CPRD

Stata code for data analysis set more off cd D:\Covid\

local casepath D:\Covid\Cases
local codepath D:\Codes
local datapath D:\Covid\

log using D:\Covid\Analysis.log, replace

*FIND PATIENT START AND END DATES // Dataset includes all SMI and non-SMI patients from the CPRD with a COVID-19 infection diagnosis between 01/02/2020 and 31/12/2021

use casepath'Patients, clear merge m:1 pracid using casepath'Practice drop _m gen dod=date(cprd_ddate,"DMY") gen dor=date(regstartdate,"DMY") gen dot=date(regenddate,"DMY") *gen douts=date(uts,"DMY") gen dolcd=date(lcd,"DMY") gen studyend=date("31032021","DMY") gen studystart=date("01022020","DMY") gen patstart=max(dor,studystart) gen patend=min(dot,dolcd,studyend,dod) *replace yob=yob+1800 drop if patend<=patstart recode region (7/8=0) (1/3=1) (4/5=2) (6=3) (9=4) (12=5), gen(Region) keep patid pracid patstart patend studyend studystart gender yob dod Region merge 1:1 patid using casepath'Indexdate_Covid.dta, keep(matched) drop _m gen Age_Covid=year(Indexdate_Covid)- yob save casepath'PatCovid, replace

*FIND Covid EVENTS forvalues i=1/134 { use casepath'Observationi', clear keep patid obsdate enterdate medcodeid consid obsid probobsid merge m:1 medcodeid using codepath'Covidcodes.dta, keep (matched) drop _m save tempi', replace }

use temp1, clear

forvalues i=2/134 { append using temp`i' }

save casepath'Medfile, replace gen doe=date(obsdate,"DMY") replace doe=date(enterdate, "DMY") if doe==. collapse (min) Indexdate_Covid=doe, by(patid) save casepath'MedCovid.dta, replace

forvalues i=1/134 { erase temp`i'.dta }

*FIND SMI EVENTS

local conditionlist SMI

foreach condition of local conditionlist { forvalues i=1/134{ use casepath'\Observationi', clear keep patid medcodeid obsdate enterdate value merge m:1 medcodeid using codepath'\condition'codes, keep(matched) drop _m save tempi', replace } use temp1, clear forvalues i=2/134{ append using tempi' } save casepath'\condition', replace

} forvalues i=1/134 { erase temp`i'.dta }

foreach condition of local conditionlist { use casepath'\condition', clear gen doe=date(obsdate,"DMY") gen sd=date(enterdate,"DMY") replace doe=sd if doe==.|doe==0 collapse (min) startcondition'=doe, by(patid) gen condition'=startcondition'!=. save casepath'\Pat`condition', replace }

*CONFOUNDERS

Body mass index

forvalues i=1/134{ use casepath'Observationi', clear merge m:1 medcodeid using codepath'BMIcodes, keep (matched) replace BMI=value if BMI==1 replace BMI=. if BMI<12|BMI>70 replace Weight=value if (Weight==1 & (value>=30 & value<=200)) replace Height=value/100 if Height==1 & value>100&value!=. replace Height=. if Height<1.2|Height>2.2 bysort patid: egen meanHeight=mean(Height) replace Height=meanHeight if Height==. replace BMI=Weight/(Height^2) if BMI==. replace BMI=. if BMI<12|BMI>70 replace BMIcat=1 if BMI<16.5 replace BMIcat=1 if BMI<16.5 replace BMIcat=2 if BMI>=16.5 &BMI<24.9999 replace BMIcat=3 if BMI>=25 &BMI<29.999 replace BMIcat=4 if BMI>=30 &BMI<. gen doe=date(obsdate,"DMY") gen sd=date(enterdate,"DMY") replace doe=sd if doe==. keep patid doe BMI BMIcat save datapath'temp`i', replace }

