Current evaluations of large language models (LLMs) primarily focus on factual knowledge retrieval, overlooking the fundamental challenge of navigating the complex, non-bijective mappings between clinical indicators and diagnoses. Existing benchmarks fail to assess whether large language models truly possess the reasoning capability required for diagnostic ambiguity scenarios, where identical clinical presentations may correspond to different etiologies, and diagnostic convergence scenarios, where heterogeneous symptoms ultimately indicate the same disease. To address this issue, we propose SUP-MIMIC, a multi-task framework utilizing MIMIC-IV-v3.1 that comprises Basic Assessment (BA), Diagnostic Divergence Task (DDT), and Diagnostic Convergence Task (DCT). Specifically, DDT is designed to evaluate the model's "one-to-many" disambiguation capability among phenotypically similar cases, while DCT assesses the model's ability to identify "many-to-one" diagnostic patterns across different pathophysiological pathways. Comprehensive evaluation of state-of-the-art LLMs reveals substantial performance degradation on DDT and DCT compared to baseline tasks, exposing a systemic reliance on statistical shortcuts over genuine causal reasoning. Our findings further highlight a conservative bias toward "healthy" predictions, implying non-trivial risks for missed diagnoses in realistic medical settings. This work establishes a rigorous methodology for quantifying clinical reasoning robustness and provides a roadmap for enhancing the safety of language models in clinical medicine.
Hashmat Shadab Malik, Anees Ur Rehman Hashmi, Numan Saeed +3cs.CV
Reasoning in multimodal large language models (MLLMs) has shown strong promise in medical imaging. However, this reasoning is usually free-form text judged only by its final answer, making it hard to interpret and verify, especially in 3D radiology, where a diagnosis should be traceable to evidence in the scan. Existing chest CT question-answering datasets compound this by reducing expert radiology reports to answer-only pairs, dropping the reasoning that links findings to conclusions and omitting the patient history clinicians rely on. As a result, reasoning-capable 3D chest CT MLLMs remain out of reach, as neither the structured supervision needed to train them nor the protocol needed to verify their reasoning yet exists. We introduce CORTEX (Clinically Organized Reasoning and sTructured EXplanation), a structured reasoning benchmark for 3D chest CT. For each question, CORTEX restores the missing reasoning as a four-stage diagnostic trace mirroring a radiologist's workflow: task understanding, visual observation, diagnostic reasoning, and answer synthesis. We generate these traces using frontier large language models with broad medical and general-domain knowledge, then filter and verify them with a stage-level evaluation protocol combining automated rubric scoring with expert radiologist review. Crucially, both the reasoning structure and evaluation rubrics are designed in close collaboration with clinicians. Built on CT-RATE, a large, publicly available chest CT dataset without reasoning annotations, CORTEX comprises 76,177 validated reasoning traces across open-ended VQA, closed-ended VQA, and report generation, providing both the structured supervision and the stage-level evaluation protocol needed to build and evaluate trustworthy reasoning models for 3D chest CT. Our dataset and evaluation code will be made publicly available upon acceptance.
DNA cis-regulatory elements (CREs) such as enhancers control gene expression levels. Accurately predicting regulatory activity from DNA sequences is valuable but challenging, as it requires understanding complex biological regulatory processes. Existing methods typically regress activity scores from sequences in a black-box manner, limiting both interpretability and regression performance. Meanwhile, large language models (LLMs) benefit from explicit reasoning processes, yet directly applying LLMs to raw DNA sequences performs poorly. In this paper, we bridge this gap by introducing R3LM, a framework that teaches LLMs reasoning-informed regression on regulatory DNA through structured biological knowledge. Specifically, we design a biologically grounded data format that structures DNA's regulatory information for improved LLM understanding, and construct CRE-ReasonBench, the first dataset that associates DNA sequences and activity scores with mechanistic reasoning traces. Through two-stage training that first teaches LLMs reasoning over structured biological information then performs regression, R3LM achieves state-of-the-art performance on enhancer prediction across three cell types, outperforming both LLMs with raw sequence input and specialized DNA models while providing interpretable mechanistic explanations. We expect R3LM as an interpretable reward model that can effectively assist biologists in CRE design. Code is available at https://github.com/DuanYi516/R3LM.