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Background:

Mediation analysis is used in epidemiology to identify pathways through which exposures influence health. The advent of high-throughput (omics) technologies gives opportunities to perform mediation analysis with a high-dimension pool of covariates.

Objective:

We aimed to highlight some biostatistical issues of this expanding field of high-dimension mediation.

Discussion:

The mediation techniques used for a single mediator cannot be generalized in a straightforward manner to high-dimension mediation. Causal knowledge on the relation between covariates is required for mediation analysis, and it is expected to be more limited as dimension and system complexity increase. The methods developed in high dimension can be distinguished according to whether mediators are considered separately or as a whole. Methods considering each potential mediator separately do not allow efficient identification of the indirect effects when mutual influences exist among the mediators, which is expected for many biological (e.g., epigenetic) parameters. In this context, methods considering all potential mediators simultaneously, based, for example, on data reduction techniques, are more adapted to the causal inference framework. Their cost is a possible lack of ability to single out the causal mediators. Moreover, the ability of the mediators to predict the outcome can be overestimated, in particular because many machine-learning algorithms are optimized to increase predictive ability rather than their aptitude to make causal inference. Given the lack of overarching validated framework and the generally complex causal structure of high-dimension data, analysis of high-dimension mediation currently requires great caution and effort to incorporate a priori biological knowledge. https://doi.org/10.1289/EHP6240