Statistical methods for mediation analysis in the era of high-throughput genomics: Current successes and future challenges

Mediation analysis investigates the intermediate mechanism through which an exposure exerts its influence on the outcome of interest. Mediation analysis is becoming increasingly popular in high-throughput genomics studies where a common goal is to identify molecular-level traits, such as gene expression or methylation, which actively mediate the genetic or environmental effects on the outcome. Mediation analysis in genomics studies is particularly challenging, however, thanks to the large number of potential mediators measured in these studies as well as the composite null nature of the mediation effect hypothesis. Indeed, while the standard univariate and multivariate mediation methods have been well-established for analyzing one or multiple mediators, they are not well-suited for genomics studies with a large number of mediators and often yield conservative p-values and limited power. Consequently, over the past few years many new high-dimensional mediation methods have been developed for analyzing the large number of potential mediators collected in high-throughput genomics studies. In this work, we present a thorough review of these important recent methodological advances in high-dimensional mediation analysis. Specifically, we describe in detail more than ten high-dimensional mediation methods, focusing on their motivations, basic modeling ideas, specific modeling assumptions, practical successes, methodological limitations, as well as future directions. We hope our review will serve as a useful guidance for statisticians and computational biologists who develop methods of high-dimensional mediation analysis as well as for analysts who apply mediation methods to high-throughput genomics studies.