Rare Disease

More than 300 million people worldwide are affected by one of over 7,000 known rare diseases, yet diagnosis remains difficult because patients initially present with incomplete and heterogeneous phenotypes. We present HPOQuest, a training-free framework for sequential phenotype acquisition in rare-disease diagnosis. Starting from a small set of observed patient phenotypes, HPOQuest maintains a probabilistic disease ranking and iteratively selects informative follow-up questions to support clinicians during patient assessment. Confirmed phenotypes update the disease ranking, while all responses update the candidate question set. Across four benchmark cohorts, HPOQuest substantially improves diagnosis from sparse initial phenotypes, with gains of up to 30% points at Recall@1 and 45% points at Recall@5. These results demonstrate that sequential phenotype acquisition can substantially improve rare-disease diagnosis from limited initial clinical evidence.

AI-assisted facial phenotyping supports rare genetic disorder prioritization by retrieving visually similar diagnosed cases from facial image reference databases such as the GestaltMatcher Database (GMDB). Existing GestaltMatcher-based retrieval frameworks compare each test image with individual gallery images in a facial phenotype embedding space. However, this pointwise formulation does not fully exploit available evidence, because patients may have multiple images and disorders may be represented by multiple diagnosed gallery patients. We propose an inference-time multi-level evidence aggregation framework that improves facial phenotype retrieval without modifying the underlying GestaltMatcher-Arc encoder. The framework combines embedding-level patient aggregation of multiple images from the same individual, patient-weighted disorder centroids, and hybrid individual-centroid scoring to integrate test-patient observations, disorder-level gallery evidence, and local nearest-neighbor evidence. We evaluated the approach on GMDB v1.1.4 across disorders represented during training (GMDB-Freq), unseen disorders (GMDB-Rare), and multi-image patient subsets, using a unified gallery containing both GMDB-Freq and GMDB-Rare disorders. Multi-level evidence aggregation improved mean per-disorder top-$N$ retrieval accuracy across all evaluation subsets. Top-1 accuracy increased from 38.52% to 48.82% on GMDB-Freq and from 19.38% to 23.79% on GMDB-Rare. On multi-image subsets, top-1 accuracy increased from 46.12% to 60.94% on GMDB-Multi-Freq and from 18.54% to 26.71% on GMDB-Multi-Rare. These findings show that inference-time aggregation can improve next-generation facial phenotype retrieval without retraining the encoder, supporting a shift from isolated single-image matching toward multi-level aggregation of patient and disorder evidence for rare-disorder prioritization.

Uncommon and off-guideline cases are difficult for clinical decision support, because physicians must make a series of management decisions under diagnostic uncertainty and rarely see the full case at once. Most large language model (LLM) benchmarks for medicine score only the final diagnosis, yet much of clinical care turns on the next appropriate action: the next test to order, the imaging study to obtain, the specialist to involve, or the differential to pursue. We introduce MedUPSQA, a dataset of 21,874 mid-stream clinical decision points built from 5,535 real case reports, and MedUPS, an alignment framework that supervises models on these intermediate decisions as they unfold along a patient's trajectory. We segment free-text case presentations into chronologically ordered, accumulating clinical chunks and align models to predict the next step with reinforcement learning (GRPO), using an external LLM-as-a-Judge reward. This objective mirrors how clinicians actually meet patients, reasoning forward from accumulating evidence toward the next decision, rather than committing to a final label. Across three backbones, mid-stream alignment raises next-step accuracy from 55.2 to 66.7 for Qwen3.6-27B, from 47.2 to 57.8 for Qwen3.5-9B, and from 37.8 to 44.4 for HuatuoGPT-3-8B, with 95% CI. In several model scales we test the objective improves accuracy more than scale, with smaller models surpassing larger, frontier models we evaluate. We further train supervised fine-tuning (SFT) baselines on the mid-stream task, SFT improves all backbones above base, indicating the target framwork carries signal independently of the optimizer. We release the dataset, code, and aligned checkpoints.

