Differential Diagnosis
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2 papers in the last four weeks, against 1 the four weeks before. 0.0% of all new papers.
Latest papers 20
Patients often have several co-occurring clinical conditions, and the findings needed to identify and disambiguate them emerge over the course of a consultation. Evaluating clinical reasoning in this setting requires both multi-turn interaction and multi-label diagnosis. We introduce CLIMB, a benchmark in which a doctor model interviews a simulated patient to recover a ground truth set of co-occurring clinical conditions. Cases are synthesized from clinical decision algorithms and diagnostic datasets, grounding multimorbid presentations in structured clinical knowledge. Across six frontier and open models, none recovers the exact set of conditions in more than 10% of interactive cases. Diagnostic performance declines when conditions co-occur, even when models receive the full clinical record and the true number of conditions. Interaction reduces performance further. In controlled experiments, models behave like single-hypothesis trackers: they anchor on the diagnosis suggested by the opening findings, keep questioning around it, and recover a second condition mainly when a finding in view points to it. Questioning them further does not complete the set but adds mostly wrong diagnoses. We formalise this pattern with a theoretical reference model of single-hypothesis tracking. The benchmark, generator, and evaluation code are available at https://anonymous.4open.science/r/CLIMB-8340.
Hyperbolic Graph Representation Learning for Differential Diagnosis on Biomedical Knowledge Graphs
Biomedical knowledge graphs combine ontology-derived hierarchies with transversal associations among heterogeneous entities such as phenotypes, diseases, genes, proteins, and patients. This hybrid structure raises the question of whether hyperbolic embeddings, which naturally capture tree-like organization, remain useful beyond purely hierarchical graphs. We present a preliminary study of hyperbolic graph representation learning for Mendelian-disease differential diagnosis on a patient-integrated biomedical graph. Experiments on isolated ontology subgraphs show that hyperbolic models achieve strong performance in substantially lower dimensions than Euclidean baselines. We then evaluate the models on a link-prediction task that ranks candidate diseases for each patient. Results suggest that hyperbolic embeddings can exploit biomedical hierarchical structure while supporting diagnostic reasoning over heterogeneous patient-level graphs.
Social Chain of Thought: A Multi-Agent Architecture Grounded in Medical Differential Diagnosis Methodology
Medical diagnostic reasoning is a high-impact use case for LLMs that carries significant implications for the health and wellbeing of users. When OpenAI (2026) reports that more than 5% of ChatGPT messages globally are healthcare-related, the transparency of these systems becomes a serious design concern. This is especially true for complex cases, where differential diagnosis often requires integrating multiple forms of specialist reasoning. Existing work has proposed multi-agent approaches to medical diagnosis, but it remains unclear when such systems are needed, why they help, and where they outperform monolithic inference. We introduce Social Chain of Thought (SCoT),a multi-round pipeline for medical differential diagnosis that structures multi-agent interaction as a deliberative framework for collabora. tive LLM reasoning. Evaluating SCoT against single-agent baselines, one-agent pipeline ablations, and best-of-n scaling, we show that its recall advantage is not reproduced by monolithic inference alone. SCoT is most successful in the hardest diagnostic cases, where multiple rounds of specialist conversation help recover ground-truth diagnoses and converge on a higher-recall differential.
Auditing Evidence Use in Medical LLM Diagnosis
Medical LLMs are often evaluated by whether they select the correct diagnosis, but diagnostic accuracy alone does not show whether the model used the case evidence appropriately. We present a behavioral audit of evidence use in medical diagnosis. For each case, we decompose patient information into evidence units, score candidate diagnoses under controlled evidence subsets, and mine low-order interactions in diagnostic margins. Because medical evidence is diagnosis-relative, the audit separates interaction discovery from failure assignment: large or negative interactions can reflect plausible differential diagnosis, while suspicious interactions require robustness checks and clinical review. We evaluate five open-weight LLMs on DDXPlus, CupCase, and MedCase. Across datasets, faithful support and differential conflict or cancellation account for most interaction strength, showing that many evidence interactions are clinically plausible rather than failures. In a DDXPlus-focused blinded five-reviewer 130-item enriched review sample, invalid or shortcut-like cases concentrate in negated or absent findings and clinically local evidence. These results show that accuracy can hide candidate evidence-use failures and motivate role-aware audits for medical LLM evaluation.
