Identification and Prediction of Clinical Phenotypes in Hospitalized Patients With COVID-19: Machine Learning From Medical Records

Background: There is significant heterogeneity in disease progression among hospitalized patients with COVID-19. The pathogenesis of SARS-CoV-2 infection is attributed to a complex interplay between virus and host immune response that in some patients unpredictably and rapidly leads to “hyperinflammation” associated with increased risk of mortality. The early identification of patients at risk of progression to hyperinflammation may help inform timely therapeutic decisions and lead to improved outcomes. Objective: The primary objective of this study was to use machine learning to reproducibly identify specific risk-stratifying clinical phenotypes across hospitalized patients with COVID-19 and compare treatment response characteristics and outcomes. A secondary objective was to derive a predictive phenotype classification model using routinely available early encounter data that may be useful in informing optimal COVID-19 bedside clinical management. Methods: This was a retrospective analysis of electronic health record data of adult patients (N=4379) who were admitted to a Johns Hopkins Health System hospital for COVID-19 treatment from 2020 to 2021. Phenotypes were identified by clustering 38 routine clinical observations recorded during inpatient care. To examine the reproducibility and validity of the derived phenotypes, patient data were randomly divided into 2 cohorts, and clustering analysis was performed independently for each cohort. A predictive phenotype classifier using the gradient-boosting machine method was derived using routine clinical observations recorded during the first 6 hours following admission. Results: A total of 2 phenotypes (designated as phenotype 1 and phenotype 2) were identified in patients admitted for COVID-19 in both the training and validation cohorts with similar distributions of features, correlations with biomarkers, treatments, comorbidities, and outcomes. In both the training and validation cohorts, phenotype-2 patients were older; had elevated markers of inflammation; and were at an increased risk of requiring intensive care unit–level care, developing sepsis, and mortality compared with phenotype-1 patients. The gradient-boosting machine phenotype prediction model yielded an area under the curve of 0.89 and a positive predictive value of 0.83. Conclusions: Using machine learning clustering, we identified and internally validated 2 clinical COVID-19 phenotypes with distinct treatment or response characteristics consistent with similar 2-phenotype models derived from other hospitalized populations with COVID-19, supporting the reliability and generalizability of these findings. COVID-19 phenotypes can be accurately identified using machine learning models based on readily available early encounter clinical data. A phenotype prediction model based on early encounter data may be clinically useful for timely bedside risk stratification and treatment personalization.