Phenotype-driven diagnostic benchmarks usually report the rank of the reference disease, but they rarely reveal which plausible alternatives are ranked above it or what evidence a tool-using model examines before making its decision. We introduce GraphRareBench, a provenance-preserving benchmark containing 2,365 ontology-derived cases and 18,093 target-confounder pairs. Each case includes a coarsened HPO query, a fixed candidate pool, graph-defined hard confounders, and source-linked evidence records. On the 237-case gene-component-disjoint test split, supervised rankers using a shared 21-feature interface achieved MRRs ranging from 0.640 to 0.740 and case-averaged target-over-confounder accuracies ranging from 0.898 to 0.916. Agents instantiated with Agents-A1 and DeepSeek-V4-Flash achieved MRRs of 0.746 and 0.718, respectively. Their paired MRR difference was not statistically significant, whereas their target-evidence coverage differed by 0.561. Together with the observation that 22.1% to 43.7% of selected Hit@10 successes still ranked at least one graph-defined hard confounder above the target, these results indicate that full-pool retrieval, hard-confounder discrimination, and observable evidence access capture complementary aspects of model behavior. GraphRareBench therefore provides a foundation for more transparent and evidence-aware evaluation of phenotype-driven diagnostic systems. Code and data are available at https://github.com/GUI0609/GraphRareBench.

In this paper, we examine the difficulties of using standard techniques for medical image classification due to long-tailed distributions (wherein rarer conditions have very few samples) resulting in bias towards diagnosing common diseases and away from rarer diseases. We then discuss and implement deep learning models with techniques such as augmentation to minimize error, especially from rarer diseases. We evaluate various different models with AP, F1 score, AUROC, and loss (all on the validation set). We conclude with the promising results from our best model, and potential applications in the healthcare space.

Rare diseases represent one of the most challenging settings for clinical decision-making, where heterogeneous presentations, sparse evidence and limited expertise create persistent uncertainty throughout the care pathway. Although artificial intelligence could help, existing systems largely address isolated tasks, particularly diagnosis, and usually rely on downstream investigations rather than information available at initial presentation. Here we show that clinical AI performance under uncertainty can be improved not by scaling a single model, but by exploiting the diversity of multiple imperfect reasoning systems. Across heterogeneous large language models, we identify divergent reasoning trajectories with complementary error patterns and develop RareLens, which learns to reconcile these perspectives into actionable decisions across four stages of rare disease care: risk screening, diagnosis, treatment planning and prognosis prediction. Built on RarelensBench, a real-world dataset of 157,525 cases spanning all 33 Orphanet categories and more than 7,000 conditions, RareLens outperformed every frontier model tested, including GPT-5, DeepSeek-R1, Claude-3.7-Sonnet and Gemini-2.5-Pro, across all stages. It achieved an area under the curve of 0.917 for screening and top-1 accuracies of 65.5% and 89.8% for diagnosis and treatment. In an external evaluation involving 1,287 cases and 23 physicians, autonomous RareLens and physicians assisted by RareLens both outperformed unaided physicians, while demonstrating that effective human-AI collaboration requires more than simply providing model outputs. These findings establish divergent model reasoning as an exploitable source of information and suggest a general strategy for building AI systems that operate reliably under high clinical uncertainty.

AI-based medication recommendation systems have attracted substantial attention due to their potential to enhance patient safety and therapeutic outcomes. Despite the clinical importance of accurately recommending rarely prescribed medications (rare-meds), we observe that most existing methods show significantly lower predictive performance for rare-meds. We attribute this issue to two intrinsic limitations: (a) the inherent scarcity of data for rare-meds and (b) limited consideration of co-recommended medications. To address these limitations, we propose GenRxR, a novel framework based on large language models (LLMs). GenRxR leverages the medical knowledge and clinical reasoning capability of LLMs to generate counterfactual medical data, mitigating the data scarcity issue for rare-meds. It also integrates an LLM into the medication recommendation process to model relationships among co-recommended medications. To further enhance the clinical reasoning, we introduce an instruction tuning step that aligns the LLM's capability with the recommendation task, enabling better handling of clinical context, including rare-meds cases. In our experiments, we show that GenRxR outperforms 14 (including 5 LLM-based) baselines in most cases. Specifically, it achieves up to 30.9% higher predictive performance for rare-meds than the strongest baseline.