Aletheia: An Offline-First Clinical Decision Support System for Differential Diagnosis in Low-Resource Healthcare Settings
Access to specialist clinical expertise remains severely limited across sub-Saharan Africa, where physician-to-patient ratios can fall below 1:25,000 in rural settings. Existing AI-assisted diagnostic tools predominantly require reliable internet connectivity and high-specification hardware, rendering them impractical for frontline healthcare workers in district hospitals and health centres. This paper presents Aletheia, an offline-first clinical decision support system designed for low-resource healthcare contexts across sub-Saharan Africa. Aletheia is built upon Qwen2.5-3B-Instruct, fine-tuned using Quantised Low-Rank Adaptation (QLoRA) on a curated dataset of 27,000 clinical reasoning samples spanning 50 disease conditions with elevated prevalence in East Africa. Evaluation demonstrates a Top-1 diagnostic accuracy of 80% (8 of 10 cases; 95% CI 49.0-94.3%), Top-3 accuracy of 100% (10 of 10; 95% CI 72.2-100%), BERTScore-F1 of 0.909, and METEOR of 0.467. These diagnostic figures are computed over a deliberately small set of ten representative clinical case categories, one case each, and are therefore indicative rather than statistically robust; the wide confidence intervals should be read alongside them. The system achieves an Expected Calibration Error (ECE) of 0.275 and passes the Africa Deep Tech Challenge 2026 (ADTC 2026) memory budget constraint of 7,168 MB, achieving a peak inference RAM of approximately 3,630 MB on the standardised benchmark laptop. These results demonstrate the feasibility of deploying large language model-based clinical reasoning at the primary care level in resource-constrained settings without cloud infrastructure.
A safety-oriented hypothetico-deductive framework for AI-assisted differential diagnosis
Diagnostic error is a major threat to patient safety, yet current large language model (LLM) systems often treat diagnosis as a one-shot prediction task, lacking safeguards against missed high-risk alternatives or rigorous verification of their reasoning. Here, we present AegisDx, a safety-oriented framework for hypothetico-deductive clinical reasoning. AegisDx coordinates specialized LLM components through role-specific contracts, structured intermediate outputs, evidence-retrieval interfaces, and verification gates to generate broad differential diagnoses, enforce explicit screening for dangerous "must-not-miss" conditions, verify reasoning against grounded medical evidence, and structure actionable next steps. We evaluated AegisDx across three layers. On literature-derived case reports from NEJM and JAMA, with GPT-oss-120B as the shared backbone, Top-3 diagnostic accuracy was 59.9% versus 52.1% for the standalone LLM on JAMA cases and 62.7% versus 51.4% on NEJM cases. On cases from Annals of Emergency Medicine, Top-3 accuracy was 85.7% versus 68.6%; against physician-consensus must-not-miss diagnosis sets, AegisDx captured at least one such condition among its top three diagnoses in 78.0% of cases versus 52.0%. In a blinded physician evaluation of 43 real-world emergency department notes from the Yale New Haven Health System compared against GPT-5, AegisDx improved the physician-rated composite safety score from 4.31 to 4.55 on a 5-point scale (adjusted p = 2.1x10^-4), with qualitative gains in must-not-miss identification and reasoning safety. Our findings suggest that engineering diagnostic AI as a safety-oriented reasoning framework, rather than optimizing raw predictive accuracy alone, can provide a safer, more transparent, and clinically meaningful layer of bedside decision support for acute care workflows.
Ekka: Automated Diagnosis of Silent Errors in LLM Inference
LLM serving frameworks are quickly evolving with a complex software stack and a vast number of optimizations. The rapid development process can introduce silent errors where output quality silently degrades without any explicit error signals. Diagnosing silent errors is notoriously difficult due to the substantial semantic gap between the high-level symptoms and the low-level root causes. We observe that diagnosis of silent errors can be effectively framed as a differential debugging problem by leveraging the existence of semantically correct reference implementations. We propose Ekka, an automated diagnosis system that identifies root causes by systematically aligning and comparing intermediate execution states between a target and a reference framework. We constructed a benchmark of real-world silent errors from popular serving frameworks, where Ekka shows 80% pass@1 diagnosis accuracy and 88% pass@5 diagnosis accuracy, outperforming state-of-the-art systems. Ekka also diagnoses 4 new silent errors from serving frameworks, all of which have been confirmed by the developers.
