title: The effect of survival bias on case-control genetic association studies of highly lethal diseases.
abstract: BACKGROUND
  Survival bias is the phenomenon by which individuals are excluded from analysis of a trait because of mortality related to the expression of that trait. In genetic association studies, variants increasing risk for disease onset as well as risk of disease-related mortality (lethality) could be difficult to detect in genetic association case-control designs, possibly leading to underestimation of a variant's effect on disease risk.
  
  
  RESULTS
  We modeled cohorts for 3 diseases of high lethality (intracerebral hemorrhage, ischemic stroke, and myocardial infarction) using existing longitudinal data. Based on these models, we simulated case-control genetic association studies for genetic risk factors of varying effect sizes, lethality, and minor allele frequencies. For each disease, erosion of detected effect size was larger for case-control studies of individuals of advanced age (age >75 years) and/or variants with very high event-associated lethality (genotype relative risk for event-related death >2.0). We found that survival bias results in no more than 20% effect size erosion for cohorts with mean age <75 years, even for variants that double lethality risk. Furthermore, we found that increasing effect size erosion was accompanied by depletion of minor allele frequencies in the case population, yielding a "signature" of the presence of survival bias.
  
  
  CONCLUSIONS
  Our simulation provides formulas to allow estimation of effect size erosion given a variant's odds ratio of disease, odds ratio of lethality, and minor allele frequencies. These formulas will add precision to power calculation and replication efforts for case-control genetic studies. Our approach requires validation using prospective data.
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Anderson
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nalls
authors.forename: Alessandro
authors.initials: A
authors.lastname: Biffi
authors.forename: Natalia S
authors.initials: NS
authors.lastname: Rost
authors.forename: Steven M
authors.initials: SM
authors.lastname: Greenberg
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Singleton
authors.forename: James F
authors.initials: JF
authors.lastname: Meschia
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rosand
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002543:Cerebral Hemorrhage / Q000235:genetics* / Q000401:mortality; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics* / Q000401:mortality; D012307:Risk Factors; D020521:Stroke / Q000235:genetics* / Q000401:mortality; D016019:Survival Analysis