论文标题
全基因组关联研究的协变量自适应家庭误率控制
Covariate Adaptive Family-wise Error Rate Control for Genome-Wide Association Studies
论文作者
论文摘要
家庭方面的错误率(FWER)已广泛用于全基因组关联研究中。随着功能基因组数据的可用性的增加,可以通过利用这些基因组功能注释来提高检测能力。以前为了在多次测试中适应协变量的努力将重点放在虚假发现率控制上,而协变量自适应FWER控制程序仍未发达。在这里,我们提出了一种新型的协变量自适应FWER控制程序,该程序结合了外部协变量,该协变量可能会详细介绍统计功率或先前的无效概率。开发了一种有效的算法来实现所提出的方法。我们证明其渐近有效性,并通过扰动型参数获得收敛速度。我们的数值研究表明,新程序比竞争方法更强大,并且在不同环境中保持稳健性。我们将提出的方法应用于英国生物库数据,并分析了27种针对关联测试的单核苷酸多态性的特征。 75个基因组注释用作协变量。我们的方法比27个特征中的21种方法检测到全基因组更重要的基因座。
The family-wise error rate (FWER) has been widely used in genome-wide association studies. With the increasing availability of functional genomics data, it is possible to increase the detection power by leveraging these genomic functional annotations. Previous efforts to accommodate covariates in multiple testing focus on the false discovery rate control while covariate-adaptive FWER-controlling procedures remain under-developed. Here we propose a novel covariate-adaptive FWER-controlling procedure that incorporates external covariates which are potentially informative of either the statistical power or the prior null probability. An efficient algorithm is developed to implement the proposed method. We prove its asymptotic validity and obtain the rate of convergence through a perturbation-type argument. Our numerical studies show that the new procedure is more powerful than competing methods and maintains robustness across different settings. We apply the proposed approach to the UK Biobank data and analyze 27 traits with 9 million single-nucleotide polymorphisms tested for associations. Seventy-five genomic annotations are used as covariates. Our approach detects more genome-wide significant loci than other methods in 21 out of the 27 traits.