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Genet Epidemiol. 2009 Jul;33(5):453-62. doi: 10.1002/gepi.20398.

Quantifying and correcting for the winner's curse in genetic association studies.

Author information

1
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, USA.

Abstract

Genetic association studies are a powerful tool to detect genetic variants that predispose to human disease. Once an associated variant is identified, investigators are also interested in estimating the effect of the identified variant on disease risk. Estimates of the genetic effect based on new association findings tend to be upwardly biased due to a phenomenon known as the "winner's curse." Overestimation of genetic effect size in initial studies may cause follow-up studies to be underpowered and so to fail. In this paper, we quantify the impact of the winner's curse on the allele frequency difference and odds ratio estimators for one- and two-stage case-control association studies. We then propose an ascertainment-corrected maximum likelihood method to reduce the bias of these estimators. We show that overestimation of the genetic effect by the uncorrected estimator decreases as the power of the association study increases and that the ascertainment-corrected method reduces absolute bias and mean square error unless power to detect association is high.

PMID:
19140131
PMCID:
PMC2706290
DOI:
10.1002/gepi.20398
[Indexed for MEDLINE]
Free PMC Article

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