be achieved by adding an extra weakly-informative mixture component. Use of historical prior information is particularly attractive for adaptive trials, as the randomization ratio can then be changed in case of prior-data conflict. Both frequentist operating characteristics and posterior summaries for various data scenarios show that these designs have desirable properties. We illustrate the methodology for a phase II proof-of-concept trial with historical controls from four studies. Robust meta-analytic-predictive priors alleviate prior-data conflicts - they should encourage better and more frequent use of historical data in clinical trials.},
  language = {en},
  number = {4},
  journal = {Biometrics},
  author = {Schmidli, Heinz and Gsteiger, Sandro and Roychoudhury, Satrajit and O'Hagan, Anthony and Spiegelhalter, David and Neuenschwander, Beat},
  month = dec,
  year = {2014},
  pages = {1023-1032},
  file = {/Users/k/Zotero/storage/NG2MKMDP/Schmidli et al. - 2014 - Robust meta-analytic-predictive priors in clinical.pdf}
}

@incollection{mayoErrorStatistics2011,
  title = {Error {{Statistics}}},
  isbn = {978-0-444-51862-0},
  language = {en},
  booktitle = {Philosophy of {{Statistics}}},
  publisher = {{Elsevier}},
  author = {Mayo, Deborah G. and Spanos, Aris},
  year = {2011},
  pages = {153-198},
  file = {/Users/k/Zotero/storage/JZB9AJ6N/Mayo and Spanos - 2011 - Error Statistics.pdf},
  doi = {10.1016/B978-0-444-51862-0.50005-8}
}

@article{ortiz-masiaM1MacrophagesActivate2016,
  title = {M1 {{Macrophages Activate Notch Signalling}} in {{Epithelial Cells}}: {{Relevance}} in {{Crohn}}'s {{Disease}}},
  volume = {10},
  issn = {1873-9946, 1876-4479},
  shorttitle = {M1 {{Macrophages Activate Notch Signalling}} in {{Epithelial Cells}}},
  doi = {10.1093/ecco-jcc/jjw009},
  abstract = {Background:\hspace{0.6em} The Notch signalling pathway plays an essential role in mucosal regeneration, which constitutes a key goal of Crohn's disease (CD) treatment. Macrophages coordinate tissue repair and several phenotypes have been reported which differ in the expression of surface proteins, cytokines and hypoxia-inducible factors (HIFs). We analysed the role of HIFs in the expression of Notch ligands in macrophages and the relevance of this pathway in mucosal regeneration.
Methods:\hspace{0.6em} Human monocytes and U937-derived macrophages were polarized towards the M1 and M2 phenotypes and the expression levels of HIF-1$\alpha$, HIF-2$\alpha$, Jagged 1 (Jag1) and delta-like 4 (Dll4) were evaluated. The effects of macrophages on the expression of hairy and enhancer of split-1 (HES1, the main target of Notch signalling) and intestinal alkaline phosphatase (IAP, enterocyte marker) in epithelial cells in co-culture were also analysed. Phenotype macrophage markers and Notch signalling were evaluated in the mucosa of CD patients.
Results:\hspace{0.6em} M1 macrophages were associated with HIF-1-dependent induction of Jag1 and Dll4, which increased HES1 protein levels and IAP activity in co-cultured epithelial cells. In the mucosa of CD patients a high percentage of M1 macrophages expressed both HIF-1$\alpha$ and Jag1 while M2 macrophages mainly expressed HIF-2$\alpha$ and we detected a good correlation between the ratio of M1/M2 macrophages and both HES1 and IAP protein levels.
Conclusion:\hspace{0.6em} M1, but not M2, macrophages are associated with HIF-1-dependent induction of Notch ligands and activation of epithelial Notch signalling pathway. In the mucosa of chronic CD patients, the prevalence of M2 macrophages is associated with diminution of Notch signalling and impaired enterocyte differentiation.},
  language = {en},
  number = {5},
  journal = {Journal of Crohn's and Colitis},
  author = {{Ortiz-Masi\'a}, D. and {Cos\'in-Roger}, J. and Calatayud, S. and Hern\'andez, C. and Al\'os, R. and Hinojosa, J. and Esplugues, J. V. and Barrachina, M. D.},
  month = may,
  year = {2016},
  keywords = {Crohns},
  pages = {582-592},
  file = {/Users/k/Zotero/storage/ZPRFA7I7/Ortiz-Masiá et al. - 2016 - M1 Macrophages Activate Notch Signalling in Epithe.pdf}
}

