Probability of detecting disease-associated single nucleotide polymorphisms in case-control genome-wide association studies
Probability of detecting disease-associated single nucleotide polymorphisms in case-control genome-wide association studies
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DOI：
10.1093/biostatistics/kxm032
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发表时间：
2008-04-01
期刊：
影响因子：
2.1
通讯作者：
Pee, David
中科院分区：
文献类型：
--
作者：
Gail, Mitchell H.;Pfeiffer, Ruth M.;Pee, David
一些病例对照全基因组关联研究(CCGWASs)通过对相应的p值进行排序，而不是通过对每个SNP应用相同的p值阈值来选择有前景的单核苷酸多态(SNPs)。对于这样的研究，我们将特定疾病相关SNP的检测概率(DP)定义为该SNP将被“T-选择”的概率，即具有用于关联趋势检验的前T个最大卡方值(或最小P值)之一。相应的阳性比例(PP)是选定的SNPs中真正与疾病相关的SNPs的比例。我们对遗传风险的固定效应模型和随机效应模型的DP和PP进行了分析和模拟研究，这些模型允许遗传风险的异质性。Dp随遗传效应大小和病例对照样本量的增加而增加，随非疾病相关SNPs数目的增加而减少，主要通过T/N之比，即SNPs总数来实现。我们发现，Dp随T的增加非常缓慢，而单位Dp随T的增加而迅速下降，如果真实疾病SNPs的数量超过T，Dp也会减少。对于1.2或更低的每个小病等位基因的遗传优势比，即使是具有1000个病例和1000个对照的CCGWAS也要求T非常大才能达到可接受的Dp，导致PP值如此低，从而使研究变得徒劳和具有误导性。我们进一步计算了使研究计划的总成本最小化所需的初始CCGWAS的样本量，该研究计划还包括对T选择的SNPs进行后续研究。如果遗传效应很小或后续研究的费用很大，那么大的初始CCGWAS是可取的。
Some case-control genome-wide association studies (CCGWASs) select promising single nucleotide polymorphisms (SNPs) by ranking corresponding p-values, rather than by applying the same p-value threshold to each SNP. For such a study, we define the detection probability (DP) for a specific disease-associated SNP as the probability that the SNP will be "T-selected," namely have one of the top T largest chi-square values (or smallest p-values) for trend tests of association. The corresponding proportion positive (PP) is the fraction of selected SNPs that are true disease-associated SNPs. We study DP and PP analytically and via simulations, both for fixed and for random effects models of genetic risk, that allow for heterogeneity in genetic risk. DP increases with genetic effect size and case-control sample size and decreases with the number of nondisease-associated SNPs, mainly through the ratio of T to N, the total number of SNPs. We show that DP increases very slowly with T, and the increment in DP per unit increase in T declines rapidly with T. DP is also diminished if the number of true disease SNPs exceeds T. For a genetic odds ratio per minor disease allele of 1.2 or less, even a CCGWAS with 1000 cases and 1000 controls requires T to be impractically large to achieve an acceptable DP, leading to PP values so low as to make the study futile and misleading. We further calculate the sample size of the initial CCGWAS that is required to minimize the total cost of a research program that also includes follow-up studies to examine the T-selected SNPs. A large initial CCGWAS is desirable if genetic effects are small or if the cost of a follow-up study is large.