use datapath'temp1, clear forvalues i=2/134 { append using datapath'temp`i' }

collapse (mean) BMI (max) BMIcat , by(patid doe) recode BMI (min/18.4999999 = 1 "Underweight 1<18.5 kg/m2") (18.5/24.9999999 = 2 "Under/Normal weight 18.5-24.9999999 kg/m2") (25/30 = 3 "Overweight 25-30 kg/m2") (30.00001/max = 4 "Obese >30 kg/m2"), gen(BMIgrp) label var BMIgrp "BMI categories at baseline (grouped)" save `casepath'\PatBMIgrp, replace

forvalues i=1/134 { erase datapath'tempi'.dta }

*SMOKING Status

forvalues i=1/134{ use casepath'Observationi', clear merge m:1 medcodeid using codepath'Smokercodes.dta, keep(matched) gen SmokerCigg=value if value>0 & value<121 gen doe=date(obsdate,"DMY") gen sd=date(enterdate,"DMY") replace doe=sd if doe==. *replace Smoker=3 if (Smoker==2 & (SmokerCigg>=11 & SmokerCigg<20))|SmokerType==3 *replace Smoker=4 if (Smoker==2 & (SmokerCigg>=20 & SmokerCigg<40)) |SmokerType==4 *replace Smoker=5 if (Smoker==2 & (SmokerCigg>=40 & SmokerCigg<121)) |SmokerType==5 keep patid doe Smoker SmokerCigg save tempi', replace

} use temp1, clear forvalues i=2/134{ append using temp`i' }

recode Smoker (0 = 0 "Never Smoked") (1 = 1 "Ex-Smoker") (2= 2 "Current Smoker") (3= 3 "Smoker < 20 ciggarettes") (4= 4 "Smoker 20-40 ciggarettes") (5= 5 "Smoker >40 ciggarettes") (. = 6 "Smoking data missing"), gen(SmokingStatus) drop Smoker rename SmokingStatus Smoker bysort patid doe: keep if [_n]==[_N] save `casepath'PatSmoker, replace

forvalues i=1/134{ erase temp`i'.dta }

*FIND ALCOHOL status

forvalues i=1/134 { use casepath'Observationi', clear merge m:1 medcodeid using codepath'Alcoholcodes.dta, keep(matched) gen Freq=0 replace Freq=1 if Alcohol==1 replace Freq=2 if Alcohol==2 replace Freq=3 if Alcohol==3 replace Freq=4 if Alcohol==4 replace Freq=5 if Alcohol==5 gen doe=date(obsdate,"DMY") gen sd=date(enterdate,"DMY") replace doe=sd if doe==. keep patid doe Freq Alcohol save tempi', replace } use temp1, clear forvalues i=2/134 { append using temp`i' }

bysort patid doe: keep if [_n]==[_N]
recode Alcohol (0 = 0 "Never drunk") (1 = 1 "Ex-Drinker")(2/5= 2 "Current Drinker") (3= 3 "Mild drinker") (4= 4 "Moderate drinker") (5= 5 "Excessive 	drinker") (. = 6 "Alcohol data missing"), gen(AlcoholStatus)
drop Alcohol
rename AlcoholStatus Alcohol
save `casepath'PatAlcohol, replace

forvalues i=1/134{ erase temp`i'.dta }

*FIND BLOOD PRESSURE levels

forvalues i=1/134 { use casepath'Observationi', clear merge m:1 medcodeid using codepath'BPcodes.dta, keep(matched) *keep if value!=. gen Systolic=value if SBP==1 gen Diastolic=value if DBP==1 gen doe=date(obsdate,"DMY") gen sd=date(enterdate,"DMY") replace doe=sd if doe==. keep patid doe Diastolic Systolic save tempi', replace } use temp1, clear forvalues i=2/134 { append using temp`i' }