@misc{bio-radMacrophagePolarizationMinireview,
  title = {{Macrophage Polarization Mini-review}},
  abstract = {Macrophage polarization review exploring the function and phenotype of M1, M2, TAM, TCR+, CD169+ macrophages, plus comparisons between mouse and human macrophages},
  language = {en, english, en},
  journal = {Bio-Rad},
  howpublished = {https://www.bio-rad-antibodies.com/macrophage-polarization-minireview.html},
  author = {{Bio-Rad}},
  keywords = {Macrophages},
  file = {/Users/k/Zotero/storage/3L9H5FLU/macrophage-polarization-minireview.html}
}

@article{dionneInfluenceVitaminM12017,
  title = {The Influence of Vitamin {{D}} on {{M1}} and {{M2}} Macrophages in Patients with {{Crohn}}'s Disease},
  volume = {23},
  issn = {1753-4267},
  doi = {10.1177/1753425917721965},
  abstract = {Defective bacterial clearance by macrophages plays an important role in Crohn's disease (CD). Phenotypes and functions of inflammatory M1 and anti-inflammatory M2 have not been studied in CD. Vitamin D supplementation reduces the severity of CD by unclear mechanisms. We studied macrophage characteristics in CD and controls and the effects of 1,25 vitamin D (1,25D). PBMC were isolated from CD patients and controls. M1 and M2 were generated by culturing of monocytes with GM-CSF and M-CSF, respectively. CD M1 and M2 showed normal phagocytosis and chemotaxis to CCL2 and fMLP. LPS-induced production of TNF-$\alpha$, IL-12p40 and IL-10 was comparable between groups. Phagocytosis was unaltered with 1,25D; migration only increased marginally. M1 produced more IL-12p40 and TNF-$\alpha$; IL-10 was greater in M2. 1,25D markedly decreased IL-12p40 by M1 and M2. 1,25D decreased TNF-$\alpha$ in CD M1; IL-10 levels were unaffected. M2 express F13A1, PTGS2, CD163, CXCL10, CD14 and MMP2, whereas TGF-$\beta$, CCL1 and CYP27B1 expression was higher in M1. Marker expression was similar between CD and controls. M1 and M2 markers were not differentially modulated by 1,25D. CD macrophages are not functionally or phenotypically different vs.
CONTROLS: 1,25D markedly decreased pro-inflammatory M1 cytokines but did not modulate polarization to anti-inflammatory M2 phenotype.},
  language = {eng},
  number = {6},
  journal = {Innate Immunity},
  author = {Dionne, Serge and Duchatelier, Carl-Frederic and Seidman, Ernest G.},
  month = aug,
  year = {2017},
  keywords = {Adult,Female,Humans,Middle Aged,Male,Adolescent,Aged,Young Adult,Aged; 80 and over,Crohns,Cytokines,Macrophages,Cell Differentiation,Cells; Cultured,Chemotaxis,Crohn Disease,Crohn’s disease,cytokines,Immunity; Innate,innate immunity,macrophages,Phagocytosis,Th1 Cells,Th2 Cells,Vitamin D},
  pages = {557-565},
  pmid = {28770666}
}

