A Hierarchical Meta-Analysis for Settings Involving Multiple Outcomes across Multiple Cohorts

Abstract: Evidence from animal models and epidemiological studies has linked prenatal alcohol exposure (PAE) to a broad range of long-term cognitive and behavioral deficits. However, there is virtually no information in the scientific literature regarding the levels of PAE associated with an increased risk of clinically significant adverse effects. During the period from 1975-1993, several prospective longitudinal cohort studies were conducted in the U.S., in which maternal reports regarding alcohol use were obtained during pregnancy and the cognitive development of the offspring was assessed from early childhood through early adulthood. The sample sizes in these cohorts did not provide sufficient power to examine effects associated with different levels and patterns of PAE. To address this critical public health issue, we have developed a hierarchical meta-analysis to synthesize information regarding the effects of PAE on cognition, integrating data on multiple endpoints from six U.S. longitudinal cohort studies. Our approach involves estimating the dose-response coefficients for each endpoint and then pooling these correlated dose-response coefficients to obtain an estimated `global' effect of exposure on cognition. In the first stage, we use individual participant data to derive estimates of the effects of PAE by fitting regression models that adjust for potential confounding variables using propensity scores. The correlation matrix characterizing the dependence between the endpoint-specific dose-response coefficients estimated within each cohort is then run, while accommodating incomplete information on some endpoints. We also compare and discuss inferences based on the proposed approach to inferences based on a full multivariate analysis