Causal Mediation Analysis for Estimating Direct and Indirect Effects of an Environmental Mixture on Child Neurodevelopment

Background/Aim: Current research suggests exposure to chemical mixtures has detrimental effects on health. New statistical methodology is needed to formalize the natural direct effect (NDE), natural indirect effect (NIE), and controlled direct effect (CDE) of a mixture of exposures on an outcome through an intermediate variable. Methods: We implemented Monte Carlo methods to estimate the NDE, NIE and CDE, through simulation of counterfactuals. This method allows for nonlinear effects and interactions between the co-exposures, mediator and covariates. Confidence intervals are obtained via bootstrapping. We applied this methodology to quantify the contribution of birth length as a mediator between in utero co-exposure of arsenic, manganese and lead, and children’s neurodevelopment, in a prospective birth cohort in rural Bangladesh. Results: We found nonlinear associations of arsenic and lead with birth length, and of manganese with neurodevelopment, and a significant interaction between arsenic and manganese on neurodevelopment. There was a significant negative association between the metal mixture and neurodevelopment, independent of birth length, comparing the co-exposure of metals at their 75th percentiles to their 25th percentiles (NDE: -0.06, 95% CI: -0.12, -0.01). The percent mediated through fetal growth was estimated to be 70%, although, the indirect effect of birth length was marginally significant (NIE: -0.13, 95% CI: -0.34, 0.08). Upon hypothetical intervention to fix birth length at the 75th percentile value of 48cm, the direct effect was no longer significant, suggesting, targeted interventions on fetal growth can block part of the adverse effect of metals on neurodevelopment (CDE: -0.07, 95% CI: -0.28, 0.15). Conclusions: Our extension of causal mediation methodology that allows for a mixture of exposures is important for environmental health applications. Applying these methods, we found a negative association of co-exposure to lead, arsenic, and manganese on neurodevelopment, independent of in utero growth, and suggestive evidence growth partially mediates the mixture.