Vision for Exposomics-Scale Investigation: A Heuristic for Exposure-Wide Association Studies (ExWAS).

Exposomics has the potential to revolutionize biomedical research. However, the transition from hypothesis-driven to discovery-driven research has created tension between expansive screening and the risk of false discoveries. To meet the rigorous expectations of funders, editors, and the broader scientific community, the field requires clear benchmarks for a specific discovery-oriented design within exposomics: the Exposure-Wide Association Study (ExWAS). Here, we propose a heuristic framework for ExWAS based on the 5 I's: Inclusive, Informative, Immense, Integrative, and Iterative. We distinguish ExWAS from the broader enterprise of exposomics: high-resolution personal sensor studies, high-throughput screening in model systems, targeted biomonitoring, and single-exposure causal studies are essential and complementary. We operationalize each 'I' as a set of graded thresholds rather than absolute gates, so that smaller groups and under-resourced cohorts can participate through federated and meta-analytic designs. Mirroring the systematic rigor of genomics, these criteria provide a roadmap for minimizing spurious associations while preserving discovery power and supporting the eventual creation of an "Exposome-Phenome Catalog" analogous to the GWAS Catalog.