Risch N
Department of Epidemiology, Yale University School of Medicine, New Haven, CT.
Am J Hum Genet. 1991 Jun;48(6):1058-64.
Controversy over the impact of multiple testing procedures in linkage analysis is reexamined in this report. Despite some recent claims to the contrary, it is shown that testing multiple markers decreases the posterior false-positive rate among significant tests, rather than increasing it; this is true whether the trait of interest is simply monogenic or complex, or even if the genetic model is misspecified. However, if the true mode of inheritance is complex, or if the genetic model is misspecified, the power to obtain a significant result when linkage is present may be reduced, while the significance level is not, leading to an inflation of the posterior false-positive rate. Furthermore, the posterior false-positive rate increases with decreasing sample size and may be unacceptably high for very small samples. By contrast, testing multiple genetic models, by varying either mode-of-inheritance parameters or diagnostic categories, does lead to an inflation of the posterior false-positive rate. A conservative correction for this case is to subtract log10t from the obtained maximum lod score, where t different genetic and/or diagnostic models have been tested.
本报告重新审视了连锁分析中多重检验程序影响方面的争议。尽管最近有一些相反的说法，但研究表明，对多个标记进行检验会降低显著检验中的后验假阳性率，而非提高该比率；无论感兴趣的性状是单基因的还是复杂的，甚至即使遗传模型被错误设定，情况都是如此。然而，如果真实的遗传模式是复杂的，或者遗传模型被错误设定，当存在连锁时获得显著结果的效能可能会降低，而显著性水平却不会降低，从而导致后验假阳性率升高。此外，后验假阳性率会随着样本量的减小而增加，对于非常小的样本，该比率可能会高到令人无法接受。相比之下，通过改变遗传模式参数或诊断类别来检验多个遗传模型，确实会导致后验假阳性率升高。针对这种情况的一种保守校正方法是，从获得的最大对数优势分数中减去log10t，其中t为已检验的不同遗传和/或诊断模型的数量。
