The Confounder-Mediator Dilemma: Should We Control for Obesity to Estimate the Effect of Perfluoroalkyl Substances on Health Outcomes?

Confounding adjustment is important for observational studies to derive valid effect estimates for inference. Despite the theoretical advancement of confounding selection procedure, it is often challenging to distinguish between confounders and mediators due to the lack of information about the time-ordering and latency of each variable in the data. This is also the case for the studies of perfluoroalkyl substances (PFAS), a group of synthetic chemicals used in industry and consumer products that are persistent and have endocrine-disrupting properties on health outcomes. In this article, we used directed acyclic graphs to describe potential biases introduced by adjusting for or stratifying by the measure of obesity as an intermediate variable in PFAS exposure analyses. We compared results with or without adjusting for body mass index in two cross-sectional data analyses: (1) PFAS levels and maternal thyroid function during early pregnancy using the Danish National Birth Cohort and (2) PFAS levels and cardiovascular disease in adults using the National Health and Nutrition Examination Survey. In these examples, we showed that the potential heterogeneity observed in stratified analyses by overweight or obese status needs to be interpreted cautiously considering collider stratification bias. This article highlights the complexity of seemingly simple adjustment or stratification analyses, and the need for careful consideration of the confounding and/or mediating role of obesity in PFAS studies.