Statistical methodology in studies of prenatal exposure to mixtures of endocrine-disrupting chemicals: A review of existing approaches and new alternatives

Background: Prenatal exposures to endocrine-disrupting chemicals (EDCs) during critical developmental windows have been implicated in the etiologies of a wide array of adverse perinatal and pediatric outcomes. Epidemiological studies have concentrated on the health effects of individual chemicals, despite the understanding that EDCs act together via common mechanisms, that pregnant women are exposed to multiple EDCs simultaneously, and that substantial toxicological evidence of adverse developmental effects has been documented. There is a move toward multipollutant models in environmental epidemiology; however, there is no current consensus on appropriate statistical methods. Objectives: We aimed to review the statistical methods used in these studies, to identify additional applicable methods, and to determine the strengths and weaknesses of each method for addressing the salient statistical and epidemiological challenges. Methods: We searched Embase, MEDLINE, and Web of Science for epidemiological studies of endocrine-sensitive outcomes in the children of mothers exposed to EDC mixtures during pregnancy and identified alternative statistical methods from the wider literature. Discussion: We identified 74 studies and analyzed the methods used to estimate mixture health effects, identify important mixture components, account for nonmonotonicity in exposure–response relationships, assess interactions, and identify windows of exposure susceptibility. We identified both frequentist and Bayesian methods that are robust to multicollinearity, performing shrinkage, variable selection, dimension reduction, statistical learning, or smoothing, including methods that were not used by the studies included in our review. Conclusions: Compelling motivation exists for analyzing EDCs as mixtures, yet many studies make simplifying assumptions about EDC additivity, relative potency, and linearity, or overlook the potential for bias due to asymmetries in chemical persistence. We discuss the potential impacts of these choices and suggest alternative methods to improve analyses of prenatal exposure to EDC mixtures