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When interest lies in causal analysis of the effects of multiple exposures on an outcome, one may be interested in investigating the interaction between the exposures. In such settings, causal analysis requires modeling the joint distribution of exposures given pertinent confounding variables. In the most general setting, this may require modeling the effect of confounding variables on the association between exposures via a second-order regression model. We consider joint modeling of exposures for causal analysis via regression adjustment and inverse weighting. In both frameworks, we also investigate the asymptotic bias of estimators when the dependence model for the generalized propensity score incorrectly assumes conditional independence of exposures or is based on a naive dependence model which does not accommodate the effect of confounders on the conditional association of exposures. We also consider the problem of a semi-continuous bivariate exposure and propose a two-stage estimation technique to study the effects of prenatal alcohol exposure, and the effects of drinking frequency and intensity on childhood cognition. [ABSTRACT FROM AUTHOR]

Alcohol consumption during pregnancy can result in a range of adverse postnatal outcomes among exposed children. However, identifying at-risk children is challenging given the difficulty to confirm prenatal alcohol exposure and the lack of early diagnostic tools. Placental surveys present an important opportunity to uncover early biomarkers to identify those at risk. Here, we report the first transcriptome-wide evaluation to comprehensively evaluate human placental pathways altered by fetal alcohol exposure. In a prospective longitudinal birth cohort in Cape Town, South Africa, we performed bulk tissue RNAseq in placenta samples from 32 women reporting heavy drinking during pregnancy and 30 abstainers/light drinkers. Weighted gene co-expression network analysis (WGCNA) and differential gene expression analysis were performed to assess associations between fetal alcohol exposure and placental gene expression patterns at a network-wide and single gene level, respectively. The results revealed altered expression in genes related to erythropoiesis and angiogenesis, which are implicated in established postnatal phenotypes related to alcohol exposure, including disruptions in iron homeostasis, growth, and neurodevelopment. The reported findings provide insights into the molecular pathways affected by prenatal alcohol exposure and highlight the potential of placental biomarkers for detecting and understanding the effects of alcohol on fetal development. [ABSTRACT FROM AUTHOR]