@article{efronFrequentistAccuracyBayesian,
  title = {Frequentist Accuracy of {{Bayesian}} Estimates},
  volume = {77},
  copyright = {\textcopyright{} 2014 Royal Statistical Society},
  issn = {1467-9868},
  doi = {10.1111/rssb.12080},
  abstract = {In the absence of relevant prior experience, popular Bayesian estimation techniques usually begin with some form of `uninformative' prior distribution intended to have minimal inferential influence. The Bayes rule will still produce nice looking estimates and credible intervals, but these lack the logical force that is attached to experience-based priors and require further justification. The paper concerns the frequentist assessment of Bayes estimates. A simple formula is shown to give the frequentist standard deviation of a Bayesian point estimate. The same simulations as required for the point estimate also produce the standard deviation. Exponential family models make the calculations particularly simple and bring in a connection to the parametric bootstrap.},
  language = {en},
  number = {3},
  journal = {Journal of the Royal Statistical Society: Series B (Statistical Methodology)},
  author = {Efron, Bradley},
  keywords = {Approximate bootstrap confidence intervals,General accuracy formula,Hierarchical and empirical Bayes,Markov chain Monte Carlo methods,Parametric bootstrap},
  pages = {617-646},
  file = {/Users/k/Zotero/storage/MJK48EG5/Efron - Frequentist accuracy of Bayesian estimates.pdf;/Users/k/Zotero/storage/S4QE7UN7/rssb.html}
}

@article{wagesDosefindingDesignMultidrug2011,
  title = {Dose-Finding Design for Multi-Drug Combinations},
  volume = {8},
  issn = {1740-7753},
  doi = {10.1177/1740774511408748},
  abstract = {BACKGROUND: Most of the current designs used for Phase I dose finding trials in oncology will either involve only a single cytotoxic agent or will impose some implicit ordering among the doses. The goal of the studies is to estimate the maximum tolerated dose (MTD), the highest dose that can be administered with an acceptable level of toxicity. A key working assumption of these methods is the monotonicity of the dose-toxicity curve.
PURPOSE: Here we consider situations in which the monotonicity assumption may fail. These studies are becoming increasingly common in practice, most notably, in phase I trials that involve combinations of agents. Our focus is on studies where there exist pairs of treatment combinations for which the ordering of the probabilities of a dose-limiting toxicity cannot be known a priori.
METHODS: We describe a new dose-finding design which can be used for multiple-drug trials and can be applied to this kind of problem. Our methods proceed by laying out all possible orderings of toxicity probabilities that are consistent with the known orderings among treatment combinations and allowing the continual reassessment method (CRM) to provide efficient estimates of the MTD within these orders. The design can be seen to simplify to the CRM when the full ordering is known.
RESULTS: We study the properties of the design via simulations that provide comparisons to the Bayesian approach to partial orders (POCRM) of Wages, Conaway, and O'Quigley. The POCRM was shown to perform well when compared to other suggested methods for partial orders. Therefore, we comapre our approach to it in order to assess the performance of the new design.
LIMITATIONS: A limitation concerns the number of possible orders. There are dose-finding studies with combinations of agents that can lead to a large number of possible orders. In this case, it may not be feasible to work with all possible orders.
CONCLUSIONS: The proposed design demonstrates the ability to effectively estimate MTD combinations in partially ordered dosefinding studies. Because it relaxes the monotonicity assumption, it can be considered a multivariate generalization of the CRM. Hence, it can serve as a link between single and multiple-agent dosefinding trials.},
  language = {eng},
  number = {4},
  journal = {Clinical Trials (London, England)},
  author = {Wages, Nolan A. and Conaway, Mark R. and O'Quigley, John},
  month = aug,
  year = {2011},
  keywords = {Humans,Research Design,Maximum Tolerated Dose,Antineoplastic Combined Chemotherapy Protocols,Computer Simulation,Bayes Theorem,Clinical Trials; Phase I as Topic,Dose-Response Relationship; Drug,Drug-Related Side Effects and Adverse Reactions},
  pages = {380-389},
  pmid = {21652689},
  pmcid = {PMC3485079}
}

