A Case-Crossover Phenome-wide Association Study (PheWAS) for Understanding Post-COVID-19 Diagnosis Patterns
Authors: Haupert Spencer R. , Shi Xu , Chen Chen , Fritsche Lars G. , Mukherjee Bhramar 
Published: July 2022

AbstractImportancePost 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.ObjectiveTo assess which diagnoses appear more frequently after a COVID-19 infection and how they differ by COVID-19 severity and vaccination status.DesignWe 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.SettingPatients tested for or diagnosed with COVID-19 at Michigan Medicine from March 10, 2020 through May 1, 2022.Participants36,856 SARS-CoV-2-positive patients and 141,615 age- and sex-matched SARS-CoV-2-negative patients as a comparison group for sensitivity analysis.ExposureSARS-CoV-2 virus infection as determined by RT-PCR testing and/or clinical evaluation.Main Outcomes and MeasuresWe 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.ResultsUsing 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 RelevanceOur 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.Key PointsQuestionWhat patterns of clinical diagnosis tend to occur more frequently after a COVID-19 infection and how do they vary by COVID-19 severity and vaccination status?FindingsIn a cohort of 36,856 COVID-19-positive patients, using a case-crossover phenome-wide association analysis that controls for within-subject confounders, we found symptoms such as anxiety disorder, cardiac dysrhythmias, and respiratory failure to be significantly associated with the “post-COVID-19 period.” Patients with severe COVID-19 were more likely to receive diagnoses related to respiratory conditions in their “post-COVID-19 period” compared to those with mild/moderate COVID-19. The landscape of phenome-wide association signals for the vaccinated group featured common chronic conditions when compared to the signals in the unvaccinated group.MeaningSymptoms across multiple organ systems, especially in the mental, circulatory, and respiratory domains, were associated with the “post-COVID-19 period.” Characterization of post-COVID-19 diagnosis patterns is crucial to understand the long term and future healthcare burden of COVID-19.