Application of a novel analytical pipeline for high-dimensional multivariate mediation analysis of environmental data

Diverse toxicological mechanisms may mediate the impact of environmental toxicants (phthalates, phenols, polycyclic aromatic hydrocarbons, and metals) on pregnancy outcomes. In this study we introduce an analytical pipeline for high-dimensional mediation analysis to identify mediation pathways (q = 63 mediators) in the relationship between environmental toxicants (p = 38 analytes) and gestational age at delivery. Our analytical pipeline included: (1) conducting pairwise mediation for unique exposure-mediator combinations, (2) subjecting mediators to Bayesian shrinkage mediation analysis and population value decomposition, and (3) exposure dimension reduction by estimating environmental risk scores. Dimension reduction demonstrated that a one unit increase in phthalate risk score was associated with a total effect of 1.09 lower gestational age (in weeks) at delivery (95% confidence interval: 1.78 - 0.36) and eicosanoids from the cytochrome p450 pathway mediated 24.5% of this effect (95% confidence interval: 4%-66%). Eicosanoid products derived from the cytochrome p450 pathway may be important mediators of phthalate toxicity.