Application of an analytical framework for multivariate mediation analysis of environmental data

Abstract

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 framework for multivariate mediation analysis to identify mediation pathways (q = 61 mediators) in the relationship between environmental toxicants (p = 38 analytes) and gestational age at delivery. Our analytical framework includes: (1) conducting pairwise mediation for unique exposure-mediator combinations, (2) exposure dimension reduction by estimating environmental risk scores, and (3) multivariate mediator analysis using either Bayesian shrinkage mediation analysis, population value decomposition, or mediation pathway penalization. Dimension reduction demonstrates that a one-unit increase in phthalate risk score is associated with a total effect of 1.07 lower gestational age (in weeks) at delivery (95% confidence interval: 0.48–1.67) and eicosanoids from the cytochrome p450 pathway mediated 26% of this effect (95% confidence interval: 4–63%). Eicosanoid products derived from the cytochrome p450 pathway may be important mediators of phthalate toxicity.

DNA methylation at birth potentially mediates the association between prenatal lead (Pb) exposure and infant neurodevelopmental outcomes

“…Mediation analyses were conducted to examine whether DNA methylation at each of the CpG sites mediated the association between prenatal Pb exposure and each neurodevelopmental outcome measure ( 50 , 51 ). The analysis was performed using the algorithms previously proposed in Imai et al This incorporates the mediate() function within the mediation package (version 4.5.0) in R ( 52 , 53 ). In this setting, we utilize the counterfactual framework to define causal effects within mediation analysis, which relies on the following assumptions to estimate parameters:…”

Exposome in human health: Utopia or wonderland?

“…For example, an analytical framework for multivariate mediation analysis was introduced to identify mediation pathways of 61 mediators in the relationship between 38 environmental toxicants (phthalates, phenols, polycyclic aromatic hydrocarbons, and metals) and gestational age at delivery. 9 More method Figure 1. Critical-window exposome with prioritized exposure factors increases the feasibility of the conventional exposome in human health risk assessment.…”

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

“…These genomics studies produce various molecular-level traits by measuring gene expression profiles and characterizing different covalent modifications of DNA and histone proteins. The molecular-level traits, including both expression and methylation, have been revealed to mediate the effects of DNA, environments and/or behaviors on many diseases and traits [5] , [19] , [20] , [21] , [22] , [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] , and hold the key to understanding the genetic and environmental foundations of disease susceptibility and phenotypic variation.…”

“…1 B). Mediation analysis is now being routinely carried out in the fields of psychology [69] , [70] , [71] , sociology [65] , [72] , [73] , epidemiology [74] , [75] , [76] , [77] , environmental science [19] , genetics [78] , [79] , [80] , [81] , [82] , [83] , [84] , and appears in a substantial proportion, sometimes more than a third, of research articles published in many disciplines [69] , [85] . Various mediation analyses performed thus far have helped establish the foundation of many important psychological and sociological theories.…”