@article{neuenschwanderCriticalAspectsBayesian2008,
  title = {Critical Aspects of the {{Bayesian}} Approach to Phase {{I}} Cancer Trials},
  volume = {27},
  issn = {1097-0258},
  doi = {10.1002/sim.3230},
  abstract = {The Bayesian approach to finding the maximum-tolerated dose in phase I cancer trials is discussed. The suggested approach relies on a realistic dose\textendash{}toxicity model, allows one to include prior information, and supports clinical decision making by presenting within-trial information in a transparent way. The modeling and decision-making components are flexible enough to be extendable to more complex settings. Critical aspects are emphasized and a comparison with the continual reassessment method (CRM) is performed with data from an actual trial and a simulation study. The comparison revealed similar operating characteristics while avoiding some of the difficulties encountered in the actual trial when applying the CRM. Copyright \textcopyright{} 2008 John Wiley \& Sons, Ltd.},
  language = {en},
  number = {13},
  journal = {Statistics in Medicine},
  author = {Neuenschwander, Beat and Branson, Michael and Gsponer, Thomas},
  year = {2008},
  keywords = {continual reassessment method,logistic model,maximum-tolerated dose},
  pages = {2420-2439},
  file = {/Users/k/Zotero/storage/RCKS78VP/Neuenschwander et al_Critical aspects of the Bayesian approach to phase I cancer trials.pdf;/Users/k/Zotero/storage/GLMLM6WL/sim.html}
}

@article{zoharSoftwareComputeConduct2003,
  title = {Software to Compute and Conduct Sequential {{Bayesian}} Phase {{I}} or {{II}} Dose-Ranging Clinical Trials with Stopping Rules},
  volume = {72},
  issn = {0169-2607},
  doi = {10.1016/S0169-2607(02)00120-7},
  abstract = {The aim of dose-ranging phase I (resp. phase II) clinical trials is to rapidly identify the maximum tolerated dose (MTD) (resp., minimal effective dose (MED)) of a new drug or combination. For the conduct and analysis of such trials, Bayesian approaches such as the Continual Reassessment Method (CRM) have been proposed, based on a sequential design and analysis up to a completed fixed sample size. To optimize sample sizes, Zohar and Chevret have proposed stopping rules (Stat. Med. 20 (2001) 2827), the computation of which is not provided by available softwares. We present in this paper a user-friendly software for the design and analysis of these Bayesian Phase I (resp. phase II) dose-ranging Clinical Trials (BPCT). It allows to carry out the CRM with stopping rules or not, from the planning of the trial, with choice of model parameterization based on its operating characteristics, up to the sequential conduct and analysis of the trial, with estimation at stopping of the MTD (resp. MED) of the new drug or combination.},
  number = {2},
  journal = {Computer Methods and Programs in Biomedicine},
  author = {Zohar, Sarah and Latouche, Aurelien and Taconnet, Mathieu and Chevret, Sylvie},
  month = oct,
  year = {2003},
  keywords = {Bayesian inference,Continual Reassessment Method,Dose-ranging studies,Stopping rules},
  pages = {117-125},
  file = {/Users/k/Zotero/storage/M8I4VF4D/Zohar et al_2003_Software to compute and conduct sequential Bayesian phase I or II dose-ranging.pdf;/Users/k/Zotero/storage/N84BR2I4/S0169260702001207.html;/Users/k/Zotero/storage/PT2H6NBQ/S0169260702001207.html}
}

@article{williamsBayesianMetaAnalysisWeakly,
  title = {Bayesian {{Meta}}-{{Analysis}} with {{Weakly Informative Prior Distributions}}},
  language = {en},
  author = {Williams, Donald R and Rast, Philippe and B\"urkner, Paul-Christian},
  pages = {19},
  file = {/Users/k/Zotero/storage/BPX6JGI3/Williams et al_Bayesian Meta-Analysis with Weakly Informative Prior Distributions.pdf}
}