collapse (mean) Diastolic Systolic, by(patid doe) gen BP=1 if Diastolic<80&Systolic<120 replace BP=2 if Diastolic>=80 & Diastolic<90|Systolic>=120 & Systolic<140 replace BP=3 if Diastolic>=90 &Diastolic<.|Systolic>=140 & Systolic<. *replace BPgrp=6 if Diastolic==.|Systolic==. recode BP (1 = 1 "Optimal BP")(2= 2 "Pre-hypertension") (3= 3 "Hypertension") (. = 4 "BP data missing"), gen(BPgrp) save `casepath'PatBPgrp, replace

forvalues i=1/134 { erase temp`i'.dta }

*FIND Total cholesterol levels forvalues i=1/134{ use casepath'\Observationi', clear merge m:1 medcodeid using codepath'Cholesterolcodes.dta, keep(matched) *keep if value!=. drop Cholesterol gen Cholesterol=value if TC==1 replace Cholesterol=. if Cholesterol>15|Cholesterol<=0 gen doe=date(obsdate,"DMY") gen sd=date(enterdate,"DMY") replace doe=sd if doe==. keep patid doe Cholesterol save tempi', replace } use temp1, clear forvalues i=2/134 { append using temp`i' }

collapse (mean) Cholesterol , by(patid doe) gen Cholesterolgrp=1 if Cholesterol<5.15 replace Cholesterolgrp=2 if Cholesterol>=5.15 & Cholesterol<6.21 replace Cholesterolgrp=3 if Cholesterol>6.20 & Cholesterol<. keep patid doe Cholesterolgrp HDLgrp LDLgrp nonHDLgrp Cholesterol LDL HDL TCratioHDL non_HDL recode Cholesterolgrp (1 = 1 " Total cholesterol <5.15")(2= 2 "Total cholesterol>=5.15 & <6.21") (3= 3 "Total cholesterol >6.20") (. = 4 "Total cholesterol data missing"), gen(TotalCholesterol) drop Cholesterolgrp rename TotalCholesterol Cholesterolgrp save `casepath'PatCholesterolgrp, replace

forvalues i=1/134 { erase temp`i'.dta }

Find triglycerides levels

forvalues i=1/134 { use casepath'Observationi', clear merge m:1 medcodeid using codepath'Triglyceridescodes.dta, keep(matched) keep if value!=. replace Triglycerides=value if value>0 & value<501 gen doe=date(obsdate,"DMY") gen sd=date(enterdate,"DMY") replace doe=sd if doe==. keep patid doe Triglycerides save tempi', replace }

use temp1, clear forvalues i=2/134 { append using temp`i' }

collapse (mean) Triglycerides, by(patid doe) gen Triglyceridesgrp=(Triglycerides>1.7 &Triglycerides<. ) keep patid doe Triglyceridesgrp Triglycerides save `casepath'PatTriglycerides, replace

forvalues i=1/134 { erase temp`i'.dta }

*FIND HbA1c levels forvalues i=1/134 { use casepath'Observationi', clear merge m:1 medcodeid using codepath'HbA1ccodes.dta, keep(matched) *keep if value!=. replace HbA1c=value replace HbA1c=(46.7+value)/28.7 if numunitid==220|numunitid==892 replace HbA1c=. if HbA1c>15 & HbA1c<. gen doe=date(obsdate,"DMY") gen sd=date(enterdate,"DMY") replace doe=sd if doe==. keep patid doe HbA1c HbA1clevel save tempi', replace } use temp1, clear forvalues i=2/134 { append using temp`i' }

collapse (mean) HbA1c (max) HbA1clevel, by(patid doe) gen HbA1cgrp=1 if HbA1c<5.7 replace HbA1cgrp=2 if HbA1c>=5.7 & HbA1c<6.5 replace HbA1cgrp=3 if HbA1c>=6.5 & HbA1c<. *replace HbA1cgrp=6 if HbA1c==. keep patid doe HbA1cgrp HbA1c recode HbA1cgrp (1 = 1 " HbA1c <5.7")(2= 2 "HbA1c>=5.7 & <6.5") (3= 3 "HbA1c >=6.5") (.= 4 "HbA1c data missing"), gen(HbA1clevel) save `casepath'PatHbA1cgrp, replace

