Environment-Wide Association Study of Chemical Biomarkers and Health Outcomes in NHANES 2017-2018: Discovery, Validation, and Dose-Response Analysis

BackgroundEnvironment-wide association studies (ExWAS) offer a systematic approach to identifying chemical biomarker-health outcome associations, yet few have applied rigorous multi-stage validation. MethodsWe screened 92 chemical biomarkers against 48 health outcomes in NHANES 2017-2018 (2,796 tests across four screening rounds; not all chemicals were crossed with all outcomes). Associations passing an initial FDR screen were subjected to cross-cycle validation in NHANES 2015-2016--the primary inferential safeguard given the adaptive screening design--followed by dose-response analysis and multiple sensitivity specifications. Survey-weighted regression models adjusted for age, sex, race/ethnicity, poverty-income ratio, BMI, and smoking. ResultsOf 26 associations passing FDR correction, 21 were testable in cross-cycle validation; of these, 15 (71%) replicated with concordant direction and p < 0.05 in a temporally independent NHANES 2015-2016 sample. Of these 15, 14 remained robust after analyte-specific sensitivity checks; urinary creatinine adjustment identified one association (iodine-BMI) as a dilution artifact. Two novel findings emerged: dimethylarsonic acid with uric acid ({beta} = 0.20 mg/dL per log-unit DMA, 95% CI: 0.15-0.26) and urinary perchlorate with BUN ({beta} = 1.21 mg/dL per log-unit perchlorate, 95% CI: 0.97-1.45); a third high-novelty association (methylmercury-waist circumference) is likely explained by fish consumption patterns. ConclusionsMulti-stage ExWAS with cross-cycle validation identified 14 robust chemical-health associations. Two novel findings--DMA-uric acid and perchlorate-BUN--survived all sensitivity checks and warrant prospective investigation.