@article{rizopoulosJMPackageJoint2010,
  title = {{{JM}}: {{An R Package}} for the {{Joint Modelling}} of {{Longitudinal}} and {{Time}}-to-{{Event Data}} | {{Rizopoulos}} | {{Journal}} of {{Statistical Software}}},
  volume = {35},
  shorttitle = {{{JM}}},
  doi = {10.18637/jss.v035.i09},
  abstract = {In longitudinal studies measurements are often collected on different types of outcomes for each subject. These may include several longitudinally measured responses (such as blood values relevant to the medical condition under study) and the time at which an event of particular interest occurs (e.g., death, development of a disease or dropout from the study). These outcomes are often separately analyzed; however, in many instances, a joint modeling approach is either required or may produce a better insight into the mechanisms that underlie the phenomenon under study. In this paper we present the R package JM that fits joint models for longitudinal and time-to-event data.},
  language = {en-US},
  number = {9},
  journal = {Journal of Statistical Software},
  author = {Rizopoulos, Dimitris},
  month = jul,
  year = {2010},
  file = {/Users/k/Zotero/storage/7W9EZFKQ/JM An R Package for the Joint Modelling of Longit.pdf;/Users/k/Zotero/storage/C9MU3UNY/v035i09.html}
}

@article{rizopoulosPackageJMbayesFitting2016,
  title = {The {{R Package JMbayes}} for {{Fitting Joint Models}} for {{Longitudinal}} and {{Time}}-to-{{Event Data Using MCMC}}},
  volume = {72},
  doi = {10.18637/jss.v072.i07},
  language = {en-US},
  number = {7},
  journal = {Journal of Statistical Software},
  author = {Rizopoulos, Dimitris},
  year = {Auguest 2016},
  keywords = {dynamic predictions,mixed models,random effects,survival analysis,time-varying covariates,validation},
  file = {/Users/k/Zotero/storage/KFBAZQLJ/The R Package JMbayes for Fitting Joint Models for Longitudinal and.pdf;/Users/k/Zotero/storage/EX6534DA/v072i07.html}
}

@article{betancourtCalibratingModelBasedInferences2018,
  archivePrefix = {arXiv},
  eprinttype = {arxiv},
  eprint = {1803.08393},
  primaryClass = {stat},
  title = {Calibrating {{Model}}-{{Based Inferences}} and {{Decisions}}},
  abstract = {As the frontiers of applied statistics progress through increasingly complex experiments we must exploit increasingly sophisticated inferential models to analyze the observations we make. In order to avoid misleading or outright erroneous inferences we then have to be increasingly diligent in scrutinizing the consequences of those modeling assumptions. Fortunately model-based methods of statistical inference naturally define procedures for quantifying the scope of inferential outcomes and calibrating corresponding decision making processes. In this paper I review the construction and implementation of the particular procedures that arise within frequentist and Bayesian methodologies.},
  journal = {arXiv:1803.08393 [stat]},
  author = {Betancourt, Michael},
  month = mar,
  year = {2018},
  keywords = {Statistics - Methodology,_tablet},
  file = {/Users/k/Zotero/storage/46UV7K2N/Betancourt_2018_Calibrating Model-Based Inferences and Decisions.pdf;/Users/k/Zotero/storage/DMY2TMZZ/1803.html}
}

@article{betancourtUnifiedTreatmentPredictive2015,
  archivePrefix = {arXiv},
  eprinttype = {arxiv},
  eprint = {1506.02273},
  primaryClass = {stat},
  title = {A {{Unified Treatment}} of {{Predictive Model Comparison}}},
  abstract = {The predictive performance of any inferential model is critical to its practical success, but quantifying predictive performance is a subtle statistical problem. In this paper I show how the natural structure of any inferential problem defines a canonical measure of relative predictive performance and then demonstrate how approximations of this measure yield many of the model comparison techniques popular in statistics and machine learning.},
  journal = {arXiv:1506.02273 [stat]},
  author = {Betancourt, Michael},
  month = jun,
  year = {2015},
  keywords = {Statistics - Methodology},
  file = {/Users/k/Zotero/storage/FDHRFGM9/Betancourt_2015_A Unified Treatment of Predictive Model Comparison.pdf;/Users/k/Zotero/storage/5VD3IY27/1506.html}
}

