Prediction of Long COVID Based on Severity of Initial COVID-19 Infection: Differences in predictive feature sets between hospitalized versus non-hospitalized index infections

Abstract Long COVID is recognized as a significant consequence of SARS-COV2 infection. While the pathogenesis of Long COVID is still a subject of extensive investigation, there is considerable potential benefit in being able to predict which patients will develop Long COVID. We hypothesize that there would be distinct differences in the prediction of Long COVID based on the severity of the index infection, and use whether the index infection required hospitalization or not as a proxy for developing predictive models. We divide a large population of COVID patients drawn from the United States National Institutes of Health (NIH) National COVID Cohort Collaborative (N3C) Data Enclave Repository into two cohorts based on the severity of their initial COVID-19 illness and correspondingly trained two machine learning models: the Long COVID after Severe Disease Model (LCaSDM) and the Long COVID after Mild Disease Model (LCaMDM). The resulting models performed well on internal validation/testing, with a F1 score of 0.94 for the LCaSDM and 0.82 for the LCaMDM. There were distinct differences in the top 10 features used by each model, possibly reflecting the differences in type and amount of pathophysiological data between the hospitalized and non-hospitalized patients and/or reflecting different pathophysiological trajectories in the development of Long COVID. Of particular interest was the importance of Plant Hardiness Zone in the feature set for the LCaMDM, which may point to a role of climate and/or sunlight in the progression to Long COVID. Future work will involve a more detailed investigation of the potential role of climate and sunlight, as well as refinement of the predictive models as Long COVID becomes increasingly parsed into distinct clinical phenotypes.