A growing body of literature suggests that developmental
exposure
to individual or mixtures of environmental chemicals (ECs) is associated
with autism spectrum disorder (ASD). However, investigating the effect
of interactions among these ECs can be challenging. We introduced
a combination of the classical exposure-mixture Weighted Quantile
Sum (WQS) regression and a machine-learning method termed Signed iterative
Random Forest (SiRF) to discover synergistic interactions between
ECs that are (1) associated with higher odds of ASD diagnosis, (2)
mimic toxicological interactions, and (3) are present only in a subset
of the sample whose chemical concentrations are higher than certain
thresholds. In a case-control Childhood Autism Risks from Genetics
and Environment (CHARGE) study, we evaluated multiordered synergistic
interactions among 62 ECs measured in the urine samples of 479 children
in association with increased odds for ASD diagnosis (yes vs no).
WQS-SiRF identified two synergistic two-ordered interactions between
(1) trace-element cadmium (Cd) and the organophosphate pesticide metabolite
diethyl-phosphate (DEP); and (2) 2,4,6-trichlorophenol (TCP-246) and
DEP. Both interactions were suggestively associated with increased
odds of ASD diagnosis in the subset of children with urinary concentrations
of Cd, DEP, and TCP-246 above the 75th percentile. This study demonstrates
a novel method that combines the inferential power of WQS and the
predictive accuracy of machine-learning algorithms to discover potentially
biologically relevant chemical–chemical interactions associated
with ASD.