RESCUE: An end-to-end multi-agent LLM system for proactive rare-disease patient screening in the EHR

Rare diseases affect a significant portion of the global population, yet patients often endure a lengthy diagnostic odyssey, frequently missing the opportunity for timely diagnoses with exome or genome sequencing (ES/GS). Existing informatics tools often rely on pre-identified patients or rigid, institution-specific rule sets, failing to address the broader operational question of clinical utility and feasibility.

We introduce RESCUE (Rare Disease Detection and Escalation Support via a Learning Health System), an end-to-end, multi-agent LLM-powered workflow designed for proactive rare-disease diagnosis across the entire electronic health record (EHR). RESCUE utilizes a team of specialized agents including Ontology, Modeling, Screening, and Review, to automate the screening process to identify candidates for diagnostic testing based on their clinical features. The Ontology Agent classifies clinical data into a four-tier genetic-evidence taxonomy; the Modeling Agent builds a positive-unlabeled (PU) XGBoost classifier to identify potential cases; the Screening Agent applies these models across the EHR population; and the Review Agent evaluates candidates by sampling clinical notes to ensure medical necessity and operational feasibility for genomic testing.

Using electronic medical record data from a pediatric hospital, our retrospective evaluation on a holdout set (n=12,591) demonstrates strong discrimination between patients who received diagnostic genomic testing and those who did not (AUC 0.808). Of nearly 500,000 patients in the institutional base, 175,842 met inclusion criteria for screening; among these, RESCUE-flagged candidates were 7.4-fold more likely to receive subsequent genomic assessments compared to controls. Blinded manual chart reviews confirmed that RESCUE identifies previously missed, medically appropriate patients for ES/GS with 80% precision, while simultaneously accounting for prior testing history.

By decoupling expert roles into modular agents, RESCUE offers a flexible, scalable, and adaptable framework for screening patients for rare-disease diagnostic genomic testing. This approach overcomes the limitations of traditional rule-based methods and provides a reproducible, agentic pathway to reduce diagnostic delays and improve patient care at an institutional scale.