Gender-Dependent Diagnostic Substitution in LLM Medical Triage: Same Symptoms, Unequal Urgency
We investigate whether large language models produce different medical triage recommendations for identical neurological symptoms when only the patient's stated gender and age vary. Using three model families--Gemini 3.5 Flash, Claude Sonnet 4.6, and GPT-5.4-mini--we present a standardized symptom profile (persistent headache, blurred vision, morning nausea, visual disturbances) across seven demographic conditions: three age groups (25, 38, 65) x two genders (male, female), plus a gender-unspecified baseline (n = 30 per condition per model, 630 total trials). We find a stark, systemic gender-dependent triage disparity: young women receive significantly lower emergency room (ER) referral rates than age-matched men (Gemini: 0% vs. 23.3%; Claude: 6.7% vs. 96.7%; GPT: 6.7% vs. 66.7%, all p < 0.001). The disparity disappears at age 65 for all models. The primary mechanism is diagnostic substitution: the models anchor on a gender-associated diagnosis, preferentially classifying young women with Idiopathic Intracranial Hypertension (IIH)--a condition epidemiologically linked to women of childbearing age--while diagnosing men with generic increased intracranial pressure with space-occupying lesions in the differential. This diagnostic closure routes female patients to lower-urgency care (outpatient doctor appointments) despite comparable severity ratings (7-9/10). Our findings demonstrate that clinical LLMs replicate documented human clinical biases by using epidemiological priors to suppress triage urgency, suggesting that AI triage engines must decouple urgency assessment from probabilistic diagnostic priors. We release all code, prompts, and raw results.
DDX-TRACE: A Benchmark for Medical Diagnostic Trajectories in VLMs
Medical diagnosis is not a single prediction from a fully specified vignette. It is a sequential workup: clinicians decide what evidence to obtain, revise a differential diagnosis, and stop when the diagnosis is sufficiently supported. Most medical AI benchmarks instead reveal the relevant context upfront and score only the final answer, making unsupported correct guesses, premature closure, inefficient workups, and poor uncertainty updating invisible. We introduce DDX-TRACE, a physician-adjudicated benchmark for multimodal neuroradiology that evaluates diagnostic trajectories under hidden evidence over 211 challenging cases. Each case begins with limited clinical history; models request imaging studies in free form, receive matched image bundles when available, update a probabilistic differential diagnosis after each turn, and stop with a localized final diagnosis. Evaluating state-of-the-art VLMs, we find that final diagnosis scores can substantially misrepresent workup quality: models may guess plausible diagnoses without essential evidence, request useful studies but misinterpret raw images, or acquire evidence inefficiently while updating uncertainty poorly. Controlled evidence variants isolate bottlenecks in planning, visual evidence extraction, and downstream differential reasoning. DDX-TRACE shifts medical AI evaluation from final answers to evidence-supported diagnostic trajectories.
MedExpMem: Adapting Experience Memory for Differential Diagnosis
Experienced physicians develop diagnostic expertise through clinical practice, acquiring not only disease knowledge but also the ability to differentiate confusable conditions. Current medical vision-language models (VLMs) lack this capability -- their parameters encode static knowledge that does not evolve across diagnostic encounters. We propose MedExpMem, an experience memory framework enabling VLM-based diagnostic agents to accumulate differential diagnosis expertise. Unlike retrieval-augmented generation, which retrieves encyclopedic disease descriptions, MedExpMem memorizes discriminative experience derived from the agent's own diagnostic failures and organizes them as pairwise differential notes encoding key discriminators, actionable decision rules and reasoning error patterns. The framework adopts a two-phase construction process mirroring physician learning: initial practice exposes knowledge gaps, and reflective re-diagnosis refines understanding. When encountering new cases, the agent retrieves experience memory to guide differential reasoning. We evaluate MedExpMem on a radiology benchmark spanning 11 subspecialties. Results demonstrate consistent accuracy improvements, maximum 7.0%, across diverse models and scales. Analytical experiments validate experience quality and robustness, demonstrating MedExpMem as a competitive method addresses medical adaptation needs beyond the reach of parameteric learning.
