Machine Learning for Pre-Culture ESBL Risk Stratification to Guide Empiric Antibiotic Selection: A 12-Hospital Study of Enterobacteriaceae Cultures

Understanding how a prediction model will perform in a new environment before deployment is essential to preventing harm when algorithms inform decision-making. Two common sources of model performance degradation are (i) covariate shift, where the target covariate distribution differs from the source, and (ii) selective labels, where the observability of outcomes depends on historical decisions. We study pre-deployment model evaluation under the joint presence of covariate shift and labeling of outcomes selectively based on observed features. In particular, we present a double machine learning procedure for estimating the target risk of an arbitrary black-box prediction model under a general loss function. We show identification of this estimand under standard assumptions and derive a bias-corrected estimator based on the influence function of the target risk. Finally, we evaluate our estimator through experiments using the eICU electronic health records database, showing that it tracks the true target risk more accurately than methods that address either selective labels or covariate shift alone, as well as baselines that combine standard plug-in approaches.

Antimicrobial stewardship (AMS) is critical in pediatric intensive care units (PICUs), where diagnostic uncertainty often drives broad-spectrum antibiotic use, increasing antimicrobial resistance and potential long-term harms. Machine learning offers a promising approach for identifying patient-level opportunities for stewardship interventions from electronic health record data, yet prior work has focused largely on adult populations and static tabular representations. We present a systematic benchmarking study of AMS intervention prediction in the PICU across the public Paediatric Intensive Care database a private cohort from the University Children's Hospital Zurich, Switzerland. We define four clinically relevant proxy targets for reducing antibiotic exposure: intravenous-to-oral switching, de-escalation, discontinuation, and short-course therapy. Under a unified evaluation framework, we compare tabular, sequence-based, and graph-based temporal models at multiple temporal resolutions. We find that predictive performance is driven primarily by target prevalence and dataset characteristics rather than model complexity. Sequence models improve the precision-recall trade-off over tabular approaches at coarse (24-hour) resolution, while finer temporal modeling provides limited additional benefit. However, these gains come at the cost of poorer calibration, with simpler tabular models yielding more reliable probability estimates. Our findings highlight the importance of target design, temporal representation, and calibration in clinical machine learning, and provide practical guidance for developing reliable decision support systems for pediatric AMS.

Perioperative risk prediction models are often limited by narrow surgical populations, incomplete intraoperative data, poor calibration, and limited interpretability. We present a domain-structured ensemble framework for perioperative outcome prediction using routinely collected electronic health record (EHR) data. Predictors are organized into patient-related, surgery-related, and anesthetics-related domains. Domain-specific gradient boosting models generate independent risk estimates that are integrated through a logistic regression meta-learner. We demonstrate the framework using postoperative delirium (POD) in a case-control sample of 5,386 surgical encounters (2,693 cases, 2,693 controls) from a statewide health information exchange. POD required both delirium-related ICD codes and a positive Confusion Assessment Method screening within seven postoperative days; patients with preexisting dementia were excluded. The stacked meta-learner achieved AUROC 0.899 (95% CI: 0.891-0.906), precision-recall AUC 0.881, and Brier score 0.126, compared with AUROC 0.849 for the best single-stage model. Domain ablation showed improved discrimination and calibration over a surgery-only model (AUROC 0.879, Brier 0.140). Temporal validation on held-out post-2017 data yielded AUROC 0.915. Calibration was excellent, with intercept -0.006 (95% CI: -0.083 to 0.070) and slope 1.035 (95% CI: 0.982 to 1.088). Decision curve analysis, corrected for case-control sampling, showed positive net benefit across clinically plausible thresholds. The modular framework supports alternative outcomes, extension of predictor domains, and dynamic risk updating, providing a scalable foundation for interpretable, calibration-aware perioperative clinical decision support.