forvalues i=1/134 { erase temp`i'.dta }

*FIND CRP levels forvalues i=1/134 { use casepath'Observationi', clear merge m:1 medcodeid using codepath'CRPcodes.dta, keep(matched) keep if value!=. replace CRP=value gen doe=date(obsdate,"DMY") gen sd=date(enterdate,"DMY") replace doe=sd if doe==. keep patid doe CRP drop if CRP<0|CRP>250 save tempi', replace }

use temp1, clear forvalues i=2/134{ append using temp`i' }

collapse (mean) CRP , by(patid doe) *replace CRPgrp=6 if CRP==. xtile CRPtertile=CRP, nq(3) recode CRP (0/1.000=0) (1.0001/2.99999=1) (3.0001/10.0000=2) (10.0001/max=3), gen(CRPgrp) keep patid doe CRP CRPgrp CRPtertile save `casepath'PatCRP, replace

forvalues i=1/134 { erase temp`i'.dta }

*Find Ethnicity

forvalues i=1/134 { use casepath'Observationi', clear merge m:1 medcodeid using codepath'Ethnicitycodes, keep(matched) gen doe=date(obsdate,"DMY") gen sd=date(enterdate,"DMY") replace doe=sd if doe==. keep patid doe Ethnicity Ethnicgrp term save tempi', replace }

use temp1, clear forvalues i=2/134{ append using temp`i' }

collapse (max) Ethnicity Ethnicgrp, by(patid doe) save `casepath'\PatEthnicity, replace

forvalues i=1/134{ erase temp`i'.dta }

FIND RELEVANT LONG-TEMR CONDITIONS/

local medlist Neoplasm Hypertension MI IHD Stroke CKD Liver T2DM COPD Asthma Autoimmune SUD Epilepsy Depression Anxiety EatingDisorder GERD Alzheimer SMI Thyroid Learningdisab ICU

foreach med of local medlist { forvalues i=1/134 { use casepath'Observationi', clear merge m:1 medcodeid using codepath'\med'codes, keep(matched) gen doe=date(obsdate,"DMY") gen sd=date(enterdate,"DMY") replace doe=sd if doe==. keep patid doe med' save tempi', replace } use temp1, clear

forvalues i=1/134{ append using temp`i' }

collapse (max) med' , by(patid doe) save casepath'\Pat`med', replace

forvalues i=1/134{ erase temp`i'.dta }

}

*FIND drug prescriptions

local druglist Immunological Corticosteroids Statins AHT NSAID Antidepressant Antipsychotic Anticoagulant Antiplatelet

foreach drug of local druglist { forvalues i=1/79 { use casepath'Therapyi', clear merge m:1 prodcodeid using drugpath'\drug'codes, keep(matched) gen doe=date(issuedate,"DMY") gen sd=date(enterdate,"DMY") replace doe=sd if doe==. keep patid doe drug' save tempi', replace } use temp1, clear

forvalues i=1/79{ append using temp`i' }

collapse (max) drug', by(patid doe) save casepath'Pat`drug', replace

forvalues i=1/79{ erase temp`i'.dta }

}

local catvarlist BMIgrp BPgrp Cholesterolgrp Smoker Alcohol HbA1cgrp CRP Ethnicity local druglist Immunological Corticosteroids Statins AHT NSAID Antidepressant Antipsychotic Anticoagulant Antiplatelet local medlist Neoplasm Hypertension MI IHD Stroke CKD Liver T2DM COPD Asthma Autoimmune SUD Epilepsy Depression Anxiety EatingDisorder GERD Alzheimer SMI Thyroid Learningdisab ICU

local confounderlist druglist' medlist' `catvarlist'

