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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]

Prenatal alcohol exposure (PAE) can result in cognitive and behavioral disabilities and growth deficits. Because alcohol-related neurobehavioral deficits may occur in the absence of overt dysmorphic features or growth deficits, there is a need to identify biomarkers of PAE that can predict neurobehavioral impairment. In this study, we assessed infant plasma extracellular, circulating miRNAs (exmiRNAs) obtained from a heavily exposed Cape Town cohort to determine whether these can be used to predict PAE-related growth restriction and cognitive impairment. PAE, controlling for smoking as a covariate, altered 27% of expressed exmiRNAs with clinically-relevant effect sizes (Cohen's d ≥ 0.4). Moreover, at 2 weeks, PAE increased correlated expression of exmiRNAs across chromosomes, suggesting potential co-regulation. In confirmatory factor analysis, the variance in expression for PAE-altered exmiRNAs at 2 weeks and 6.5 months was best described by three-factor models. Pathway analysis found that factors at 2 weeks were associated with (F1) cell maturation, cell cycle inhibition, and somatic growth, (F2) cell survival, apoptosis, cardiac development, and metabolism, and (F3) cell proliferation, skeletal development, hematopoiesis, and inflammation, and at 6.5 months with (F1) neurodevelopment, neural crest/mesoderm-derivative development and growth, (F2) immune system and inflammation, and (F3) somatic growth and cardiovascular development. Factors F3 at 2 weeks and F2 at 6.5 months partially mediated PAE-induced growth deficits, and factor F3 at 2 weeks partially mediated effects of PAE on infant recognition memory at 6.5 months. These findings indicate that infant exmiRNAs can help identify infants who will exhibit PAE-related deficits in growth and cognition. [ABSTRACT FROM AUTHOR]

Diffusion tensor imaging (DTI) studies have shown that prenatal exposure to methamphetamine is associated with alterations in white matter microstructure, but to date no tractography studies have been performed in neonates. The striato-thalamo-orbitofrontal circuit and its associated limbic-striatal areas, the primary circuit responsible for reinforcement, has been postulated to be dysfunctional in drug addiction. This study investigated potential white matter changes in the striatal-orbitofrontal circuit in neonates with prenatal methamphetamine exposure. Mothers were recruited antenatally and interviewed regarding methamphetamine use during pregnancy, and DTI sequences were acquired in the first postnatal month. Target regions of interest were manually delineated, white matter bundles connecting pairs of targets were determined using probabilistic tractography in AFNI-FATCAT, and fractional anisotropy (FA) and diffusion measures were determined in white matter connections. Regression analysis showed that increasing methamphetamine exposure was associated with reduced FA in several connections between the striatum and midbrain, orbitofrontal cortex, and associated limbic structures, following adjustment for potential confounding variables. Our results are consistent with previous findings in older children and extend them to show that these changes are already evident in neonates. The observed alterations are likely to play a role in the deficits in attention and inhibitory control frequently seen in children with prenatal methamphetamine exposure. [ABSTRACT FROM AUTHOR]

Identification of children with fetal alcohol spectrum disorders (FASD) is difficult because information regarding prenatal exposure is often lacking, a large proportion of affected children do not exhibit facial anomalies, and no distinctive behavioral phenotype has been identified. Castellanos and Tannock have advocated going beyond descriptive symptom-based approaches to diagnosis to identify biomarkers derived from cognitive neuroscience. Classical eyeblink conditioning and magnitude comparison are particularly promising biobehavioral markers of FASD-eyeblink conditioning because a deficit in this elemental form of learning characterizes a very large proportion of alcohol-exposed children; magnitude comparison because it is a domain of higher order cognitive function that is among the most sensitive to fetal alcohol exposure. Because the neural circuitry mediating both these biobehavioral markers is well understood, they have considerable potential for advancing understanding of the pathophysiology of FASD, which can contribute to development of treatments targeted to the specific deficits that characterize this disorder. [ABSTRACT FROM AUTHOR]

Objectives: Inuit in Canada experience alarming levels of food insecurity, but nutritional and physiological consequences are poorly documented, especially in school-age children. The objective of this study was to assess the relation of food insecurity to iron deficiency and stature in school-aged Inuit children from Nunavik (Northern Quebec)., Methods: Food insecurity, iron deficiency, and stature were assessed in a cohort of children. Food insecurity was determined by interviewing the children's mothers. Multiple logistic regression was used to evaluate the association of food insecurity to iron deficiency and short stature. We defined short stature as a height in the lowest tertile for age and sex, based on Canadian growth charts. The relation of food insecurity to height (cm) was analyzed with a general linear model. Statistical models controlled for age, sex, normal/overweight/obese status, prenatal lead exposure and postnatal polychlorinated biphenyls exposure., Results: Half of the children (49.7%, n=145) were food insecure, while one third were iron depleted, 12.6% had anaemia, and 8.7% had iron-deficiency anaemia. The multivariate odds ratio of anaemia was 1.82 (95% CI: 0.97, 3.42, p=0.06) for food-insecure children. Prevalence of short stature was 18.7%. Food-insecure children were an average of 2 cm shorter (95% CI: -0.48, -3.17) than food-secure children (p<0.01)., Conclusion: In this population, food-insecure children have greater burdens of nutritional deficiencies and slower linear growth. Considering the high prevalence of food insecurity among Inuit children in Nunavik, nutritional deficiencies and adverse effects on development should be carefully monitored.