ICML 2026 论文列表

Reliable epidemic forecasting is critical for public health decision-making yet remains challenging due to data sparsity and the non-stationary nature of disease dynamics. While recent hybrid models attempt to integrate mechanistic principles with data-driven approaches, they often relegate mechanistic priors to merely auxiliary features or regularization terms. This design not only obscures the interpretability of the mechanistic contribution but also fails to inherit the capability of physical models to generalize under non-stationary dynamics, as the core architecture remains predominantly data-driven. To address these limitations, we propose EpiDiff, a unified framework that synergizes epidemiological domain knowledge with the generative power of diffusion models. Unlike methods that rigidly fuse features, EpiDiff employs a novel uncertainty-aware steering mechanism during inference. Specifically, we quantify the posterior uncertainty of mechanistic estimations and use it to dynamically modulate the diffusion process. Extensive experiments on real-world datasets demonstrate that EpiDiff consistently outperforms state-of-the-art baselines in accuracy and robustness, particularly under non-stationary distributions, while offering transparent insights into model reliance by explicitly visualizing when the forecast is governed by mechanistic laws versus data-driven patterns.

The rapid adoption of large language models (LLMs) in digital health has been driven by a "scaling-first" philosophy, i.e., the assumption that clinical intelligence increases with model size and data. However, real-world clinical needs include not only effectiveness, but also reliability and reasonable deployment cost. Since clinical decision-making is inherently collaborative, we challenge the monolithic scaling paradigm and ask whether a Small Agent Group (SAG) can support better clinical reasoning. SAG shifts from single-model intelligence to collective expertise by distributing reasoning, evidence-based analysis, and critical audit through a collaborative deliberation process. To assess the clinical utility of SAG, we conduct extensive evaluations using diverse clinical metrics spanning effectiveness, reliability, and deployment cost. Our results show that SAG achieves superior performance compared to a single giant model, both with and without additional optimization or retrieval-augmented generation. These findings suggest that the synergistic reasoning represented by SAG can substitute for model parameter growth in clinical settings. Overall, SAG offers a scalable solution to digital health that better balances effectiveness, reliability, and deployment efficiency.

We present SleepLM, a family of sleep-language foundation models that enable human sleep alignment, interpretation, and interaction with natural language. Despite the critical role of sleep, learning-based sleep analysis systems operate in closed label spaces (e.g., predefined stages or events) and fail to describe, query, or generalize to novel sleep phenomena. SleepLM bridges natural language and multimodal polysomnography, enabling language-grounded representations of sleep physiology. To support this alignment, we introduce a multilevel sleep caption generation pipeline that enables the curation of the first large-scale sleep-text dataset, comprising over 100K hours of data from more than 10,000 individuals. Furthermore, we present a unified pretraining objective that combines contrastive alignment, caption generation, and signal reconstruction to better capture physiological fidelity and cross-modal interactions. Extensive experiments on real-world sleep understanding tasks verify that SleepLM outperforms state-of-the-art in zero-shot and few-shot learning, cross-modal retrieval, and sleep captioning. Importantly, SleepLM also exhibits intriguing capabilities including language-guided event localization, targeted insight generation, and zero-shot generalization to unseen tasks. To support reproducibility and future work, we open-source the captioning pipeline, pretrained checkpoints, and the model architectures at https://github.com/yang-ai-lab/SleepLM.

Learning beneficial treatment allocations for a patient population is an important problem in precision medicine. For such allocations, a certain proportion of treated patients may not receive any benefit. This proportion of unnecessary treated represents a `treatment risk' which is a waste of resources and may, in addition, expose patients to unnecessary adverse effects. Therefore, we aim to control the treatment risk when learning beneficial allocations. This learning problem is complicated by the fact that the treatment risk is generally not identifiable from either randomized trial or observational data. We propose a certifiable learning method that controls treatment risk, using finite samples in the partially identified setting. The method is illustrated using both simulated and real data.

Despite the central role of sensor-derived measurements such as imaging traits and plasma biomarkers in biomedical research and clinical practice, existing generative models for disease prediction largely depend on event-level representations from hospital and registry data. Given the multi-factorial nature of human disease, the absence of explicit modeling of social determinants of health (SDoH) limits the capacity for personalized disease modeling and clinical decision support. To address this limitation, we propose a generative model with ICD-coded proxies of SDoH for \textit{in silico} modeling of disease reasoning, a conditioned latent diffusion framework that establishes the connection between multi-organ sensor data with tokenized healthcare events. Specifically, we introduce a novel geometric diffusion model to characterize the temporal evolution of complex data representation such as brain networks (region-to-region connectivity encoded in a graph), in parallel with diffusion models for tabular data from other organ systems. Together, we integrate the generative model with digitalized SDoH proxies (coined **DiffDT**) for simulated intervention and reasoning of future disease trajectories. We conduct extensive experiments on the UK Biobank (UKB) dataset, which contains organ-specific imaging traits, including brain (44,834), heart (23,987), liver (28,722), and kidney (32,155), along with nearly 500k medical history sequences (age range: 25$\sim$89 years). Our **DiffDT** achieves significant improvements over state-of-the-art human disease autoregressive models and imaging trait generative baselines.