*FIND EVENT NEAREST TO BASELINE (Covid-19 infection date - ensures that SMI diagnosis precededed a COVID-19 infection)

foreach confounder of local confounderlist { display "confounder'" use casepath'PatCovid, clear collapse (min) Indexdate_Covid dod patstart patend yob gender Region, by(patid) merge 1:m patid using casepath'Patconfounder', keep(matched) drop _merge drop if doe>Indexdate_Covid gen diff=abs(Indexdate_Covid-doe) bysort patid: egen mindiff=min(diff) keep if diff==mindiff *bysort patid: gen n=[_N] *drop if doe>Indexdate_Covid&n>1 bysort patid: keep if [_n]==1 keep patid doe confounder'* save casepath'`confounder', replace }

*MERGE CONFOUNDERS use casepath'PatCovid, clear collapse (min) Indexdate_Covid dod patstart patend yob gender Region, by(patid) keep patid foreach confounder of local confounderlist { display "confounder'" merge 1:1 patid using casepath'\confounder' drop _merge

	}
	
	foreach drug of local druglist {
	replace `drug'=0 if `drug'==.
}

 foreach med of local medlist {
	replace `med'=0 if `med'==.
}

save `casepath'\AllConfounders, replace





* STATISTICAL ANALYSIS

* create a dataset for analysis by bringing together cases and matched controls, including relevant confounders

use casepath'PatCovid, clear merge 1:1 patid using casepath'\AllConfounders drop _m merge 1:1 patid using casepath'imd2015_5.dta // linkage to patient-derived Index of Multiple Deprivation file provided by the CPRD drop _m save casepath'\AllPatConfounders, replace

Create a continuous and a binary multimorbidity variable from multiple long-term conditions

egen MM=rowtotal(Neoplasm Hypertension MI IHD Stroke CKD Liver T2DM COPD Asthma Autoimmune SUD Epilepsy Depression Anxiety EatingDisorder GERD Alzheimer SMI Parkinson Thyroid Learningdisab)

recode MM (0=0) (1=1) (2/max=2), gen(MM_binary)

Multiple imputation - included a wider range of variables that might influence the relationships between different study variables and the study outcome

mi set wide mi register imputed BMIgrp BPgrp Cholesterolgrp Smoker Alcohol Ethnicity CRPgrp imd2015_5 mi register regular Age_Covid gender Neoplasm Hypertension MI IHD Stroke CKD Liver T2DM COPD Asthma Autoimmune SUD Epilepsy Depression Anxiety EatingDisorder GERD Alzheimer SMI Thyroid Learningdisab ICU Immunological Corticosteroids Statins AHT NSAID Antidepressant Antipsychotic Anticoagulant Antiplatelet Region MM_binary MM Death set seed 912346 mi impute chained (mlogit) Alcohol Smoker Ethnicity (ologit) BPgrp BMIgrp Cholesterolgrp CRPgrp imd2015_5 =Age_Covid gender Neoplasm Hypertension MI IHD Stroke CKD Liver T2DM COPD Asthma Autoimmune SUD Epilepsy Depression Anxiety EatingDisorder GERD Alzheimer SMI Thyroid Learningdisab ICU Immunological Corticosteroids Statins AHT NSAID Antidepressant Antipsychotic Anticoagulant Antiplatelet Region MM_binary MM Death , add(20) force augment save `datapath'\MIPatCovid.dta, replace