Medical Model Synthesis Architectures: A Case Study
Medicine is rife with high-stakes uncertainty. Doctors routinely make clinical judgments and decisions that juggle many fundamental unknowns, like predictions about what might be causing a patients' symptoms or decisions about what treatment to try next. Despite increasing interest in developing AI systems that aid or even replace doctors in clinical settings, current systems struggle with calibrated reasoning under uncertainty, and are often deeply opaque about their reasoning. We propose a framework for AI systems that can make practically useful but formally transparent clinical predictions under uncertainty. Given a clinical situation, our framework (MedMSA) uses language models to retrieve relevant prior knowledge, but constructs a formal probabilistic model to support calibrated and verifiable inferences under uncertainty. We show how an initial proof-of-concept of this framework can be used for differential diagnosis, producing an uncertainty-weighted list of potential diagnoses that could explain a patients' symptoms, and discuss future applications and directions for applying this framework more generally for safe clinical collaborations.
MedAction: Towards Active Multi-turn Clinical Diagnostic LLMs
Most existing LLM diagnoses are evaluated on static, single-turn settings where complete patient information is provided upfront, an oversimplification of real clinical practice. We study active diagnosis: the real-life clinical process of starting from initial observation, ordering tests, interpreting results, and updating a differential diagnosis across multiple turns. Through systematic analysis, we identify three recurring failure modes in current LLMs: ungrounded test ordering, unreliable diagnostic update, and degraded multi-turn coherence. Together, these failures reveal a core deficit: existing medical training data teaches models to reason from complete information but not to act under evolving, partial evidence. To address this gap, we introduce MedAction, a tree-structured distillation pipeline that synthesizes diverse and high-quality multi-turn diagnostic trajectories via LLM-environment interaction. We propose two knowledge-graph-grounded metrics to filter trajectory quality: Disease Trajectory Consistency (DTC), which tracks whether the model's hypothesis converges toward the correct diagnosis, and Reasoning-Action Consistency (RAC), which verifies that belief updates are driven by gathered evidence. Using this pipeline, we construct MedAction-32K, a dataset of 32,681 trajectories from 2,896 PMC cases. Fine-tuning an 8B model on MedAction-32K achieves state-of-the-art performance among open-source models on both MedR-Bench and our curated MedAction-300-Hard benchmark, pushing the edge for open-source medical LLMs.
SymptomAI: Toward a Conversational AI Agent for Everyday Symptom Assessment
Language models excel at diagnostic assessments on curated medical case-studies and vignettes, performing on par with, or better than, clinical professionals. However, existing studies focus on complex scenarios with rich context making it difficult to draw conclusions about how these systems perform for patients reporting symptoms in everyday life. We deployed SymptomAI, a set of conversational AI agents for end-to-end patient interviewing and differential diagnosis (DDx), via the Fitbit app in a study that randomized participants (N=13,917) to interact with five AI agents. This corpus captures diverse communication and a realistic distribution of illnesses from a real world population. A subset of 1,228 participants reported a clinician-provided diagnosis, and 517 of these were further evaluated by a panel of clinicians during over 250 hours of annotation. SymptomAI DDx were significantly more accurate (OR = 2.56, p < 0.001) than those from independent clinicians given the same dialogue in a blinded randomized comparison. Moreover, agentic strategies which conduct a dedicated symptom interview that elicit additional symptom information before providing a diagnosis, perform substantially better than baseline, user-guided conversations (p < 0.001). An auxiliary analysis on 1,509 conversations from a general US population panel validated that these results generalize beyond wearable device users. We used SymptomAI diagnoses as labels for all 13,917 participants to analyze over 500,000 days of wearable metrics across nearly 400 unique conditions. We identified strong associations between acute infections and physiological shifts (e.g., OR > 7 for influenza). While limited by self-reported ground truth, these results demonstrate the benefits of a dedicated and complete symptom interview compared to a user-guided symptom discussion, which is the default of most consumer LLMs.
