Updated rank model docs

docs/index.rst

@@ -25,7 +25,8 @@ Contents:
    structure
    vcfParser
    qcCollect
-   genmod_score
+   rank_modelv1.10
+   rank_modelv1.5
    configuration_file
    pedigree_file
    IDN

docs/rank_modelv1.10.rst

@@ -0,0 +1,249 @@
+rank_modelv1.10
+==================
+
+Genmod score uses the `weighted sum model`_ (WSM) approach to rank the most likely
+pathogenic variant.
+
+Generally, the higher value the more likely pathogenic variant. 
+
+Genmod_score uses config files to define the rank model, which enables customized
+set-up and versioning of rank models.
+
+The WSM uses the following alternatives and weights in the rank model:
+
+Rank score range: -25 <= rs <= 27
+
+`Consequence`_
+~~~~~~~~~~~~~~
+Each alleles variant effect on individual transcripts are evaluated using a rule-based approach
+defined by `SO-terms`_. The SO-terms themselves are ranked in order of severity and this ranking
+is used to defined the weight of the consequence alternative. The performance score is based
+on the most severe consequence within each gene.
+
+Performance value for the SO-terms:
+ - transcript_ablation = 10
+ - initiator_codon_variant = 9
+ - frameshift_variant = 8
+ - stop_gained = 8
+ - start_lost = 8
+ - stop_lost = 8
+ - splice_acceptor_variant = 8
+ - splice_donor_variant = 8
+ - inframe_deletion = 5
+ - transcript_amplification = 5
+ - splice_region_variant = 5
+ - missense_variant = 5
+ - protein_altering_variant = 5
+ - inframe_insertion = 5
+ - incomplete_terminal_codon_variant = 5
+ - synonymous_variant = 2
+ - non_coding_transcript_exon_variant = 1
+ - mature_miRNA_variant = 1
+ - non_coding_transcript_variant = 1
+ - regulatory_region_variant = 1
+ - upstream_gene_variant = 1
+ - regulatory_region_amplification = 1
+ - TFBS_amplification = 1
+ - 5_prime_UTR_variant = 1
+ - intron_variant = 1
+ - 3_prime_UTR_variant = 1
+ - feature_truncation = 1
+ - TF_binding_site_variant = 1
+ - stop_retained_variant = 1
+ - feature_elongation = 1
+ - regulatory_region_ablation = 1
+ - TFBS_ablation = 1
+ - coding_sequence_variant = 1
+ - downstream_gene_variant = 1
+ - NMD_transcript_variant = 1
+ - intergenic_variant = 0
+ - not_reported = 0
+
+Frequency
+~~~~~~~~~
+The alternative allele frequency (AF) in public databases (`1000G`_, `ExAC`_). The highest reported 
+alternative frequency reported from the databases is used to calculate the performance value.
+
+Definitions:
+ - Not reported: AF Na
+ - Rare: AF <= 0.005
+ - Intermediate: 0.005 <= AF <= 0.02
+ - Common:  AF > 0.02
+
+Performance value for maximum AF:
+ - Not reported = 3
+ - Rare = 2
+ - Intermediate = 1
+ - Common = -12
+
+Inheritance Model(s)
+~~~~~~~~~~~~~~~~~~~~
+The segregation pattern for the variant within the family. These models are currently annotated
+using `genmod`_ models.
+
+Definitions:
+ - Autsomal Recessive, denoted 'AR_hom'
+ - Autsomal Recessive denovo, denoted 'AR_hom_dn'
+ - Autsomal Dominant, 'AD'
+ - Autsomal Dominant denovo, 'AD_dn'
+ - Autosomal Compound Heterozygote, 'AR_comp'
+ - X-linked dominant, 'XD'
+ - X-linked dominant de novo, 'XD_dn'
+ - X-linked Recessive, 'XR'
+ - X-linked Recessive de novo, 'XR_dn'
+
+Performance value for inheritance models:
+ - Valid model = 1
+ - No model = -12
+
+Protein Functional Prediction
+~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
+The predicted functional effect on the protein.
+Currently 2 protein effect predictors are used (`Sift`_, `PolyPhen2`_).
+Each predictors can contribute 1 point each to the overall protein predictor performance score.
+
+SIFT predicts whether an amino acid substitution is likely to affect protein function based
+on sequence homology and the physico-chemical similarity between the alternate amino acids [`1`_].
+
+PolyPhen-2 predicts the effect of an amino acid substitution on the structure and function
+of a protein using sequence homology, Pfam annotations, 3D structures from PDB where available,
+and a number of other databases and tools (including DSSP, ncoils etc [`2`_].
+
+Definitions:
+
+ - Sift Terms:
+
+   - "D" Deleterious (score<=0.05)
+   - "T" Tolerated (score>0.05) 
+
+ - `PolyPhen2HumVar`_ Terms:
+
+   - "D": Probably damaging (>=0.909)
+   - "P": Possibly damaging (0.447<=pp2_hvar<=0.909)
+   - "B": Benign (pp2_hvar<=0.446)
+
+Performance value for protein predictors:
+
+ - Sift:
+
+   - D = 1
+
+ - PolyPhen2HumVar:
+
+   - D or P = 1
+
+Variant Quality Filter
+~~~~~~~~~~~~~~~~~~~~~~
+Each variant call has a filter tranche attached to it indicating the quality of the actual
+variant call. 
