Organizations: Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark · GSK, Providence, RI, USA · School of Pharmacy, University of Rhode Island, Kingston, RI, USA
Background: Disease severity is a multidimensional construct difficult to capture with rule-based approaches in Electronic Healthcare Records (EHR). Agentic large language model (LLM) systems could synthesise clinical evidence and reason over EHRs, but remain unevaluated for this task. Methods: MOSAIC is a two-phase agentic LLM framework for severity phenotyping, using type 2 diabetes (T2D) as a proof-of-concept. MOSAIC was evaluated on a synthetic cohort (SyntheticMass; open-weight N = 4,886; closed-weight N = 200) against three algorithmic ground truths (DCSI, DiSSCo, Cooper) and against all-cause mortality and incident complications. Open-weight (locally deployable) and proprietary pipelines were also compared. Results: The generated framework spanned domains absent from the comparators, including biomarker-based glycaemic staging, beta-cell function, and social determinants of health. Open-weight MOSAIC matched the proprietary pipeline (closed- vs open-weight weighted kappa = 0.773) and reached moderate agreement with Cooper (kappa = 0.597) and DCSI (kappa = 0.534) and fair agreement with DiSSCo (kappa = 0.320). Agent-based (Type 1) tiers showed significant separation of all-cause mortality (log-rank p < 0.001; crude hazard ratios 1.6-2.4 for non-Baseline tiers), with non-monotonic separation at the upper tiers, and an inverse gradient for incident complications (log-rank p < 0.001) consistent with depletion of susceptibles. Agentic classification also diverged from deterministic execution of the same rubric (MOSAIC Frozen; kappa = 0.428), indicating reasoning beyond fixed rules. Conclusion: MOSAIC shows agentic LLM systems can generate and apply clinically meaningful severity phenotypes from structured EHR data in T2D. Extending it to other diseases with similarly multidimensional severity warrants further research.
Large language models (LLMs) offer promising clinical decision support but remain vulnerable to hallucinated facts, unsupported recommendations, and citation errors. We present DIASENTINEL, a fully on-premise multi-agent system for one-year type 2 diabetes mellitus (T2DM) risk screening and guideline-grounded report generation from electronic health records (EHRs). The system integrates calibrated risk prediction, deterministic clinical signal extraction, Reciprocal Rank Fusion over American Diabetes Association (ADA) guidelines, and a hybrid verification layer combining rule-based checks with LLM entailment. The demonstration provides a real-time batch-screening dashboard and an interactive patient report interface with cited recommendations, verification results, and raw EHR comparison. DIASENTINEL demonstrates a practical framework for reliable, auditable, and privacy-preserving LLM-based clinical decision support.
Disease severity classification for genetic conditions is subjective and labor-intensive, creating bottlenecks in genomic screening, where commercial panels vary widely in size and overlap. We developed an autonomous AI agent integrating Reasoning and Acting (ReAct) with Retrieval-Augmented Generation (RAG) to classify 10,211 Human Phenotype Ontology terms. It uses American College of Medical Genetics (ACMG)-endorsed severity guidelines and American College of Obstetricians and Gynecologists (ACOG) quality-of-life criteria to retrieve PubMed literature, generate interpretable reasoning chains, and independently verify claims. At the phenotype level, using expert-curated cohorts, the agent achieved 93.55% accuracy (MCC 0.9237) with 82.6% to 91.4% of claims supported by direct evidence or valid inferences. Gene-level severity was aggregated across 8,738 pairs, identifying 3,283 autosomal recessive pairs with severe or profound presentations. External validation showed 95.2% concordance with Mackenzie's Mission gene list. This system enables standardized panel design by providing reliable, automated classification supported by direct evidence.
Tohid Ghasemnejad, Ahmadreza Argha, Mark Grosser +7
Clinical early warning systems built on electronic health records, in which clinical observations are recorded as irregularly sampled medical time series (ISMTS), must deliver both calibrated risk scores for patient triage and interpretable rationales that clinicians can verify. Large Language Models (LLMs) have been explored for this task, yet they collapse graded clinical risk into overconfident binary predictions. This risk polarization undermines both calibration and cross-patient comparability. To address this, we propose TRIAGE, a framework that trains an LLM to generate dialectical reasoning over competing clinical outcomes by eliciting outcome-specific rationales. This dialectical formulation mitigates risk polarization, enabling a single LLM to yield continuous risk scores grounded in explicit clinical reasoning. Evaluated on three ISMTS benchmarks, TRIAGE achieves an average AUPRC improvement of 3.3% and reduces calibration error by 81% compared to the competitive baselines. An LLM-as-a-judge assessment further shows that our rationales surpass post-hoc explanations from the baseline by 20% in clinical reasoning quality. The source code is available at https://github.com/HyeongWon-Jang/TRIAGE .