arXiv subjects

Jonathan A. Bernstein

Publications and source records attributed to Jonathan A. Bernstein.

2 recordsLinked to original sources

arXiv2026

RareCollab: an LLM-powered framework for multimodal reasoning in Mendelian disease diagnosis

Rare disease diagnosis increasingly relies on integrating genomic, phenotypic and transcriptomic evidence, yet these signals remain difficult to reconcile within a common interpretive framework. Here we present RareCollab, an LLM-powered framework for multimodal reasoning in Mendelian disease diagnosis that integrates more than 100 diagnostic evidence signals across DNA, RNA, phenotype, curated variant-level knowledge, and in-silico pathogenicity evidence. This design enables large language models to operate as calibrated, interpretable reasoning modules rather than as a single end-to-end ranker. We applied RareCollab to 890 patients from three cohorts, including 119 Undiagnosed Diseases Network probands with paired DNA and RNA data, constituting a large systematic benchmark for multimodal rare disease diagnosis under paired genomic and transcriptomic evaluation. In this real-world multimodal benchmark, RareCollab prioritized 94% of diagnostic genes within the top 10. Across recall thresholds from top 1 to top 10, it consistently outperformed proprietary phenotype-driven LLM baselines including Claude Sonnet 4.6 and GPT-5-mini by more than 25% on average and surpassed established state-of-the-art variant prioritization methods by 11%-24%. RareCollab also reshapes the diagnostic contribution of RNA evidence, which contributes to prioritization of the diagnostic gene in 35% of cases (42/119). Together, these results establish RareCollab as a scalable and interpretable framework for multimodal rare disease diagnosis.

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arXiv2024

GREGoR: Accelerating Genomics for Rare Diseases

Rare diseases are collectively common, affecting approximately one in twenty individuals worldwide. In recent years, rapid progress has been made in rare disease diagnostics due to advances in DNA sequencing, development of new computational and experimental approaches to prioritize genes and genetic variants, and increased global exchange of clinical and genetic data. However, more than half of individuals suspected to have a rare disease lack a genetic diagnosis. The Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium was initiated to study thousands of challenging rare disease cases and families and apply, standardize, and evaluate emerging genomics technologies and analytics to accelerate their adoption in clinical practice. Further, all data generated, currently representing ~7500 individuals from ~3000 families, is rapidly made available to researchers worldwide via the Genomic Data Science Analysis, Visualization, and Informatics Lab-space (AnVIL) to catalyze global efforts to develop approaches for genetic diagnoses in rare diseases (https://gregorconsortium.org/data). The majority of these families have undergone prior clinical genetic testing but remained unsolved, with most being exome-negative. Here, we describe the collaborative research framework, datasets, and discoveries comprising GREGoR that will provide foundational resources and substrates for the future of rare disease genomics.

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