Comorbidity Exposure-Window Definitions and Multidimensional Disparities in Long COVID Risk: Evidence from a U.S. National Cohort (2020-2024)
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Long COVID (LC) affects millions of individuals worldwide, particularly those with preexisting comorbidities. However, whether these comorbidities should be defined before SARS-CoV-2 infection or before LC diagnosis remains unresolved, and this methodological choice may substantially bias estimates of comorbidity-associated LC risk. In addition, most previous studies were conducted during earlier phases of the pandemic and relied on relatively small or geographically restricted cohorts, limiting understanding of temporal trends and population disparities in LC risk. Leveraging Electronic Health Records (EHR) from 6,130,413 adults with documented COVID-19 across 49 U.S. states in the National COVID Cohort Collaborative (N3C) from 2020 to 2024, we evaluated the impact of different comorbidity exposure-window definitions on LC risk estimation. We utilized ensemble cross-fitted double/debiased machine learning to adjust for complex individual- and county-level confounders. Across the 16 major comorbidities evaluated, defining conditions before SARS-CoV-2 infection, rather than before LC diagnosis, yielded 23%-115% higher adjusted attributable risks and 6%-37% higher adjusted relative risks. Additionally, comorbidity-associated risks generally declined from 2020 to 2024, with substantial demographic, socioeconomic, geographic, and multimorbidity-related disparities persisting throughout the study period. These findings identify temporal exposure-window specification as a major source of bias in LC epidemiology. Failure to distinguish preexisting comorbidities from conditions identified during postinfection follow-up can substantially alter estimates of disease burden, the identification of high-risk populations, and the interpretation of temporal and geographic disparities. More broadly, our results highlight how temporal misclassification of exposures in longitudinal EHR studies can distort risk attribution and population-level inference.
Source: medRxiv
Institutions: University of Georgia, University of California, Berkeley
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Center for Clinical and Translational Sciences (CCTS), The OSU Center for Clinical and Translational Science: Advancing Today's Discoveries to Improve Health, University of Massachusetts Center for Clinical and Translational Science, Wake Forest Clinical and Translational Science Award, Together: Transforming and Translating Discovery to Improve Health, Georgetown-Howard Universities Center for Clinical and Translational Science (GHUCCTS), Duke CTSA, Center for Clinical and Translational Science, The Harvard Clinical and Translational Science Center, Stanford Center for Clinical & Translational Education and Research (Spectrum), UNM HSC Clinical and Translational Science Center, University of Minnesota Clinical and TranslationalmScience Institute (UMN CTSI), Institute for Clinical and Translational Science, Tufts Clinical and Translational Science Institute, The integrated Translational Health Research Institute of Virginia (iTHRIV): Using Data to Improve Health, MSHS Translational Science Hub, A National Center for Digital Health Informatics Innovation, Northwestern University Clinical and Translational Science Institute (NUCATS), Center for Clinical and Translational Research, Center for Clinical and Translational Science and Training, Miami Clinical and Translational Science Institute, Expanding Translational Research in Arkansas, Utah Center for Clinical and Translational Science, American Indian - Alaska Native Clinical and Translational Research Center (AI-AN CTRC), Clinical and Translational Science Award, North Carolina Translational and Clinical Science Institute (NC TraCS), Michigan Institute for Clinical and Health Research (MICHR), Hispanic Alliance for Clinical and Translational Research (Alliance), Scripps Translational Science Institute, New Jersey Alliance for Clinical Translational Science: NJ ACTS, Clinical and Translational Science Institute at Childrens National, The University of Rochester Clinical and Translational Science Award Hub, Indiana Clinical and Translational Sciences Institute, Clinical and Translational Science Award, Clinical and Translational Science Award, Johns Hopkins Institute for Clinical and Translational Research, The University of Iowa Clinical and Translational Science Award, University of Buffalo Clinical and Translational Science Institute, Institute for Integration of Medicine & Science: A Partnership to Improve Health, Colorado Clinical and Transational Sciences Institute, South Carolina Clinical & Translational Research Institute (SCTR), Boston University Clinical and Translational Science Institute, Clinical and Translational Science Collaborative of Cleveland, UC San Diego Clinical and Translational Research Institute, Frontiers Clinical and Translational Science Institute at the University of Kansas, Advance Clinical and Translational Research (Advance-CTR), Clinical and Translational Science Award, University of Pittsburgh Clinical and Translational Science Institute, UC Davis Clinical and Translational Science Center, Northern New England Clinical and Translational Research Network, University of Wisconsin Institute for Clinical and Translational Research, Clinical and Translational Science Center, Mayo Clinic Center for Clinical and Translational Science (CCaTS), West Virginia Clinical and Translational Science Institute: A Statewide Organization Building Research Excellence and Engaging Communities to Improve Health, Refining Predictive Models for Neglected and Emerging Infectious Diseases, Vanderbilt Institute for Clinical and Translational Research (VICTR), Oregon Clinical and Translational Research Institute, Clinical and Translational Science Award, Oklahoma Shared Clinical and Translational Resources, Drivers of individual variation in influenza vaccine response and protection from infection, Great Plains IDeA-CTR, Delaware Clinical and Translational Research ACCEL Program, Penn State Clinical and Translational Science Institute, Southern California Clinical and Translational Science Institute, Institutional Clinical and Translational Science Award, Washington University Institute of Clinical and Translational Sciences, Mississippi Center for Clinical and Translational Research, The Institute for Translational Medicine, Georgia Clinical & Translational Science Alliance (Georgia CTSA), Institute of Translational Health Sciences, Louisiana Clinical and Translational Science Center, Yale Clinical and Translational Science Award, Kentucky Center for Clinical and Translational Science, Developing, Demonstrating, and Disseminating Innovative Programs to Achieve Translational Success, UCLA Clinical and Translational Science Institute, Clinical and Translational Science Institute, UTMB Clinical and Translational Science Award
OpenAlex ID: W7168270342