Abstract
BackgroundHumans are exposed to mixtures of chemicals across their lifetimes, a concept sometimes called the “exposome.” Mixtures likely have temporal “critical windows” of susceptibility like single agents and measuring them repeatedly might help to define such windows. Common approaches to evaluate the effects of chemical mixtures have focused on their effects at a single time point. Our goal is to expand upon these previous techniques and examine the time-varying critical windows for metal mixtures on subsequent neurobehavior in children.MethodsWe propose two methods, joint weighted quantile sum regression (JWQS) and meta-weighted quantile sum regression (MWQS), to estimate the effects of chemical mixtures measured across multiple time points, while providing data on their critical windows of exposure. We compare the performance of both methods using simulations. We also applied both techniques to assess second and third trimester metal mixture effects in predicting performance in the Rapid Visual Processing (RVP) task from the Cambridge Neuropsychological Test Automated Battery (CANTAB) assessed at 6–9 years in children who are part of the PROGRESS (Programming Research in Obesity, GRowth, Environment and Social Stressors) longitudinal cohort study. The metals, arsenic, cadmium (Cd), cesium, chromium, lead (Pb) and antimony (Sb) were selected based on their toxicological profile.ResultsIn simulations, JWQS and MWQS had over 80% accuracy in classifying exposures as either strongly or weakly contributing to an association. In real data, both JWQS and MWQS consistently found that Pb and Cd exposure jointly predicted longer latency in the RVP and that second trimester exposure better predicted the results than the third trimester. Additionally, both JWQS and MWQS highlighted the strong association Cd and Sb had with lower accuracy in the RVP and that third trimester exposure was a better predictor than second trimester exposure.ConclusionsOur results indicate that metal mixtures effects vary across time, have distinct critical windows and that both JWQS and MWQS can determine longitudinal mixture effects including the cumulative contribution of each exposure and critical windows of effect.
Highlights
Humans are exposed to mixtures of chemicals across their lifetimes, a concept sometimes called the “exposome.” Mixtures likely have temporal “critical windows” of susceptibility like single agents and measuring them repeatedly might help to define such windows
Overall both methods perform well in both scenarios, with an overall accuracy of at least 83.2% for both methods in the two scenarios. We find that both joint weighted quantile sum regression (JWQS) and meta-weighted quantile sum regression (MWQS) perform better in terms of accuracy when the two time points have similar contributions
We see that the correlation structure is complex but that that there is a high correlation for the same metal measured at the two different time points
Summary
Humans are exposed to mixtures of chemicals across their lifetimes, a concept sometimes called the “exposome.” Mixtures likely have temporal “critical windows” of susceptibility like single agents and measuring them repeatedly might help to define such windows. The most relevant mixture may not be defined cross-sectionally but may instead reflect joint exposure across time, i.e., a multi-hit hypothesis [5]. Defining mixtures solely as cross-sectional combinations of joint exposure, even longitudinally, could miss mixture effects that occur across time. Chemical “a” measured in the second trimester of pregnancy might not interact with chemical “b” measured in the second trimester, but may instead interact with chemical “b” measured in the third trimester This creates the need and opportunity to develop methods to better fit mixtures research into accepted biological theories such as developmental origins of health and disease (DOHaD), multi-hit hypotheses and critical windows of susceptibility. DOHaD, multi-hit hypotheses and critical windows all converge in prenatal life and uncovering periods of heightened windows of susceptibility is of great interest, if they occur in a longitudinal, sequential manner
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