Motivation: Rare disease (RD) diagnosis is frequently delayed due to the similarities in symptoms to common disease variants. Machine Learning Algorithms applied to Electronic Health Records show promise for accelerating the diagnosis; however, legal and privacy concerns pose significant barriers. To address these issues, Synthetic Data Generation is an alternative method for obtaining Electronic Health Records and can be applied with any Machine Learning algorithm for benchmarking and development purposes. Despite the availability of Synthetic Data Generation algorithms, support for generating a subset of patients that differ in a definable degree from the majority to simulate patients with RD is often lacking. Results: We present SYNRARE, a graphical user interface based on the Synthea framework that enables easier modification and generation of synthetic Electronic Health Records of RD patients, which differ only to a definable degree from patients with common diseases, thereby enabling the benchmarking and testing of algorithms under controlled technical conditions. SYNRARE enables researchers to rapidly benchmark their Machine Learning algorithms across any scenario. Availability and implementation: SYNRARE, including detailed instructions for installing, is available at https://gitlab.sdu.dk/screen4care/synrare.

Chest X-ray multi-label classification is a core task in intelligent medical imaging diagnosis. However, real clinical data often exhibit extreme long-tailed distributions, leading to degraded performance on rare diseases in tail classes. This issue is not only driven by data scarcity but also by two intrinsic factors:1) attenuation of tail-class lesion representations under complex anatomical backgrounds, and 2) dominance of head classes in modeling label co-occurrence relationships. To address these challenges, we propose TRCGL-Net. First, a learnable text-guided conditional diffusion model is employed to generate high-quality tail-class chest X-ray image samples under disease semantic constraints, improving data diversity and realism of rare disease patterns while alleviating class imbalance and preserving pathology-consistent semantics.Second, a channel reweighting mechanism is introduced to perform feature recalibration by emphasizing disease-relevant feature channels, thereby improving feature discriminability under long-tailed distributions.A class-aware attention mechanism is further applied to generate class-specific attention maps, enabling the model to localize disease-relevant regions and focus on fine-grained lesion areas.Finally, a graph convolution network based on label co occurrence is introduced to establish an information propagation mechanism among categories. Experiments on the PadChest dataset show that the proposed method achieves a tail-class mAP of 0.4904, an overall mAP of 0.4408, and an mAUC of 0.8989, outperforming state-of-the-art methods. TRCGL-Net effectively improves recognition performance for rare diseases under long-tailed distributions and mitigates the impact of extreme class imbalance in chest X-ray multi-label classification.

Mechanistic modeling via ordinary differential equations (ODEs) provides interpretable descriptions of complex dynamics and enables inference of underlying mechanisms, which is particularly valuable in clinical settings. However, in rare diseases, both the structure and parameters of the model are typically unknown, while individual-level data is scarce, noisy, heterogeneous, and subject to privacy constraints. In such settings, population-level summary statistics provide a practical privacy-preserving data representation, while capturing heterogeneity further requires modeling parameters as distributions rather than fixed values. Yet no existing method jointly discovers ODE structure and refines parameter distributions solely from summary statistics. We present AgentODE, an end-to-end framework that addresses this gap. An LLM proposes candidate ODE structures, while a tool-augmented inference agent iteratively refines parameter distributions through a diagnosis--update loop, operating on population-level summary statistics alone. We evaluate AgentODE on three benchmark problems across different fields and two clinical datasets, including the rare disease recessive dystrophic epidermolysis bullosa (RDEB), with only 231 observations across 46 patients. AgentODE recovers functionally consistent ODE structures across all settings, and experiments on RDEB demonstrates that in sparse and noisy data settings reasoning from summary statistics promotes mechanistically principled structure discovery, whereas baselines with individual-level data access recover implausible structures despite better predictive performance. AgentODE opens new possibilities for mechanistic modeling of rare diseases directly from population-level summary statistics, where data scarcity and privacy constraints have traditionally limited such analyses.