Are Multimodal LLMs Ready for Clinical Dermatology? A Real-World Evaluation in Dermatology
Multimodal large language models (MLLMs) have demonstrated promise on publicly available dermatology benchmarks. However, benchmark performance may not generalize to real-world dermatologic decision-making. To quantify this benchmark-to-bedside gap, we evaluated four open-weight MLLMs (InternVL-Chat v1.5, LLaVA-Med v1.5, SkinGPT4 and MedGemma-4B-Instruct) and one commercial MLLM (GPT-4.1) across three publicly available dermatology datasets and a retrospective multi-site hospital-based dermatology consultation cohort comprising 5,811 cases and 46,405 clinical images. Models were evaluated on two clinically relevant tasks: differential diagnosis generation and severity-based triage. Diagnostic performance was modest on public datasets and declined substantially in the real-world cohort. On public benchmarks, top-3 diagnostic accuracy reached 26.55% for the best open-weight model and 42.25% for GPT-4.1. On real-world consultation cases using images alone, top-3 diagnostic accuracy fell to 1.50%-13.35% among open-weight models and 24.65% for GPT-4.1. Incorporating clinical context improved performance across all models, increasing top-3 diagnostic accuracy up to 28.75% among open-weight models and 38.93% for GPT-4.1. However, model outputs were highly sensitive to incomplete or erroneous consultation context. For severity-based triage, models achieved moderate sensitivity (above 60%), suggesting potential utility for screening but insufficient reliability for clinical deployment. These findings demonstrate that benchmark performance substantially overestimates the real-world clinical capability of current dermatology MLLMs.
MultiDx: A Multi-Source Knowledge Integration Framework towards Diagnostic Reasoning
Diagnostic prediction and clinical reasoning are critical tasks in healthcare applications. While Large Language Models (LLMs) have shown strong capabilities in commonsense reasoning, they still struggle with diagnostic reasoning due to limited domain knowledge. Existing approaches often rely on internal model knowledge or static knowledge bases, resulting in knowledge insufficiency and limited adaptability, which hinder their capacity to perform diagnostic reasoning. Moreover, these methods focus solely on the accuracy of final predictions, overlooking alignment with standard clinical reasoning trajectories. To this end, we propose MultiDx, a two-stage diagnostic reasoning framework that performs differential diagnosis by analyzing evidence collected from multiple knowledge sources. Specifically, it first generates suspected diagnoses and reasoning paths by leveraging knowledge from web search, SOAP-formatted case, and clinical case database. Then it integrates multi-perspective evidence through matching, voting, and differential diagnosis to generate the final prediction.~Extensive experiments on two public benchmarks demonstrate the effectiveness of our approach.
MIND: Unified Inquiry and Diagnosis RL with Criteria Grounded Clinical Supports for Psychiatric Consultation
Psychiatric consultation requires agents to elicit discriminative evidence, map uncertain narratives to diagnostic criteria, and decide when evidence suffices. Existing dialogue and retrieval-augmented systems condition policies on raw histories or appended passages, leaving observed evidence, missing checks, differentials, and support reliability entangled. We introduce MIND, a criteria-grounded evidence-state decision interface. At each turn, MIND constructs a typed state containing observed evidence, unresolved criterion checks, active differentials, criterion-linked supports, and reliability metadata. A training-split Psychiatric Reasoning Bank supplies gated supports, turning retrieval into state construction rather than prompt injection. The same state conditions action selection, process rewards, information-gain scoring, and trajectory rectification. Under EMR-grounded simulator protocols, MIND improves accuracy by 8.8 and 7.3 points over strong inference-only, RAG, and RL baselines, with gains transferring to public MDD-5k dialogues. Matched interventions attribute these gains to the shared state rather than prompt length, retrieval text, or formatting. MIND targets screening-level decision support, not autonomous diagnosis. Code is available at https://github.com/Lingxi-mental-health/MIND.Å
Think Like a Doctor: Conversational Diagnosis through the Exploration of Diagnostic Knowledge Graphs
Conversational diagnosis requires multi-turn history-taking, where an agent asks clarifying questions to refine differential diagnoses under incomplete information. Existing approaches often rely on the parametric knowledge of a model or assume that patients provide rich and concrete information, which is unrealistic. To address these limitations, we propose a conversational diagnosis system that explores a diagnostic knowledge graph to reason in two steps: (i) generating diagnostic hypotheses from the dialogue context, and (ii) verifying hypotheses through clarifying questions, which are repeated until a final diagnosis is reached. Since evaluating the system requires a realistic patient simulator that responds to the system's questions, we adopt PatientSim, a persona-driven patient simulator, together with patient profiles from MIMIC-IV. We further adapt it with low-specificity symptom reporting to reflect how real-world patients describe symptoms vaguely during early clinical encounters. Experiments show improved diagnostic accuracy and efficiency over strong baselines, and physician evaluations support the realism of our simulator and the clinical utility of the generated clarifying questions. Our code will be released upon publication.
