arXiv subjects

Undiagnosed Diseases Network

Publications and source records attributed to Undiagnosed Diseases Network.

4 recordsLinked to original sources

arXiv2026

Teaching agentic AI to generalize expert diagnostic reasoning in rare diseases

Rare disease diagnosis depends on expert reasoning that is scarce and difficult to transfer. Large language models rank the correct disease first in only 35.4% of benchmark cases and often rely on learned phenotype-disease associations rather than reusable diagnostic reasoning strategies. We developed liteOdyssey through Policy Iteration with Human Feedback, a process in which model failures and expert corrections are iteratively consolidated into a clinician-gated, natural-language policy executed by a language model. Across 1,243 public benchmark cases spanning 722 rare diseases, liteOdyssey ranked the correct disease first in 59.3% of cases versus 26.5% without the policy, with comparable gains in cases involving diseases excluded from policy development. The same policy transferred across model families and sizes without retraining. Adaptation of the policy to the Undiagnosed Diseases Network (UDN) improved diagnostic accuracy among 515 UDN patients, with gains confirmed by blinded physician adjudication. These results show that expert reasoning can be externalized into an inspectable and revisable natural-language policy that generalizes across rare diseases, transfers across model backbones, and adapts to a real-world patient cohort.

cs.AI↗

arXiv2026

Teaching large language models to reason like expert diagnosticians

Differential diagnosis is an iterative process that integrates patient information with broader medical knowledge. Clinical case series such as the NEJM Clinicopathologic Conferences (CPCs), published continuously since 1923, feature expert physicians who demonstrate diagnostic reasoning to peers, and have been used for decades to evaluate AI. However, prior AI evaluations have largely focused on final diagnostic accuracy rather than nuanced clinical reasoning. Here, we introduce Dr. CaBot, an agentic AI system that emulates an expert diagnostician by generating written and narrated slide-based presentations from an initial case description alone. CaBot recently generated the first AI diagnosis published in the 100+ year history of the NEJM CPCs. In blinded evaluations, physicians misclassified the source of the differential (CaBot vs. physician-written) in 46/62 (74%) of trials and rated them favorably across quality dimensions. When tasked with solving cases for 72 patients with undiagnosed disease from the NIH Undiagnosed Diseases Network, CaBot identified the working diagnosis in 50/72 (69%) of cases from referral notes alone. To promote transparency and research, we also developed CPC-Bench, a physician-validated benchmark based on 7,102 CPCs and 47,648 questions across 10 tasks. We show that CaBot outperforms frontier models on CPC-Bench, and release both CaBot and CPC-Bench publicly to foster progress in clinical AI.

cs.AI↗

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.

q-bio.GN↗

arXiv2025

KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation

Heterozygous mutations in KMT2B are associated with an early-onset, progressive, and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal, and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein-truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5 to 37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke-Fahn-Marsden Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year, and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002, and P = 0.012).

q-bio.NC↗