@article{ristlMethodsAnalysisMultiple2018,
  title = {Methods for the Analysis of Multiple Endpoints in Small Populations: {{A}} Review},
  volume = {0},
  issn = {1054-3406},
  shorttitle = {Methods for the Analysis of Multiple Endpoints in Small Populations},
  doi = {10.1080/10543406.2018.1489402},
  abstract = {While current guidelines generally recommend single endpoints for primary analyses of confirmatory clinical trials, it is recognized that certain settings require inference on multiple endpoints for comprehensive conclusions on treatment effects. Furthermore, combining treatment effect estimates from several outcome measures can increase the statistical power of tests. Such an efficient use of resources is of special relevance for trials in small populations. This paper reviews approaches based on a combination of test statistics or measurements across endpoints as well as multiple testing procedures that allow for confirmatory conclusions on individual endpoints. We especially focus on feasibility in trials with small sample sizes and do not solely rely on asymptotic considerations. A systematic literature search in the Scopus database, supplemented by a manual search, was performed to identify research papers on analysis methods for multiple endpoints with relevance to small populations. The identified methods were grouped into approaches that combine endpoints into a single measure to increase the power of statistical tests and methods to investigate differential treatment effects in several individual endpoints by multiple testing.},
  number = {0},
  journal = {Journal of Biopharmaceutical Statistics},
  author = {Ristl, Robin and Urach, Susanne and Rosenkranz, Gerd and Posch, Martin},
  month = jul,
  year = {2018},
  keywords = {Combined outcomes,composite endpoints,multiple endpoints,multiple testing,multivariate responses,rare diseases,small populations},
  pages = {1-29},
  file = {/Users/k/Zotero/storage/7AZ2MJJ5/Ristl et al. - Methods for the analysis of multiple endpoints in .pdf},
  pmid = {29985752}
}

@article{targanNatalizumabTreatmentActive2007,
  title = {Natalizumab for the {{Treatment}} of {{Active Crohn}}'s {{Disease}}: {{Results}} of the {{ENCORE Trial}}},
  volume = {132},
  issn = {0016-5085},
  shorttitle = {Natalizumab for the {{Treatment}} of {{Active Crohn}}'s {{Disease}}},
  doi = {10.1053/j.gastro.2007.03.024},
  abstract = {Background \& Aims: A randomized placebo-controlled trial evaluated the efficacy of natalizumab induction therapy in patients with Crohn's disease. Methods: Patients (N = 509) with moderately to severely active Crohn's disease and active inflammation characterized by elevated C-reactive protein concentrations were randomized (1:1) to receive natalizumab 300 mg or placebo intravenously at Weeks 0, 4, and 8. The primary end point was induction of response ($\geq$70-point decrease from baseline in the Crohn's Disease Activity Index score at Week 8 sustained through Week 12). Additional efficacy end points included the proportion of patients with sustained remission (Crohn's Disease Activity Index score $<$150 points) and response or remission over time. Results: Response at Week 8 sustained through Week 12 occurred in 48\% of natalizumab-treated patients and 32\% of patients receiving placebo (P $<$ .001). Sustained remission occurred in 26\% of natalizumab-treated patients and 16\% of patients receiving placebo (P = .002). Week 4 response rates were 51\% for natalizumab and 37\% for placebo (P = .001). Responses remained significantly higher at subsequent assessments (P $<$ .001) in natalizumab-treated patients. Natalizumab-treated patients also had significantly higher remission rates at Weeks 4, 8, and 12 (P $\leq$ .009). The frequency and types of adverse events were similar between treatment groups. Conclusions: Natalizumab induced response and remission at Week 8 that was sustained through Week 12. Response and remission rates for natalizumab were superior to those for placebo at Weeks 4, 8, and 12, demonstrating the early and sustained efficacy of natalizumab as induction therapy in patients with elevated C-reactive protein and active Crohn's disease. Natalizumab was well tolerated in this study.},
  number = {5},
  journal = {Gastroenterology},
  author = {Targan, Stephan R. and Feagan, Brian G. and Fedorak, Richard N. and Lashner, Bret A. and Panaccione, Remo and Present, Daniel H. and Spehlmann, Martina E. and Rutgeerts, Paul J. and Tulassay, Zsolt and Volfova, Miroslava and Wolf, Douglas C. and Hernandez, Chito and Bornstein, Jeffrey and Sandborn, William J.},
  month = may,
  year = {2007},
  pages = {1672-1683},
  file = {/Users/k/Zotero/storage/784YTG48/Targan et al. - 2007 - Natalizumab for the Treatment of Active Crohn’s Di.pdf;/Users/k/Zotero/storage/5K27L4QJ/S0016508507005380.html}
}

