The effect of survival bias on case-control genetic association studies of highly lethal diseases

Christopher D. Anderson, Michael A. Nalls, Alessandro Biffi, Natalia S. Rost, Steven M. Greenberg, Andrew B. Singleton, James F. Meschia, Jonathan Rosand

Research output: Contribution to journalArticle

28 Scopus citations

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. Methods and Results: We modeled cohorts for 3 diseases of high lethality (intracerebral hemorrhage, ischemic stroke, andmyocardial 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.

Original languageEnglish (US)
Pages (from-to)188-196
Number of pages9
JournalCirculation: Cardiovascular Genetics
Volume4
Issue number2
DOIs
StatePublished - Apr 1 2011

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Keywords

  • Epidemiology
  • Genetics
  • Hemorrhage
  • Myocardial infarction
  • Stroke

ASJC Scopus subject areas

  • Genetics
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)

Cite this

Anderson, C. D., Nalls, M. A., Biffi, A., Rost, N. S., Greenberg, S. M., Singleton, A. B., Meschia, J. F., & Rosand, J. (2011). The effect of survival bias on case-control genetic association studies of highly lethal diseases. Circulation: Cardiovascular Genetics, 4(2), 188-196. https://doi.org/10.1161/CIRCGENETICS.110.957928