Joint significance tests for mediation effects of socioeconomic adversity on adiposity via epigenetics

Abstract

Mediation analysis has become a popular practice in biomedical research. We conduct mediation analyses to investigate whether epigenetic variations mediate the effect of socioeconomic disadvantage on adiposity. Mediation effects can be expressed as a product of two parameters: one for the exposure-mediator association and the other for the mediator-outcome association conditional on the exposure. Under multi-mediator models, we study joint significance tests which examine the two parameters separately and compare with the widely used product significance tests which focus on the product of two parameters. Normal approximation of product significance tests depends on both effect size and sample size. We show that joint significance tests are intersection-union tests with size $\alpha$ and asymptotically more powerful than the normality-based product significance tests. Based on the theoretical results, we construct powerful testing procedures for gene-based mediation analyses and path-specific analyses. Advantage of joint significance tests is supported by simulation as well as the results of locus-based and gene-based mediation analyses of chromosome 17. Our analyses suggest that methylation of FASN gene mediates the effect of socioeconomic adversity on adiposity.