Dynamic Decision Learning: Test-Time Evolution for Abnormality Grounding in Rare Diseases

Rare diseases affect millions of individuals worldwide, yet timely diagnosis remains a major public health challenge due to scarcity of specialized clinical expertise. While large language models (LLMs) show promise to support rare disease diagnosis, current models are constrained by insufficient clinical deployability, limited clinically grounded evidence, and scarcity of training data. Here we present RaDaR (Rare Disease navigatoR), an open-source, compact reasoning LLM (32B parameters) for rare disease diagnosis. RaDaR was trained with 49,170 publicly available free-text cases and 104,666 synthetic cases with reasoning-enhanced training. RaDaR showed the strongest performance among evaluated open-source models, including the 671B DeepSeek-R1, across public benchmarks and four external validation centers. In a retrospective cohort, RaDaR prioritized the final diagnosis before documented clinical suspicion in 61.06 percent of cases, corresponding to a potential lead time of 1.87 months and 50.18 percent of the within-center interval. In a randomized physician-assistance trial, RaDaR assistance improved physicians' rare-disease diagnostic accuracy by 21.44 percentage points compared with internet search alone. Synthetic-data ablations suggested that phenotype-anchored narratives provide useful training signal for long-tail rare diseases, with a monotonic scaling trend within the tested data range. Together, RaDaR and its development and validation framework provide a deployable rare-disease reasoning model and a reproducible development framework for diagnostic AI under data scarcity.

Large-scale pretrained foundation models have revolutionized general medical screening, but often falter on rare diseases because such conditions are underrepresented in real-world clinical datasets. While retrieval-augmented diagnosis attempts to mitigate this, conventional static methods frequently succumb to the hubness problem, retrieving visually similar but semantically incorrect common diseases. To address this, we propose Evo-RAD, a self-evolving agentic framework that transforms evidence acquisition into a dynamic decision-making task. We formulate retrieval as a Markov Decision Process (MDP) where a graphbased agent observes the reference set state and executes actions to purge discordant evidence (DELETE), acquire pathologically consistent samples (INSERT), or conclude the evolution (TERMINATE). Optimized via Group Relative Policy Optimization (GRPO) with a homogeneityaware reward, the agent learns to maximize the diagnostic homogeneity of the support reference set. Experiments on retinal disease benchmarks show that Evo-RAD substantially improves rare-disease diagnosis, outperforming retinal foundation models by +21.04%, while also surpassing retrieval-based and parameter-efficient fine-tuning methods by +3.56%. Code is available at https://github.com/SDH-Lab/Evo-RAD.

Zero-shot anomaly localisation via vision-language models (VLMs) offers a compelling approach for rare pathology detection, yet its performance is fundamentally limited by the absence of healthy anatomical context. We reformulate zero-shot localisation as a comparative inference problem in which anomalies are identified through structured comparison against reference distributions of normal anatomy. We introduce WALDO, a training-free framework grounded in optimal transport theory that enables comparative reasoning through: (i) entropy-weighted Sliced Wasserstein distances for anatomically-aware reference selection from DINOv2 patch distributions, (ii) Goldilocks zone sampling exploiting the non-monotonic relationship between reference similarity and localisation accuracy, and (iii) self-consistency aggregation via weighted non-maximum suppression. We theoretically analyse the Goldilocks effect through distributional divergence, and show that references with moderate similarity minimize a bias-variance trade-off in comparative visual reasoning. On the NOVA brain MRI benchmark, WALDO with Qwen2.5-VL-72B achieves $43.5_{\pm1.6}\%$ mAP@30 (95% CI: [40.4, 46.7]), representing a 19% relative improvement over zero-shot baselines. Cross-model evaluation shows consistent gains: GPT-4o achieves $32.0_{\pm6.5}\%$ and Qwen3-VL-32B achieves $32.0_{\pm6.6}\%$ mAP@30. Paired McNemar tests confirm statistical significance ($p<0.01$). Source code is available at https://github.com/bkainz/WALDO_MICCAI26_demo .