4.6 Article

A Multiple-Testing Procedure for High-Dimensional Mediation Hypotheses

Journal

JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION
Volume 117, Issue 537, Pages 198-213

Publisher

TAYLOR & FRANCIS INC
DOI: 10.1080/01621459.2020.1765785

Keywords

Composite null hypothesis; Intersection-union test; Joint significance; Mediation analysis

Funding

  1. National Institute of Health [R01 CA222833, U10CA180819, U01 CA182883, P50CA097186]

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Mediation analysis is gaining attention in epidemiologic studies and clinical trials, but existing methods have limitations. In this article, a multiple-testing procedure is proposed to accurately control error rates and improve power. Two data analysis examples demonstrate the effectiveness of the proposed method, and an R package is provided for implementation.
Mediation analysis is of rising interest in epidemiologic studies and clinical trials. Among existing methods, the joint significance test yields an overly conservative Type I error rate and low power, particularly for high-dimensional mediation hypotheses. In this article, we develop a multiple-testing procedure that accurately controls the family-wise error rate (FWER) and the false discovery rate (FDR) when testing high-dimensional mediation hypotheses. The core of our procedure is based on estimating the proportions of component null hypotheses and the underlying mixture null distribution ofp-values. Theoretical developments and simulation experiments prove that the proposed procedure effectively controls FWER and FDR. Two mediation analyses on DNA methylation and cancer research are presented: assessing the mediation role of DNA methylation in genetic regulation of gene expression in primary prostate cancer samples; exploring the possibility of DNA methylation mediating the effect of exercise on prostate cancer progression. Results of data examples include well-behaved quantile-quantile plots and improved power to detect novel mediation relationships. An R package HDMT implementing the proposed procedure is freely accessible in CRAN.for this article are available online.

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