Risk Factors and Predictive Modeling for Post-Acute Sequelae of SARS-CoV-2 Infection: Findings from EHR Cohorts of the RECOVER Initiative (preprint)

Background Patients who were SARS-CoV-2 infected could suffer from newly incidental conditions in their post-acute infection period. These conditions, denoted as the post-acute sequelae of SARS-CoV-2 infection (PASC), are highly heterogeneous and involve a diverse set of organ systems. Limited studies have investigated the predictability of these conditions and their associated risk factors. Method In this retrospective cohort study, we investigated two large-scale PCORnet clinical research networks, INSIGHT and OneFlorida+, including 11 million patients in the New York City area and 16.8 million patients from Florida, to develop machine learning prediction models for those who are at risk for newly incident PASC and to identify factors associated with newly incident PASC conditions. Adult patients aged  20 with SARS-CoV-2 infection and without recorded infection between March 1st, 2020, and November 30th, 2021, were used for identifying associated factors with incident PASC after removing background associations. The predictive models were developed on infected adults. Results We find several incident PASC, e.g., malnutrition, COPD, dementia, and acute kidney failure, were associated with severe acute SARS-CoV-2 infection, defined by hospitalization and ICU stay. Older age and extremes of weight were also associated with these incident conditions. These conditions were better predicted (C-index >0.8). Moderately predictable conditions included diabetes and thromboembolic disease (C-index 0.7-0.8). These were associated with a wider variety of baseline conditions. Less predictable conditions included fatigue, anxiety, sleep disorders, and depression (C-index around 0.6). Conclusions This observational study suggests that a set of likely risk factors for different PASC conditions were identifiable from EHRs, predictability of different PASC conditions was heterogeneous, and using machine learning-based predictive models might help in identifying patients who were at risk of developing incident PASC. 

Machine Learning for Identifying Data-Driven Subphenotypes of Incident Post-Acute SARS-CoV-2 Infection Conditions with Large Scale Electronic Health Records: Findings from the RECOVER Initiative (preprint)

The post-acute sequelae of SARS-CoV-2 infection (PASC) refers to a broad spectrum of symptoms and signs that are persistent, exacerbated, or newly incident in the post-acute SARS-CoV-2 infection period of COVID-19 patients. Most studies have examined these conditions individually without providing concluding evidence on co-occurring conditions. To answer this question, this study leveraged electronic health records (EHRs) from two large clinical research networks from the national Patient-Centered Clinical Research Network (PCORnet) and investigated patients’ newly incident diagnoses that appeared within 30 to 180 days after a documented SARS-CoV-2 infection. Through machine learning, we identified four reproducible subphenotypes of PASC dominated by blood and circulatory system, respiratory, musculoskeletal and nervous system, and digestive system problems, respectively. We also demonstrated that these subphenotypes were associated with distinct patterns of patient demographics, underlying conditions present prior to SARS-CoV-2 infection, acute infection phase severity, and use of new medications in the post-acute period. Our study provides novel insights into the heterogeneity of PASC and can inform stratified decision-making in the treatment of COVID-19 patients with PASC conditions.

DICE: Deep Significance Clustering for Outcome-Aware Stratification (preprint)

We present deep significance clustering (DICE), a framework for jointly performing representation learning and clustering for "outcome-aware" stratification. DICE is intended to generate cluster membership that may be used to categorize a population by individual risk level for a targeted outcome. Following the representation learning and clustering steps, we embed the objective function in DICE with a constraint which requires a statistically significant association between the outcome and cluster membership of learned representations. DICE further includes a neural architecture search step to maximize both the likelihood of representation learning and outcome classification accuracy with cluster membership as the predictor. To demonstrate its utility in medicine for patient risk-stratification, the performance of DICE was evaluated using two datasets with different outcome ratios extracted from real-world electronic health records. Outcomes are defined as acute kidney injury (30.4\%) among a cohort of COVID-19 patients, and discharge disposition (36.8\%) among a cohort of heart failure patients, respectively. Extensive results demonstrate that DICE has superior performance as measured by the difference in outcome distribution across clusters, Silhouette score, Calinski-Harabasz index, and Davies-Bouldin index for clustering, and Area under the ROC Curve (AUC) for outcome classification compared to several baseline approaches.

DICE: Deep Significance Clustering for Outcome-Driven Stratification (preprint)

We present deep significance clustering (DICE), a framework for jointly performing representation learning and clustering for “outcome-driven” stratification. Motivated by practical needs in medicine to risk-stratify patients into subgroups, DICE brings self-supervision to unsupervised tasks to generate cluster membership that may be used to categorize unseen patients by risk levels. DICE is driven by a combined objective function and constraint which require a statistically significant association between the outcome and cluster membership of learned representations. DICE also performs a neural architecture search to optimize cluster membership and hyper-parameters for model likelihood and classification accuracy. The performance of DICE was evaluated using two datasets with different outcome ratios extracted from real-world electronic health records of patients who were treated for coronavirus disease 2019 and heart failure. Outcomes are defined as in-hospital mortality (15.9%) and discharge home (36.8%), respectively. Results show that DICE has superior performance as measured by the difference in outcome distribution across clusters, Silhouette score, Calinski-Harabasz index, and Davies-Bouldin index for clustering, and Area under the ROC Curve for outcome classification compared to baseline approaches.