A Specialized Large Language Model for Clinical Reasoning and Diagnosis in Rare Diseases

Rare diseases affect hundreds of millions worldwide, yet diagnosis often spans years. Convectional pipelines decouple noisy evidence extraction from downstream inferential diagnosis, and general/medical large language models (LLMs) face scarce real world electronic health records (EHRs), stale domain knowledge, and hallucinations. We assemble a large, domain specialized clinical corpus and a clinician validated reasoning set, and develop RareSeek R1 via staged instruction tuning, chain of thought learning, and graph grounded retrieval. Across multicenter EHR narratives and public benchmarks, RareSeek R1 attains state of the art accuracy, robust generalization, and stability under noisy or overlapping phenotypes. Augmented retrieval yields the largest gains when narratives pair with prioritized variants by resolving ambiguity and aligning candidates to mechanisms. Human studies show performance on par with experienced physicians and consistent gains in assistive use. Notably, transparent reasoning highlights decisive non phenotypic evidence (median 23.1%, such as imaging, interventions, functional tests) underpinning many correct diagnoses. This work advances a narrative first, knowledge integrated reasoning paradigm that shortens the diagnostic odyssey and enables auditable, clinically translatable decision support.

Active Source Free Domain Adaptation

Source free domain adaptation (SFDA) aims to transfer a trained source model to the unlabeled target domain without accessing the source data. However, the SFDA setting faces an effect bottleneck due to the absence of source data and target supervised information, as evidenced by the limited performance gains of newest SFDA methods. In this paper, for the first time, we introduce a more practical scenario called active source free domain adaptation (ASFDA) that permits actively selecting a few target data to be labeled by experts. To achieve that, we first find that those satisfying the properties of neighbor-chaotic, individual-different, and target-like are the best points to select, and we define them as the minimum happy (MH) points. We then propose minimum happy points learning (MHPL) to actively explore and exploit MH points. We design three unique strategies: neighbor ambient uncertainty, neighbor diversity relaxation, and one-shot querying, to explore the MH points. Further, to fully exploit MH points in the learning process, we design a neighbor focal loss that assigns the weighted neighbor purity to the cross-entropy loss of MH points to make the model focus more on them. Extensive experiments verify that MHPL remarkably exceeds the various types of baselines and achieves significant performance gains at a small cost of labeling.