Rare disease differential diagnosis is a critical yet arduous clinical task, requiring physicians to identify precise phenotypes from complex, unstructured patient symptoms and execute intricate reasoning within a vast search space. However, existing AI approaches typically rely on pipeline-based phenotype extraction or retrieval-augmented generation, which suffer from critical information loss due to predefined ontologies, retrieval bottlenecks, and a lack of diagnostic logic. To address these challenges, we introduce RareDxR1, an end-to-end reasoning-centric large language model designed for open-domain rare disease diagnosis directly from unstructured clinical notes. We design a progressive end-to-end training framework by synergizing knowledge internalization with autonomous evolutionary learning, thereby bypassing reliance on structured phenotypes and closed-set decision-making. To overcome the limitations of RAG and phenotype restriction, we enabled the deep internalization of fragmented rare-disease knowledge directly into the model's parameters. Moreover, to bridge the gap between model generation and expert reasoning, we propose Reflection-Enhanced Reasoning Sampling (RERS), a strategy that synthesizes expert-level diagnostic trajectories by learning from failures without human annotation. Additionally, we propose a dual-level curriculum reinforcement learning approach for gradually mastering rare disease diagnosis. Experimental results demonstrate that RareDxR1 achieves state-of-the-art accuracy across different benchmarks, marking a significant breakthrough in open-domain rare disease diagnosis. Our code and dataset will be publicly available.

Data scarcity is a major bottleneck in medical Multiple Instance Learning (MIL), especially for rare diseases or expensive modalities. We introduce a statistically grounded patient augmentation approach that generates realistic patients directly in embedding space. Using Gaussian Mixture Models as a probabilistic clustering approach on pooled instance embeddings from all patients, our method learns disease-specific "recipes"-statistical distributions of instances across unsupervised clusters. New patients are then generated by sampling embeddings from clusters based on learned recipes. Unlike existing methods that require examples from all categories, our method can generate patients offline by re-mixing pooled embeddings. Generated patients are further selected based on uncertainty quantification to improve MIL performance. We evaluate our method across three clinically relevant scarcity scenarios: (i) cross-dataset transfer, where an entirely missing "healthy" class is generated using statistics from an external cohort; (ii) low-data regimes, where class sizes are extremely limited; and (iii) small-cohort non-image tasks, including single-cell RNA-seq and flow cytometry. Across all experiments, our method improves performance over baseline, often outperforming other bag-mixing strategies. Notably, in the missing-class scenario, a performance comparable to full-dataset training is achieved, demonstrating its potential for rare disease diagnostic and privacy-preserving patient augmentation. The code is available at https://github.com/marrlab/RECIPE

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.

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.

Rare diseases affect over $300$ million patients across more than $7{,}000$ conditions, yet no single hospital encounters enough cases of any one condition for reliable diagnosis. Cross-hospital collaboration could help by allowing a diagnosing institution to use distributed, case-specific diagnostic evidence, but privacy regulations restrict the transmission of identifiable clinical text across institutional boundaries. This setting raises two challenges: existing medical agent systems often rely on textual evidence exchange, while raw latent states such as hidden states and KV caches may still reveal prompt-derived clinical content. We introduce LatentDx, a latent multi-agent communication framework in which hospital agents keep private clinical records and retrieved cases local, and send compact latent KV blocks to a host agent for rare-disease diagnosis. LatentDx supports two deployment settings: same-backbone hospital agents use latent KV distillation, while hospitals with different LLM backbones use cross-family latent alignment. On CrossRare-Bench, a self-built large-scale rare-disease benchmark with hospital-level partitions, LatentDx improves cross-hospital diagnostic performance while reducing reconstructable clinical content relative to raw-latent communication baselines.

