Transportability of bacterial infection prediction models for critically ill patients.

OBJECTIVE: Bacterial infections (BIs) are common, costly, and potentially life-threatening in critically ill patients. Patients with suspected BIs may require empiric multidrug antibiotic regimens and therefore potentially be exposed to prolonged and unnecessary antibiotics. We previously developed a BI risk model to augment practices and help shorten the duration of unnecessary antibiotics to improve patient outcomes. Here, we have performed a transportability assessment of this BI risk model in 2 tertiary intensive care unit (ICU) settings and a community ICU setting. We additionally explored how simple multisite learning techniques impacted model transportability. METHODS: Patients suspected of having a community-acquired BI were identified in 3 datasets: Medical Information Mart for Intensive Care III (MIMIC), Northwestern Medicine Tertiary (NM-T) ICUs, and NM "community-based" ICUs. ICU encounters from MIMIC and NM-T datasets were split into 70/30 train and test sets. Models developed on training data were evaluated against the NM-T and MIMIC test sets, as well as NM community validation data. RESULTS: During internal validations, models achieved AUROCs of 0.78 (MIMIC) and 0.81 (NM-T) and were well calibrated. In the external community ICU validation, the NM-T model had robust transportability (AUROC 0.81) while the MIMIC model transported less favorably (AUROC 0.74), likely due to case-mix differences. Multisite learning provided no significant discrimination benefit in internal validation studies but offered more stability during transport across all evaluation datasets. DISCUSSION: These results suggest that our BI risk models maintain predictive utility when transported to external cohorts. CONCLUSION: Our findings highlight the importance of performing external model validation on myriad clinically relevant populations prior to implementation.

Integrative analysis of functional genomic screening and clinical data identifies a protective role for spironolactone in severe COVID-19.

We demonstrate that integrative analysis of CRISPR screening datasets enables network-based prioritization of prescription drugs modulating viral entry in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by developing a network-based approach called Rapid proXimity Guidance for Repurposing Investigational Drugs (RxGRID). We use our results to guide a propensity-score-matched, retrospective cohort study of 64,349 COVID-19 patients, showing that a top candidate drug, spironolactone, is associated with improved clinical prognosis, measured by intensive care unit (ICU) admission and mechanical ventilation rates. Finally, we show that spironolactone exerts a dose-dependent inhibitory effect on viral entry in human lung epithelial cells. Our RxGRID method presents a computational framework, implemented as an open-source software package, enabling genomics researchers to identify drugs likely to modulate a molecular phenotype of interest based on high-throughput screening data. Our results, derived from this method and supported by experimental and clinical analysis, add additional supporting evidence for a potential protective role of the potassium-sparing diuretic spironolactone in severe COVID-19.