Erratum: Delta-Centralization Fails to Control for Population Stratification in Genetic Association Studies

<i>Objective:</i> To investigate the validity of simulations and assumptions used to underpin the delta-centralization (DC) method for correcting for population stratification in genetic association studies; to assess the effectiveness of DC compared to genomic control (GC) under valid simulation conditions; and to highlight other studies employing similarly flawed simulations. <i>Methods:</i> DC and GC use data from unlinked null loci to correct the test statistic at the target locus, but differ in the way the correction is performed. We compare DC and GC under two simulation approaches: an invalid approach adopted by the originators of DC, which permits subpopulation allele frequency matching of null markers to the target locus; and a valid approach, based on the Balding-Nichols model, which does not allow subpopulation matching. <i>Results:</i> DC works under invalid simulation conditions (subpopulation allele frequency matching), but not under our valid ones. We use theoretical arguments to assert that there are no valid conditions under which DC might work. We identify several studies which have adopted similarly invalid simulation approaches in this field. <i>Conclusion:</i> DC fails to control for population stratification and should not be used. Other results from studies which have used the same invalid simulation approach should be treated cautiously.

研究目标：探究用于支撑遗传关联研究中校正群体分层（population stratification）的Δ中心化（delta-centralization, DC）方法所依赖的模拟实验与假设的有效性；评估在合规模拟条件下，DC相较于基因组控制（genomic control, GC）的校正效果；并指出其他采用类似缺陷模拟方案的研究。
研究方法：DC与GC均通过未连锁的零位点数据校正目标位点的检验统计量，但二者的校正流程存在差异。本研究在两类模拟框架下对比DC与GC的表现：其一为DC提出者所采用的不合规框架，该框架允许零位点标记与目标位点进行亚种群等位基因频率匹配；其二为基于鲍尔丁-尼科尔斯模型（Balding-Nichols model）的合规框架，该框架不允许亚种群匹配操作。
研究结果：DC仅在不合规的模拟条件（即允许零位点标记与目标位点进行亚种群等位基因频率匹配）下可正常发挥校正作用，而在本研究采用的合规模拟条件下失效。本研究通过理论论证表明，DC不存在可生效的合规应用场景。此外，本研究还识别出该领域内多篇采用同类缺陷模拟方案的研究。
研究结论：DC无法实现群体分层校正，因此不应被采用。针对采用该类不合规模拟方案的研究所得出的其他结果，应谨慎采信。