We propose a spectral-based, unsupervised representation learning framework to derive low-dimensional embeddings for clinical concepts and patients in rare disease cohorts from electronic health records, where data are high-dimensional but sample sizes are limited. To overcome this challenge, we incorporate a knowledge matrix extracted from a broader population that shares a partially overlapping subspace with the rare-disease cohort. Our method departs from existing approaches by relaxing restrictive one-to-one signal-alignment assumptions between the latent data matrix and knowledge matrix, allowing more flexible and realistic forms of structured sharing. We introduce a novel two-step spectral embedding procedure: first, we identify and remove irrelevant components from the knowledge matrix; then, we apply a projection-based method to separately recover shared and heterogeneous components. Simulations and an analysis of a real-world multiple sclerosis cohort show that the proposed method outperforms competing approaches, particularly in challenging scenarios where shared signals are weak and only partially aligned, as is common in rare-disease data.

Prion diseases are rare, rapidly progressive, and fatal neurodegenerative disorders that remain difficult to diagnose, particularly in their early stages because of nonspecific clinical presentations. However, to our knowledge, there is no publicly available prion-disease-focused dataset designed to capture a broad range of clinically relevant entities from the biomedical literature. We introduce PrionNER, a manually annotated named entity recognition dataset for prion disease clinical information in PubMed abstracts. The current release comprises 317 abstracts, 2,943 sentences, and 6,955 text-bound entity annotations spanning 15 coarse-grained and 31 fine-grained clinically oriented entity types covering diseases, symptoms, diagnostics, findings, anatomy, treatments, and temporal and statistical evidence. Inter-annotator agreement reaches 81.78 exact-match F1, indicating strong annotation consistency. We benchmark supervised BERT baselines, W2NER, and zero-shot extractors on PrionNER. W2NER is the strongest supervised model, and Gemma-4-31B is the strongest zero-shot model, but the benchmark remains challenging, especially for structurally complex mentions and fine-grained clinically adjacent label distinctions. PrionNER provides a clinically grounded benchmark for prion-disease information extraction and supports research on rare-disease biomedical NLP under low-resource, fine-grained, and non-flat extraction conditions. The dataset, annotation guidelines, and evaluation scripts are available at https://github.com/daotuanan/PrionNER/.

Children with rare genetic diseases often exhibit distinctive facial phenotypes, yet developing computer vision systems for early diagnosis remains challenging due to extreme data scarcity, privacy constraints, and limited data sharing in pediatric settings. These challenges not only hinder automated diagnosis but also restrict the availability of visual resources for clinical genetic counseling. While prior work has shown that synthetic data can augment real datasets and preserve phenotype-level semantics, it remains unclear whether synthetic data alone is sufficient for learning in ultra-low-resource pediatric settings. In this work, we study the synthetic-only regime for pediatric rare disease recognition. Under a controlled experimental setup, models are trained exclusively on phenotype-aware synthetic facial images at increasing scales. We find that synthetic-only training achieves performance comparable to real-data-only baselines at sufficient scale across multiple backbones, suggesting that high-fidelity synthetic data can approximate clinically meaningful distributions. These findings together further enable the use of synthetic pediatric facial images as privacy-preserving resources for genetic education and counseling, supporting clinician training and patient communication. Our results highlight the potential of computer vision to improve data efficiency and expand accessible visual tools in children's healthcare.

Rare diseases such as inborn errors of immunity (IEI) require early diagnosis to prevent end organ damage and improve quality of life. Hurdles in accessing and curating large scale electronic health record (EHR) data limit routine data driven analyses to remain on the forefront of IEI and other rare disease trends. Development of machine learning (ML) algorithms in IEI for pattern recognition as well as published methodology examining how to systematically process and integrate complex medical data is limited. Our proposed pipeline, including data curation and ML clustering algorithms, is designed to recognize novel rare disease patterns and extract IEI- associated features from a national data registry. Our methodology for EHR data formatting and processing presents the pipeline that transforms raw immunologic lab data into vectors. This is further combined with hyperparameter tuning for diseases pattern recognition via clustering. This study refines IEI feature awareness, develops data tool kits for rare disease populations analysis, and expands on transforming complex medical records in data structures interpretable by unsupervised ML.

