An Exposome-Wide Interaction Study to Identify Hidden Environmental Factors Affecting Susceptible Populations: Application to Chemical-Social Vulnerability Interactions on Cognitive Function

Background Exposome-wide association studies (ExWAS) systematically evaluate numerous environmental exposures, but typically focus on the mean effect, determining whether the association is statistically significant for the average individual. This approach may overlook environmental chemicals that specifically affect susceptible subpopulations. We conducted an exposome-wide interaction study (ExWIS) to identify environmental chemicals associated with cognitive function in the context of social vulnerability.

We examined associations between 147 biomarker-based chemicals and cognitive function among 4,982 adults aged 60 and older in the National Health and Nutrition Examination Survey (NHANES) 1999-2000 and 2011-2014. Social vulnerability index (SVI) was calculated as a composite measure encompassing race/ethnicity, income, education, health insurance, housing type, food security, and employment. Initially, we ran survey-weighted linear regressions between each chemical and cognition, adjusting for SVI, age, sex, smoking status, serum cotinine, fish consumption, NHANES cycle, and urinary creatinine (marginal association models). Subsequently, we repeated these models with a linear interaction term between each chemical and SVI (interaction models).

In marginal association models, 16 chemicals including smoking-related compounds, polyaromatic hydrocarbons, and metals were associated with cognitive function (unadjusted p<0.05). In interaction models, four additional chemicals–urinary mercury, diethylthiophosphate, perfluorononanoate, and perfluoroundecanoate–not identified in the marginal association models showed significant interactions with SVI.

This study demonstrates the utility of the ExWIS framework to identify environmental factors that affect susceptible populations but may be missed by the mean effect-based ExWAS approach. Considering interaction effects is essential for accurate environmental risk assessment and identification of neurotoxicants in at-risk populations. HIGHLIGHTS In a nationally representative sample of older adults, chemical exposures and social factors are cross-sectionally associated with cognitive function. Proof of concept exposome-wide interaction study (ExWIS) demonstrates jointly incorporating chemicals and social factors identifies exposures relevant for susceptible populations. The hypothesis generating ExWIS approach presented here may be broadly relevant for other outcomes and studies. Competing Interest Statement The authors have declared no competing interest. Funding Statement This analysis was supported by the National Institute on Aging (R01 AG070897, K01 AG084821, P30 AG072931) and the National Institute for Environmental Health Sciences (P30 ES017885). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All NHANES data are publicly available through the US National Center for Health Statistics (https://www.n.cdc.gov/nchs/nhanes/default.aspx). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Statement All NHANES data are publicly available through the US National Center for Health Statistics. Code to produce these analyses and graphics is available through GitHub (https://github.com/bakulskilab/Cognition_SVI_ExWIS).