@article{viechtbauerConductingMetaAnalysesMetafor,
  title = {Conducting {{Meta}}-{{Analyses}} in {{R}} with the Metafor {{Package}}},
  doi = {10.18637/jss.v036.i03},
  abstract = {The metafor package provides functions for conducting meta-analyses in R. The package includes functions for fitting the meta-analytic fixed- and random-effects models and allows for the inclusion of moderators variables (study-level covariates) in these models. Meta-regression analyses with continuous and categorical moderators can be conducted in this way. Functions for the Mantel-Haenszel and Peto's one-step method for meta-analyses of 2 x 2 table data are also available. Finally, the package provides various plot functions (for example, for forest, funnel, and radial plots) and functions for assessing the model fit, for obtaining case diagnostics, and for tests of publication bias.},
  language = {en-US},
  journal = {Journal of Statistical Software},
  author = {Viechtbauer, Wolfgang},
  file = {/Users/k/Zotero/storage/BN8KIE8Q/Conducting Meta-Analyses in R with the metafor Pac.pdf;/Users/k/Zotero/storage/M7BGJJ7A/v036i03.html}
}

@misc{eijkComparingMethodsCombine2018,
  title = {Comparing Methods to Combine Functional Loss and Mortality in Clinical Trials for Amyotrophic Lateral Sclerosis},
  abstract = {Comparing methods to combine functional loss and mortality in clinical trials for amyotrophic lateral sclerosis Ruben PA van Eijk,1 Marinus JC Eijkemans,2 Dimitris Rizopoulos,3 Leonard H van den Berg,4,* Stavros Nikolakopoulos5,* 1Department of Neurology, University Medical Center Utrecht, Utrecht, the Netherlands; 2Department of Biostatistics, University Medical Center Utrecht, Utrecht, the Netherlands; 3Department of Biostatistics, Erasmus University Medical Center, Rotterdam, the Netherlands; 4Department of Neurology, University Medical Center Utrecht, Utrecht, the Netherlands; 5Department of Biostatistics, University Medical Center Utrecht, Utrecht, the Netherlands *These authors contributed equally to this work Objective: Amyotrophic lateral sclerosis (ALS) clinical trials based on single end points only partially capture the full treatment effect when both function and mortality are affected, and may falsely dismiss efficacious drugs as futile. We aimed to investigate the statistical properties of several strategies for the simultaneous analysis of function and mortality in ALS clinical trials. Methods: Based on the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, we simulated longitudinal patterns of functional decline, defined by the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) and conditional survival time. Different treatment scenarios with varying effect sizes were simulated with follow-up ranging from 12 to 18\&nbsp;months. We considered the following analytical strategies: 1) Cox model; 2) linear mixed effects (LME) model; 3) omnibus test based on Cox and LME models; 4) composite time-to-6-point decrease or death; 5) combined assessment of function and survival (CAFS); and 6) test based on joint modeling framework. For each analytical strategy, we calculated the empirical power and sample size. Results: Both Cox and LME models have increased false-negative rates when treatment exclusively affects either function or survival. The joint model has superior power compared to other strategies. The composite end point increases false-negative rates among all treatment scenarios. To detect a 15\% reduction in ALSFRS-R decline and 