Xiao Rui, Boehnke Michael
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, USA.
Genet Epidemiol. 2009 Jul;33(5):453-62. doi: 10.1002/gepi.20398.
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.
基因关联研究是检测导致人类疾病的基因变异的有力工具。一旦确定了一个相关变异,研究人员也会对估计所确定的变异对疾病风险的影响感兴趣。由于一种被称为“胜者诅咒”的现象,基于新的关联发现对基因效应的估计往往存在向上偏差。在初始研究中对基因效应大小的高估可能会导致后续研究缺乏足够的效力,从而失败。在本文中,我们量化了胜者诅咒对一阶段和两阶段病例对照关联研究中等位基因频率差异和优势比估计值的影响。然后,我们提出一种确认校正的最大似然方法来减少这些估计值的偏差。我们表明,未校正估计值对基因效应的高估会随着关联研究的效力增加而降低,并且除非检测关联的效力很高,否则确认校正方法会降低绝对偏差和均方误差。