Rare diseases dominate the diagnostic challenge in medical imaging yet are severely underrepresented in clinical datasets, causing classifiers to fail on exactly the conditions where reliable detection matters most. Generative augmentation can supply the missing tail-class coverage, but coarse disease labels aggregate diverse subtypes and acquisition settings into multi-modal conditionals that bias generators toward dominant submodes, while a shared Gaussian source forces rare subpopulations through disproportionately long transport paths. We propose an offline strategy that introduces informative priors at two levels: first, we partition each coarse label into coherent submodes via Gaussian mixture modeling in the generative model's latent space; second, we learn subclass-conditioned source distributions that re-center and re-scale the starting distribution per submode, shortening trajectories and reducing within-subclass dispersion. To prevent degenerate solutions we impose explicit geometric control, moderately concentrating normalized displacement directions around learnable prototypes while capping path-length outliers. On long-tailed chest X-ray (MIMIC-LT, NIH-LT) and CT slice (CT-RATE) benchmarks the proposed method consistently improves tail-class generation fidelity and diversity (FID, IRS) and is a promising augmentation strategy that reliably improves downstream balanced accuracy and macro-F1 over a non-augmented baseline across modalities.

Activated PI3K8 Syndrome (APDS) is a rare genetic immune disorder caused by variants in PIK3CD or PIK3R1, with highly heterogeneous symptoms that often delay diagnosis. Early recognition is hampered by overlapping clinical presentations and limited clinician awareness, motivating systematic, data-driven approaches to detect APDS-associated phenotypic patterns in routine electronic health records. Traditional linear scoring systems cannot capture complex symptom interactions, while deep learning models, though expressive, often lack interpretability. To bridge this gap, we propose Shapley regression, a novel game-theoretic model replacing the linear predictor with a k-additive cooperative game, explicitly modeling co-occurrence of symptoms while maintaining the transparency and convexity of logistic regression. We carry out an empirical study of our lightweight method on eight public biomedical datasets, showing that a 2-additive model with $l_{2}$ regularization achieves an optimal trade-off between predictive power and noise robustness. We also apply it to a real-world cohort of 222 patients, on which Shapley regression accurately distinguished APDS cases from matched controls, confirming and validating phenotypes known to be associated with APDS, and facilitating the exploration of pairwise interactions between symptoms, validated by clinical experts.

Accurate and timely diagnosis is essential for effective treatment, particularly in the context of rare diseases. However, current diagnostic workflows often lead to prolonged assessment times and low accuracy. To address these limitations, we introduce Hygieia, a multi-modal AI agent system designed to support precision disease diagnosis by integrating diverse data sources, including phenotypic features, genetic profiles, and clinical records. Hygieia features a router-based and knowledge-enhanced framework that mitigates hallucination and tailors diagnostic strategies to different disease categories. Notably, it prioritizes risk-related genomic factors for rare diseases and provides confidence scores to assist clinical decision-making. We conducted a comprehensive evaluation demonstrating that Hygieia achieves state-of-the-art performance across multiple diagnostic benchmarks. In collaboration with clinical experts from Yale School of Medicine and Duke-NUS Medical School, we further validated its practical utility by showing (1) Hygieia's superior diagnostic performance compared to physicians with an improvement from 12%-60% and (2) its effectiveness in assisting clinicians with medical records for handling real-world cases. Our findings indicate that Hygieia not only enhances diagnostic accuracy and interpretability but also significantly reduces clinician workload, highlighting its potential as a valuable tool in clinical decision support systems.

