An external exposome-wide association study of COVID-19 mortality in the United States.

The risk factors for severe COVID-19 beyond older age and certain underlying health conditions are largely unknown. Recent studies suggested that long-term environmental exposures may be important determinants of severe COVID-19. However, very few environmental factors have been studied, often separately, without considering the totality of the external environment (i.e., the external exposome). We conducted an external exposome-wide association study (ExWAS) using the nationwide county-level COVID-19 mortality data in the contiguous US. A total of 337 variables characterizing the external exposome from 8 data sources were integrated, harmonized, and spatiotemporally linked to each county. A two-phase procedure was used: (1) in Phase 1, a random 50:50 split divided the data into a discovery set and a replication set, and associations between COVID-19 mortality and individual factors were examined using mixed-effect negative binomial regression models, with multiple comparisons addressed, and (2) in Phase 2, a multivariable regression model including all variables that are significant from both the discovery and replication sets in Phase 1 was fitted. A total of 13 and 22 variables were significant in the discovery and replication sets in Phase 1, respectively. All the 4 variables that were significant in both sets in Phase 1 remained statistically significant in Phase 2, including two air toxicants (i.e., nitrogen dioxide or NO, and benzidine), one vacant land measure, and one food environment measure. This is the first external exposome study of COVID-19 mortality. It confirmed some of the previously reported environmental factors associated with COVID-19 mortality, but also generated unexpected predictors that may warrant more focused evaluation.