Single-cell RNA sequencing provides insights into gene expression at single-cell resolution, yet inferring temporal processes from these static snapshot measurements remains a fundamental challenge. Current approaches utilizing neural differential equations and flows are sensitive to overfitting and lack careful considerations of biological variability. In this work, we propose a generative framework that models population trends using a latent heteroscedastic Gaussian process (GP) approximated by Hilbert space methods. To address the absence of genuine cell trajectories, we leverage an optimal transport (OT) objective that aligns generated and observed population distributions. Our method explicitly captures biological heterogeneity by incorporating cell-specific latent time and cell type conditioning to disentangle temporal asynchrony and trajectories to different cell types. We demonstrate state-of-the-art performance on complex interpolation and extrapolation benchmarks and introduce a novel gradient-based strategy for inferring perturbation trajectories.

The realization of autonomous scientific experimentation is currently limited by LLMs' struggle to grasp the strict procedural logic and accuracy required by biological protocols. To address this fundamental challenge, we present BioProBench, a comprehensive resource for procedural reasoning in biology. BioProBench is grounded in BioProCorpus, a foundational collection of 27,000 human-written protocols. From this corpus, we systematically constructed a dataset of over 550,000 task instances, offering both a large-scale training resource and a rigorous benchmark with novel metrics. Evaluating 10 mainstream LLMs, we find that while general comprehension is high, performance drops significantly on tasks demanding deep reasoning, quantitative precision, and safety awareness. To demonstrate the value of BioProCorpus in mitigating these issues, we developed \textbf{ProAgent}, grounded in our corpus, ProAgent substantially advances the state-of-the-art. Code and data are available at: https://github.com/YuyangSunshine/bioprotocolbench and https://huggingface.co/datasets/BioProBench/BioProBench .

Understanding how cellular morphology, gene expression, and spatial context jointly shape tissue function is a central challenge in biology. Image-based spatial transcriptomics technologies now provide high-resolution measurements of cell images and gene expression profiles, but existing methods typically analyze these modalities in isolation or at limited resolution. We address the problem by introducing SPATIA, a multi-level generative and predictive model that learns unified, spatially aware representations by fusing morphology, gene expression, and spatial context from the cell to the tissue level. SPATIA also incorporates a spatially conditioned generative framework with confidence-aware OT reweighting and morphology-profile alignment for modeling target-state morphology distributions. Specifically, we propose a confidence-aware flow matching objective that reweights weak optimal-transport pairs based on uncertainty. We further apply morphology-profile alignment to encourage biologically meaningful image generation, enabling the modeling of microenvironment-dependent phenotypic transitions. We assembled a multi-scale dataset consisting of 25.9 million cell-gene pairs across 17 tissues. We benchmark SPATIA against 18 models across 12 tasks, spanning categories such as phenotype generation, annotation, clustering, gene imputation, and cross-modal prediction. SPATIA achieves improved performance over state-of-the-art models, improving generative fidelity by 8\% and predictive accuracy by up to 3\%.

When reliable target structures are unavailable at scale or phenotypes arise from dysregulated pathways, transcriptomic perturbations provide a system-level functional readout for drug action. In this work, we formalize Transcriptome-based Drug Design (TBDD) as a generative inverse problem: designing drug molecules conditioned on desired transcriptomic state transitions. We analyze the inherently ill-posed nature of this task, which is further complicated by the profound domain gap between biology and chemistry and by the sparsity of transcriptomic signals. To address these challenges, we propose CURE (A CellUlar Response Engine), a multi-resolution transcriptome-guided diffusion framework. CURE features a specialized Transcriptome Perturbation Functional Feature Extractor (TFE) that (1) distills function-oriented perturbation embeddings from pre/post states, (2) aligns these signatures to dual chemical views to bridge the cross-modal gap, and (3) performs heterogeneity-aware aggregation to extract robust state-specific signals from noisy transcriptomic data. Extensive evaluations on both standard benchmarks and rigorous out-of-distribution protocols demonstrate that CURE consistently outperforms strong baselines in structural quality and functional consistency. Furthermore, we validate its practical utility via a zero-shot gene-inhibitor design task, highlighting the potential of phenotype-driven generative discovery.

Medical workflows routinely combine reading images with producing visual and textual outputs, making both image understanding and generation central to medical AI. Most existing systems, however, address these abilities in isolated models, losing the shared knowledge that a unified architecture could exploit. To bridge this gap, we present UniMedVL, the first unified medical model that seamlessly integrates multimodal understanding and generation capabilities within a single model without switching weights. We achieve this via a tailored progressive training pipeline where understanding and generation mutually reinforce each other. To effectively train UniMedVL, we curate UniMedVL-5M, the first large-scale medical dataset comprising over 5.6M instances across 8 medical imaging modalities, tailored for multimodal input-output tasks in unified medical understanding and generation. Experimental results demonstrate that UniMedVL achieves competitive performance on five medical understanding benchmarks. Crucially, UniMedVL natively supports diverse interleaved generation tasks, e.g., virtual staining, super-resolution, cross-modal synthesis, essential for complex medical workflows. Our code and dataset are publicly available.