Main survival analysis syntax for predicting all-cause mortality

  			use `datapath'MIPatCovid.dta, clear
  			gen ageDeath=year(dod)-yob
  			gen Death_date=dod 
  			gen Covidstart=date("01022020","DMY")
  			*gen FirstCovid=date("30092020","DMY") // this is the end date of the first wabe of the COVID-19 pandemic
  			*gen SecondCovid=date("01102020","DMY") // use this date for start time definition on analyses during the second wave
  		    gen starttime=max(Covidstart,patstart)
  			gen exittime=min(Death_date,patend) 
  			*gen exittime=min(Death_date,patend, FirstCovid) // algorithm for determining the exit time of follow-up for the first wave analyses
  			*gen starttime=max(SecondCovid, patstart) // algorithm for determining the start time of follow-up in the second wave analyses 
              drop if starttime>=exittime
              drop if Death_date<=starttime
  		    replace Death_date=date("31122022","DMY") if Death_date==. //create an arbitray date for patients that were right censored
  		    mi stset Death_date, failure(Dead) origin(starttime) exit(exittime) id(patid)
  			sts graph,by(SMI) ci risktable(, order(1 "No SMI" 2 "SMI") rowtitle(, justification(left))) legend(ring(0) position(2) rows(2))
  		    sts graph,by(SMI) adjustfor(gender BMIgrp Smoker Ethnicity Region Neoplasm Liver IHD MI Stroke T2DM CKD COPD Asthma Autoimmune Epilepsy Depression Anxiety GERD EatingDisorder Alzheimer SUD ICU Immunological Corticosteroid)
  			strate SMI, per(1000)
  			mi estimate, hr: stcox SMI gender Age_Covid , vce(robust)
  			parmest, eform saving(`casepath'\AgeGender_adjusted, replace
  			estat phtest, de
  			mi estimate, hr: stcox SMI Age_Covid ib1.BMIgrp i.(gender Hypertension Smoker Liver Neoplasm IHD MI Stroke T2DM CKD Epilepsy COPD Autoimmune Asthma Depression Anxiety GERD EatingDisorder Alzheimer SUD Immunological Corticosteroid ICU Ethnicity Region), vce(robust) 		
  			parmest, eform saving(`casepath'\AdjustedResults, replace)
  			mi estimate: estat phtest, de

MM macthed case-control study - sensitivity analyses to reduce disparities in LTC between SMI and non SMI groups

  			use `datapath'MIPatCovid.dta, clear
  			gen Covidstart=date("01022020","DMY")
  			mi stset Covidstart , failure(SMI) scale(365.25) id(patid)
  			set seed 06072008
  			sttocc, match(gender Age_Covid patstart MM) n(5) nodots
  			save `datapath'MatchedCovid, replace
  			gen ageDeath=year(dod)-yob
  			gen Death_date=dod 
  			gen starttime=max(Covidstart,patstart)
  			gen exittime=min(Death_date,patend) 
  			drop if starttime>=exittime
              drop if Death_date<=starttime
  		    replace Death_date=date("31122022","DMY") if Death_date==.
  		    mi stset Death_date, failure(Dead) origin(starttime) exit(exittime) id(patid)
  			strate, per(1000)
  			sts graph,by(_case) ci risktable(, order(1 "No SMI" 2 "SMI") rowtitle(, justification(left))) legend(ring(0) position(2) rows(2))
  		    sts graph,by(_case) adjustfor(gender BMIgrp Smoker Ethnicity Region Neoplasm Liver IHD MI Stroke T2DM CKD COPD Asthma Autoimmune Epilepsy Depression Anxiety GERD EatingDisorder Alzheimer SUD ICU Immunological Corticosteroid)
  			mi estimate, hr: stcox _case gender Age_Covid , vce(robust)
  			parmest, eform saving(`datapath'MatchedAgeGenderadjusted, replace)
  			estat phtest, de
  			mi estimate, hr: stcox _case Age_Covid i.b1.BMIgrp i.(gender Hypertension Smoker Liver Neoplasm IHD MI Stroke T2DM CKD Epilepsy COPD Autoimmune Asthma Depression Anxiety GERD EatingDisorder Alzheimer SUD Immunological Corticosteroid ICU Ethnicity Region), vce(robust) 		
  			parmest, eform saving(`datapath'MatchedadjustedFull, replace)
  			*estat phtest, de
  		}

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