Darmendra Ramcharran

Joe B Hakim, Jeffery L Painter, Darmendra Ramcharran et al.

Large language models (LLMs) are useful tools with the capacity for performing specific types of knowledge work at an effective scale. However, LLM deployments in high-risk and safety-critical domains pose unique challenges, notably the issue of ``hallucination,'' where LLMs can generate fabricated information. This is particularly concerning in settings such as drug safety, where inaccuracies could lead to patient harm. To mitigate these risks, we have developed and demonstrated a proof of concept suite of guardrails specifically designed to mitigate certain types of hallucinations and errors for drug safety, and potentially applicable to other medical safety-critical contexts. These guardrails include mechanisms to detect anomalous documents to prevent the ingestion of inappropriate data, identify incorrect drug names or adverse event terms, and convey uncertainty in generated content. We integrated these guardrails with an LLM fine-tuned for a text-to-text task, which involves converting both structured and unstructured data within adverse event reports into natural language. This method was applied to translate individual case safety reports, demonstrating effective application in a pharmacovigilance processing task. Our guardrail framework offers a set of tools with broad applicability across various domains, ensuring LLMs can be safely used in high-risk situations by eliminating the occurrence of key errors, including the generation of incorrect pharmacovigilance-related terms, thus adhering to stringent regulatory and quality standards in medical safety-critical environments.

Manuela Del Castillo Suero, Arnault-Quentin Vermillet, Nicole Sonne Heckmann et al.

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.