Medical imaging datasets are often characterized by extreme class imbalances, where rare pathologies are significantly underrepresented compared to common conditions. This imbalance poses a dual challenge for Open-Set Recognition (OSR): models must maintain high classification accuracy on known classes while reliably rejecting unknown samples unseen during training in the clinical settings. While recently proposed Deep Simplex Classifier (DSC)\cite{cevikalp2024reaching} and UnCertainty-aware Deep Simplex Classifier (UCDSC)\cite{Aditya_2026_WACV} successfully leverage Neural Collapse to ensure maximal inter-class separation, they rely on a uniform margin that does not account for the varying densities of medical classes. In this paper, we propose DMDSC an enhanced framework featuring a dynamic margin approach. Our approach automatically adapts class-specific margins based on label frequency, enforcing a higher penalty and tighter feature clustering for rare pathologies to counteract the effects of data imbalance. Extensive experiments conducted on diverse medical benchmarks on BloodMNIST\cite{medmnistv2}, OCTMNIST\cite{medmnistv2}, DermaMNIST\cite{medmnistv2}, and BreaKHis~\cite{spanhol2015dataset} datasets, demonstrate that our framework outperforms state-of-the-art methods.

Clinical abnormality grounding for rare diseases is often hindered by data scarcity, making supervised fine-tuning impractical and single-pass inference highly unstable. We propose Dynamic Decision Learning (DDL), a framework that enables frozen large vision-language models (LVLMs) to refine their decisions across both language and visual spaces by optimizing instructions and consolidating predictions under visual perturbations. This process improves localization quality and produces a consensus-based reliability score that quantifies model confidence. Results on brain imaging benchmarks, including a rare-disease dataset with 281 pathology types across models ranging from 3B to 72B parameters, show that DDL improves mAP@75 by up to 105% on rare-disease cases and outperforms adaptation baselines and supervised fine-tuning. Furthermore, DDL demonstrates stronger calibration between reliability scores and localization accuracy under severe distribution shifts and increasing task difficulty. Code is available at: https://lijunrio.github.io/DDL/

Frontier large language models generate clinically accurate outputs, but their citations are often fabricated. We term this the Provenance Gap. We tested five frontier LLMs across 36 clinician-validated scenarios for three rare neuromuscular disease pairs. No model produced a clinically relevant PubMed identifier without prompting. When explicitly asked to cite, the best model achieved 15.3% relevant PMIDs; the majority resolved to real publications in unrelated fields. We present HEG-TKG (Hierarchical Evidence-Grounded Temporal Knowledge Graphs), a system that grounds clinical claims in temporal knowledge graphs built from 4,512 PubMed records and curated sources with quality-tier stratification and 1,280 disease-trajectory milestones. In a controlled three-arm comparison using the same synthesis model, HEG-TKG matches baseline clinical feature coverage while achieving 100% evidence verifiability with 203 inline citations. Guideline-RAG, given overlapping source documents as raw text, produces zero verifiable citations. LLM judges cannot distinguish fabricated from verified citations without PubMed audit data. Independent clinician evaluation confirms the verifiability advantage (Cohen's d = 1.81, p < 0.001) with no degradation on safety or completeness. A counterfactual experiment shows 80% resistance to injected clinical errors with 100% detectability via citation trace. The system deploys on-premise via open-source models so patient data never leaves institutional infrastructure.

