Approaches for incorporating environmental mixtures as mediators in mediation analysis

Mediation analysis offers an essential and rapidly expanding tool in environmental health studies to investigate the contribution of environmental factors towards observed associations between risk factors and health outcomes. When evaluating environmental factors, there may be particular interest in quantifying the impact of exposure to environmental mixtures on human health. In this context, evaluating the joint effect of multiple chemicals or pollutants, rather than individual examination, allows accurate identification of risk factors, assessment of interactions, and ultimately development of more targeted public health interventions. While mediation analysis has been extended to incorporate several methodological complexities specific to environmental factors, little attention has been given to integrating the analysis of environmental mixtures. The aim of this review is to present some of the available methods for environmental mixtures, and discuss how these methods can be integrated within a mediation analysis framework. By incorporating these methods into a mediation framework, investigators will be able to evaluate the contribution of environmental mixtures as mediators of exposure-outcome associations, based on methodologies that are currently available. While standard regression-based methods for multiple mediators can be used, these can easily become unstable as the number of mixture components increases. Summary and classification methods, or hierarchical modeling, can reduce the number of mediators by creating scores or possibly uncorrelated subgroups. This approach allows retrieving indirect effects due to the mixture or to a specific subgroup, but makes identification of component-specific effects and interactions complicated. Finally, one can use various approaches for analyzing mixtures in a two-stage fashion, selecting relevant mediators to be included in the final model. We focused this review on techniques that have been presented to the environmental health community and that can be conducted with major statistical software. We encourage researchers to move beyond the evaluation of one environmental factor at a time to the assessment of the joint effects of environmental mixtures when a mediation model is of interest. Available methods target different aspects related to environmental mixtures and the choice of the suitable approach will depend on data structures and the research question of interest.