+
+Definitions:
+
+ - PASS 
+ - Other (Tranches e.g. For GATK [`3`_]: "VQSRTrancheBOTH99.90to100.00"
+
+Performance value for variant quality filter:
+ - PASS = 3
+ - Other = 0
+
+Conservation
+~~~~~~~~~~~~
+The level of conservation for a sequence element (`PhastCons`_ [`4`_]), nucleotides or classes of 
+nucleotides `PhyloP`_ [`5`_] both from the `Phast`_ [`6`_] package as well as genomic constraint score
+`GERP`_ [`7`_] is used. The Phast datasets used in the conservation calculation were generated
+by the UCSC/Penn State Bioinformatics comparative genomics alignment pipeline. A description of this analysis can be found at `UCSC`_. Each type of 
+conservation can contribute 1 point each to the overall conservation performance score.
+
+Definitions:
+
+ - Conserved
+
+   - PhastCons: 0.8 >= Score <= 1
+   - GERPRS: Score >= 2
+   - PhyloP: Score > 2,5
+
+Performance value for conservation:
+ - Conserved:
+
+   - PhastCons = 1
+   - PhyloP = 1	
+   - GERP = 1
+
+Combined Annotation Dependent Depletion (CADD)
+~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
+`CADD`_ is a tool for scoring the deleteriousness of single nucleotide variants as well as 
+insertion/deletions variants in the human genome. C-scores strongly correlate with allelic
+diversity, pathogenicity of both coding and non-coding variants, and experimentally measured
+regulatory effects, and also highly rank causal variants within individual genome sequences.
+The CADD-score is a pre-calculated for all SNVs and for indel from 1000G-project [`8`_].
+
+Definitions:
+
+- Strongly deleterious (CADD > 40)
+- deleterious (CADD > 30)
+- Mildly deleterious (CADD > 20)
+- Probably deleterious (CADD > 10)
+
+Performance value for CADD:
+
+- Strongly deleterious = 4
+- Deleterious = 3
+- Mildly deleterious = 2
+- Probably deleterious = 1
+
+
+ClinVar
+~~~~~~~
+`ClinVar`_ [`9`_] is a freely accessible, public archive of reports of the relationships
+among human variations and phenotypes, with supporting evidence. 
+
+Definitions:
+
+ - Uncertain significance = 0
+ - Not provided = 1
+ - Benign = 2
+ - Likely benign = 3
+ - Likely pathogenic = 4
+ - Pathogenic = 5
+ - Drug response = 6
+ - Histocompatibility = 7
+ - Other = 255
+
+Performance value for ClinVar:
+ - Uncertain significance = 0
+ - Not provided = 0
+ - Benign = -1
+ - Likely benign = 0
+ - Likely pathogenic = 1
+ - Pathogenic = 2
+ - Drug response = 0
+ - Histocompatibility = 0
+ - Other = 0
+
+
+.. _weighted sum model: http://en.wikipedia.org/wiki/Weighted_sum_model
+.. _Consequence: http://www.ensembl.org/info/genome/variation/predicted_data.html
+.. _SO-terms: http://www.sequenceontology.org/
+.. _1000G: http://www.1000genomes.org/
+.. _ExAC: http://exac.broadinstitute.org/about
+.. _MutationTaster: http://www.mutationtaster.org/
+.. _genmod: https://github.com/moonso/genmod
+.. _Sift: http://sift.jcvi.org/
+.. _PolyPhen2: http://genetics.bwh.harvard.edu/pph2/
+.. _PolyPhen2HumVar: http://genetics.bwh.harvard.edu/pph2/dokuwiki/overview#prediction
+.. _PhastCons: http://compgen.bscb.cornell.edu/phast/help-pages/phastCons.txt
+.. _PhyloP: http://compgen.bscb.cornell.edu/phast/help-pages/phyloP.txt
+.. _Phast: http://compgen.bscb.cornell.edu/phast/
+.. _UCSC: http://genome.ucsc.edu/cgi-bin/hgTrackUi?db=hg19&g=cons100way
+.. _GERP: http://mendel.stanford.edu/SidowLab/downloads/gerp/
+.. _CADD: http://cadd.gs.washington.edu/
+.. _ClinVar: http://www.ncbi.nlm.nih.gov/clinvar/
+.. _1: http://www.ncbi.nlm.nih.gov/pubmed/?term=22689647
+.. _2: http://www.ncbi.nlm.nih.gov/pubmed/?term=20354512
+.. _3: http://www.ncbi.nlm.nih.gov/pubmed?term=20644199
+.. _4: http://www.ncbi.nlm.nih.gov/pubmed/?term=16024819
+.. _5: http://www.ncbi.nlm.nih.gov/pubmed/?term=14660683
+.. _6: http://www.ncbi.nlm.nih.gov/pubmed/?term=21278375
+.. _7: http://www.ncbi.nlm.nih.gov/pubmed/?term=15965027
+.. _8: http://www.ncbi.nlm.nih.gov/pubmed/?term=24487276
+.. _9: http://www.ncbi.nlm.nih.gov/pubmed/?term=24234437

docs/genmod_score.rst → docs/rank_modelv1.5.rst

@@ -1,4 +1,4 @@
-genmod_score
+rank_modelv1.5
 ==================
 
 Genmod_score uses the `weighted sum model`_ (WSM) approach to rank the most likely
@@ -9,7 +9,7 @@ Generally, the higher value the more likely pathogenic variant.
 Genmod_score uses config files to define the rank model, which enables customized
 set-up and versioning of rank models.
 
-The WSM uses the following alternatives and weights in rank model "gm_cmms_v1.4":
+The WSM uses the following alternatives and weights in rank model "v1.5":
 
 Rank score range: -25 <= rs <= 23