Chest X-ray (CXR) interpretation is hindered by the long-tailed distribution of pathologies and the open-world nature of clinical environments. Existing benchmarks often rely on closed-set classes from a single institution, failing to capture the prevalence of rare diseases or the appearance of novel findings. To address this, we present the CXR-LT challenge. The first event, CXR-LT 2023, established a large-scale benchmark for long-tailed multi-label CXR classification and identified key challenges in rare disease recognition. CXR-LT 2024 further expanded the label space and introduced a zero-shot task to study generalization to unseen findings. Building on the success of CXR-LT 2023 and 2024, this third iteration of the benchmark introduces a multi-center dataset comprising over 145,000 images from PadChest and NIH Chest X-ray datasets. Additionally, all development and test sets in CXR-LT 2026 are annotated by radiologists, providing a more reliable and clinically grounded evaluation than report-derived labels. The challenge defines two core tasks this year: (1) Robust Multi-Label Classification on 30 known classes and (2) Open-World Generalization to 6 unseen (out-of-distribution) rare disease classes. This paper summarizes the overview of the CXR-LT 2026 challenge. We describe the data collection and annotation procedures, analyze solution strategies adopted by participating teams, and evaluate head-versus-tail performance, calibration, and cross-center generalization gaps. Our results show that vision-language foundation models improve both in-distribution and zero-shot performance, but detecting rare findings under multi-center shift remains challenging. Our study provides a foundation for developing and evaluating AI systems in realistic long-tailed and open-world clinical conditions.

The rapid digitization of histopathology slides has opened new opportunities for computational tools in clinical and research workflows. Content-based slide retrieval can help pathologists identify morphologically and semantically related precedent cases, supporting expert diagnosis and example-based education. Effective retrieval of whole-slide images (WSIs), however, remains challenging because gigapixel slides contain abundant irrelevant content, focal diagnostic patterns and slide-level semantic information that must be represented at a practicable search cost. Here we present PathSearch, a retrieval framework that combines fine-grained attentive mosaics with slide-level embeddings aligned through vision-language contrastive learning. Trained on 6,926 slide-report pairs, PathSearch captures both fine-grained morphological cues and high-level semantic patterns to enable accurate and flexible retrieval. The framework supports two key functionalities: (1) mosaic-based image-to-image (I2I) retrieval, ensuring accurate and efficient slide search; and (2) multimodal retrieval, where text queries can directly retrieve relevant slides. PathSearch was evaluated on eight tasks comprising 5,021 evaluation slides, spanning malignancy assessment on frozen and hematoxylin and eosin (H&E)-stained slides, lymph-node metastasis detection, tumor subtyping, mixed-gallery rare-cancer retrieval, and hepatocellular carcinoma (HCC) risk stratification. Internal and external experimental results demonstrate that PathSearch consistently outperforms the strongest existing methods without compromising multimodal accuracy. A multi-center reader study further demonstrated increases in task-level mean diagnostic accuracy, confidence, and inter-observer agreement with PathSearch's support. Together, these results support the effectiveness of PathSearch across diverse retrieval tasks and evaluation settings.

Individuals with suspected rare genetic disorders often undergo multiple clinical evaluations, imaging studies, laboratory tests, and genetic tests over a prolonged period of time, a process commonly described as the diagnostic odyssey. Addressing this odyssey has substantial clinical, psychosocial, and economic benefits. Many rare genetic diseases have distinctive facial features that artificial intelligence algorithms can use to facilitate clinical diagnosis, to prioritize candidate diseases for further laboratory or genetic testing, and to support the phenotype-driven reinterpretation of genome or exome sequencing data. Existing methods that use frontal facial photographs were built on conventional convolutional neural networks, rely exclusively on facial images, and cannot capture non-facial phenotypic traits or demographic information that are essential for accurate diagnosis. Here we introduce GestaltMML, a multimodal machine learning approach based solely on the Transformer architecture. It integrates facial images, demographic information (age, sex, ethnicity), and clinical notes (optionally a list of Human Phenotype Ontology terms) to improve prediction accuracy. We evaluate GestaltMML on 528 diseases from the GestaltMatcher Database and on several in-house and published cohorts, including Beckwith-Wiedemann syndrome, Sotos syndrome, NAA10-related neurodevelopmental syndrome, Cornelia de Lange syndrome, and KBG syndrome. GestaltMML improves on the state-of-the-art image-only ensembled model, narrows the diagnostic accuracy gap for patients from under-represented ancestries, and clarifies when multimodal fusion is beneficial and when image-only inference is preferable. The results suggest that GestaltMML can greatly narrow the candidate diagnoses of rare diseases and may facilitate the reinterpretation of sequencing data.