Leveraging Open-Source Large Language Models to Identify Undiagnosed Patients with Rare Genetic Aortopathies

Abstract

Rare genetic aortopathies are frequently undiagnosed due to phenotypic heterogeneity, and delayed diagnosis can lead to fatal cardiac outcomes. While genetic testing can enable early proactive interventions, it relies on primary care physicians to recognize a genetic basis for symptoms and then refer patients to clinical genetics. Broad-scale screening methods are needed to identify cases that do not fit an obvious diagnostic pattern. Clinical notes, rich in narrative details, may support the automated flagging of patients for genetic testing. Given the strength of Large Language Models (LLMs) in processing unstructured text, we developed an open-source LLM-enabled genetic testing recommendation pipeline, which leverages retrieval augmented generation (RAG) on curated genetic aortopathy-related corpora to utilize relevant clinical knowledge for identifying patients likely to benefit from genetic testing. The pipeline was validated using 22,510 patient progress notes from 500 individuals (250 cases, 250 controls) in the Penn Medicine BioBank, and successfully categorized 425 out of 499 patients, with one case requiring further clinician evaluation due to incomplete information. The pipeline achieved a patient-level recommendation accuracy of 0.834, precision of 0.835, sensitivity of 0.831, specificity of 0.836, F1-score of 0.833, and F3-score of 0.832. Our LLM-enabled workflow integrating RAG showed strong performance in recommending genetic testing for patients with rare genetic aortopathies. These findings illustrate the feasibility of using open-source LLMs to support identification of patients who may benefit from genetic testing based on free-text clinical notes, providing a potential decision-support tool to assist clinicians in earlier recognition of rare genetic disease risks.