A Case-Crossover Phenome-wide Association Study (PheWAS) for Understanding Post-COVID-19 Diagnosis Patterns

Abstract

Importance: Post COVID-19 condition (PCC) is known to affect a large proportion of COVID-19 survivors. Robust study design and methods are needed to understand post-COVID-19 diagnosis patterns in all COVID-19 survivors, not just the ones clinically diagnosed with PCC. Objective: To assess which diagnoses appear more frequently after a COVID-19 infection and how they differ by COVID-19 severity and vaccination status. Design: We applied a case-crossover phenome-wide association study (PheWAS) in a retrospective cohort of COVID-19 survivors, comparing the occurrences of 1,649 diagnosis-based phenotype codes (PheCodes) pre- and post-COVID-19 infection periods in the same individual using a conditional logistic regression. Setting: Patients tested for or diagnosed with COVID-19 at Michigan Medicine from March 10, 2020 through May 1, 2022. Participants: 36,856 SARS-CoV-2-positive patients and 141,615 age- and sex-matched SARS-CoV-2-negative patients as a comparison group for sensitivity analysis. Exposure: SARS-CoV-2 virus infection as determined by RT-PCR testing and/or clinical evaluation. Main Outcomes and Measures: We compared the rate of occurrence of 1,649 disease classification codes in "pre-" and "post-COVID-19 periods". We studied how this pattern varied by COVID-19 severity and vaccination status at the time of infection. Results: Using a case-crossover PheWAS framework, we found mental, circulatory, and respiratory disorders to be strongly associated with the "post-COVID-19 period" for the overall COVID-19-positive cohort. A total of 325 PheCodes reached phenome-wide significance (p<3e-05), and top hits included cardiac dysrhythmias (OR=1.7 [95%CI: 1.6-1.9]), respiratory failure, insufficiency, arrest (OR=3.1 [95%CI: 2.7-3.5]) and anxiety disorder (OR=1.7 [95%CI: 1.6-1.8]). In the patients with severe disease, we found stronger associations with many respiratory and circulatory disorders, such as pneumonia (p=2.1e-18) and acute pulmonary heart disease (p=2.4e-8), and the "post-COVID-19 period," compared to those with mild/moderate disease. Test negative patients exhibited a somewhat similar association pattern to those fully vaccinated, with mental health and chronic circulatory diseases rising to the top of the association list in these groups. Conclusions and Relevance: Our results confirm that patients experience myriad symptoms more than 28 days after SARS-CoV-2 infection, but especially mental, circulatory, and respiratory disorders. Our case-crossover PheWAS approach controls for within-person confounders that are time-invariant. Comparison to test negatives with a similar design helped identify enrichment specific to COVID-19. As we look into the future, we must be aware of COVID-19 survivors' healthcare needs in the period after infection.