Few shot chain-of-thought driven reasoning to prompt LLMs for open ended medical question answering
In this paper, we propose a modified version of the MedQA-USMLE dataset, named MEDQA-OPEN, which contains open-ended medical questions without options to mimic clinical scenarios, along with clinician-approved reasoned answers. Additionally, we implement a prompt driven by Chain of Thought (CoT) reasoning, CLINICR, to mirror the prospective process of incremental reasoning, reaching a correct response to medical questions. We empirically demonstrate how CLINICR outperforms the state-of-the-art 5-shot CoT-based prompt (Liévin et al., 2022). We also present an approach that mirrors real-life clinical practice by first exploring multiple differential diagnoses through MCQ-CLINICR and subsequently narrowing down to a final diagnosis using MCQ-ELIMINATIVE. Finally, emphasizing the importance of response verification in medical settings, we utilize a reward model mechanism, replacing the elimination process performed by MCQ-ELIMINATIVE.
MedCollab: IBIS-Guided Multi-Agent Collaboration with Hierarchical Disease Relation Chains for Clinical Diagnosis
Clinical diagnosis is a gradual process of evidence integration, in which physicians move from symptoms and medical history to examinations, competing hypotheses, disease relations, and treatment decisions. Large language models have advanced medical text understanding and generation. Yet their clinical use remains limited by weak evidence grounding, opaque reasoning, and inconsistent links among differential diagnosis, final diagnosis, diagnostic basis, and treatment planning. We introduce MedCollab, a multi-agent framework for full-cycle clinical diagnosis and report generation. MedCollab coordinates specialist and examination agents according to patient records. It structures agent deliberation with an Issue-Based Information System (IBIS) protocol, so that each diagnostic position is supported by patient-specific evidence and medical knowledge. It also builds Hierarchical Disease Relation Chains (HDRC) to connect accepted hypotheses through progression, complication, and comorbidity relations. During multi-round deliberation, a verifier-guided consensus module evaluates evidence support, medical plausibility, and logical conflicts. It then adjusts agent contributions and filters unsupported reasoning. Experiments on ClinicalBench and MIMIC-IV show that MedCollab outperforms leading LLMs and medical multi-agent baselines in diagnostic accuracy, evidence consistency, and clinical reasoning quality. These results indicate that structured and auditable collaboration can produce more faithful and clinically coherent diagnostic reports.
NSIDDx: A Design Framework for Neuro-Symbolic, Practitioner-First Differential Diagnosis in Low-Resource Settings
LLM-based diagnostic systems achieve high semantic accuracy on benchmarks, but open-ended evaluation on clinically uncommon presentations reveals a systematic gap between headline accuracy and verifiable clinical reliability. We evaluate an LLM+rare-disease-RAG pipeline across two cohorts and show that the paradigm produces confident outputs that are frequently unverifiable and systematically resistant to clinician interrogation. We present NSIDDx (Neuro-Symbolic Integrated Differential Diagnosis System), a design framework arguing that DDx systems in low-resource settings must treat the clinician as an active reasoning agent. We instantiate this through a neuro-symbolic pipeline with ternary symptom encoding, contradiction detection, audit strings, and practitioner override - running offline on consumer hardware. We distill five design principles for clinician-in-the-loop clinical NLP and invite the prospective studies needed to validate the claim at scale.