34\% decline in hazard with 80\% power after 18\&nbsp;months, the Cox model requires 524 patients, the LME model 794 patients, the omnibus test 526 patients, the composite end point 1,274 patients, the CAFS 576 patients and the joint model 464 patients. Conclusion: Joint models have superior statistical power to analyze simultaneous effects on survival and function and may circumvent pitfalls encountered by other end points. Optimizing trial end points is essential, as selecting suboptimal outcomes may disguise important treatment clues. Keywords: joint models, CAFS, clinical trials, amyotrophic lateral sclerosis},
  language = {English},
  journal = {Clinical Epidemiology},
  howpublished = {https://www.dovepress.com/comparing-methods-to-combine-functional-loss-and-mortality-in-clinical-peer-reviewed-fulltext-article-CLEP},
  author = {van Eijk, Ruben PA and Eijkemans, Marinus JC and Rizopoulos, Dimitris and van den Berg, Leonard H. and Nikolakopoulos, Stavros},
  month = mar,
  year = {2018},
  file = {/Users/k/Zotero/storage/ZVZ3I8LJ/Eijk et al_2018_Comparing methods to combine functional loss and mortality in clinical trials.pdf;/Users/k/Zotero/storage/U8LD59JR/comparing-methods-to-combine-functional-loss-and-mortality-in-clinical-peer-reviewed-fulltext-a.html},
  doi = {10.2147/CLEP.S153196}
}

@article{blanchardToxicityEquivalenceRange2011,
  title = {Toxicity Equivalence Range Design ({{TEQR}}): {{A}} Practical {{Phase I}} Design},
  volume = {32},
  issn = {15517144},
  shorttitle = {Toxicity Equivalence Range Design ({{TEQR}})},
  doi = {10.1016/j.cct.2010.09.011},
  abstract = {Purpose: This paper introduces the target equivalence range (TEQR) design, a frequentist implementation of the modified toxicity probability interval (mTPI) design, as a competitor to the standard 3 + 3 design (3 + 3). The 3 + 3 is the work horse design in Phase I. It is good at determining if a safe dose exits, but provides poor accuracy and precision in estimating the level of toxicity at the maximum tolerated dose (MTD). Its main competitor, the continual reassessment method (CRM) has not found a true niche in the Phase I armamentarium resulting from statistical and implementation complexities.
Methods: We describe the four competing designs (3 + 3, mTPI, CRM, and TEQR), comparing them based on i) operating characteristics from simulated trials, and ii) ease of implementation.
Results: The TEQR is better than the 3 + 3 when compared on; 1) number of times the dose at or nearest the target toxicity level was selected as the MTD, 2) number of patients assigned to dose levels at or nearest the MTD, 3) overall trial dose limiting toxicity rate and 4) accuracy and precision of estimates for the rate of toxicity at the MTD. Further it is reasonably comparable to the CRM and mTPI on 1\textendash{}3.
Conclusion: The TEQR offers trial designers a competitor to the 3 + 3 for ease of implementation with better operating characteristics and the added attraction of a glimpse of activity at the MTD. The R package TEQR, freely available from the comprehensive R archive network, includes functions to calculate dose escalation guidelines and operating characteristics.},
  language = {en},
  number = {1},
  journal = {Contemporary Clinical Trials},
  author = {Blanchard, M. Suzette and Longmate, Jeffrey A.},
  month = jan,
  year = {2011},
  pages = {114-121},
  file = {/Users/k/Zotero/storage/B87KNZHH/Blanchard_Longmate_2011_Toxicity equivalence range design (TEQR).pdf}
}