Parameter-efficient adaptation has made LLMs practical for domain prediction, but standard LoRA still relies on a static low-rank update and does not expose the latent interactions that often drive scientific labels. We introduce iLoRA. To our knowledge, it is the first Bayesian graph-conditioned LoRA framework. It infers a latent interaction graph from the input and uses it to generate input-conditioned LoRA updates. As a result, iLoRA learns prediction and latent interaction structure jointly, rather than training a predictor and applying interaction analysis only post hoc. We instantiate this idea for microbiome diagnosis, where disease state can depend on both species-level abundance and microbe–microbe cross-talk, and evaluate it in two complementary settings: interactive QA with human-annotated graphs, which tests latent structure recovery, and multi-cohort IBD diagnosis, which tests biomedical utility. Across both settings, iLoRA improves over strong LoRA and Bayesian adaptation baselines, recovers graphs aligned with human annotations and cohort-level microbiome associations, and provides calibrated uncertainty with moderate graph-branch overhead.

Medical vision-language models (VLMs) have rapidly advanced as general-purpose multimodal assistants, yet their deployment in 3D Computed Tomography (CT) analysis remains constrained by a persistent mismatch between optimization objectives and clinical rigor. Current Reinforcement Learning (RL) paradigms still rely on lexical proxy signals that induce Evaluation Hallucinations, where models optimize linguistic fluency rather than factual clinical correctness, leading to diagnostically critical errors. To bridge this gap, we introduce the Clinical Abnormality Benchmarking Substrate (CABS), a structured system that decomposes radiology reports into verifiable clinical semantic units. Using CABS, we identify a Mechanistic Divergence in standard RL, where surface-similarity rewards drive policy gradients to bypass medical facts. We therefore propose Trajectory-Integral Feedback GRPO (TIF-GRPO), a novel framework integrating control-theoretic principles into policy optimization. By formulating clinical reasoning as a pseudo-temporal trajectory for anomaly discovery, TIF-GRPO regulates anatomy-aware rewards via an integral feedback loop that penalizes persistent omissions as cumulative state errors and suppresses hallucinations as excessive control effort. Experiments on 3D CT benchmarks demonstrate that our approach significantly enhances abnormality detection and clinical faithfulness, establishing a new paradigm for fine-grained regulation in medical VLMs. Our project is available at https://github.com/ZJU4HealthCare/TIF-GRPO.

Tertiary structure-based RNA design aims to generate RNA sequences that can fold into desired 3D structures, but remains a challenging problem due to the scarcity of annotated data, structural noise, and the intrinsic complexity of RNA topology. Existing structure-to-sequence frameworks largely rely on static k-nearest neighbor graphs and rigid message passing schemes, which fail to capture the flexible and heterogeneous nature of RNA geometry. To address these issues, we propose a unified framework, ATL-FGD, that integrates Adaptive Topology Learning (ATL) and FiLM-Guided Distillation (FGD) for robust RNA design. ATL introduces a differentiable edge gating mechanism to jointly learn topology and representation, enabling the model to construct data-driven, layer-adaptive graphs that better reflect structural dynamics and biochemical consistency. On top of this, FGD bridges structural and sequence representations via feature-wise linear modulation, softly transferring the semantic knowledge from RNA foundation models without relying on them during inference. Extensive experiments on tertiary structure-based RNA design benchmarks demonstrate that our approach achieves significant improvements in both sequence recovery and structural fidelity.

Estimating density ratios between pairs of intractable data distributions is a core problem in probabilistic modeling, enabling principled comparisons of sample likelihoods under different data-generating processes across conditions. While exact-likelihood models such as normalizing flows offer a promising approach to density ratio estimation, naive evaluations are computationally expensive and prone to discretization errors because they require simulating each distribution's likelihood independently. In this work, we leverage condition-aware flow matching to derive a single dynamical formulation for tracking density ratios along generative trajectories. We demonstrate competitive performance on simulated benchmarks for closed-form ratio estimation, and show that our method supports versatile tasks in single-cell genomics data analysis, where likelihood-based comparisons of cellular states across experimental conditions enable treatment effect estimation and batch correction evaluation.

Single-cell perturbation modeling is fundamental for understanding and predicting cellular responses to genetic perturbations. However, existing approaches, from causal representation learning to foundation models, often struggle with an overlooked challenge: gene expression is dominated by perturbation-invariant information, while perturbation-specific signals are intrinsically sparse. As a result, learned representations either entangle invariant and perturbation-specific information, leading to spurious and non-generalizable predictors, or suppress perturbation-specific signals altogether, rendering them ineffective for prediction. To address this, we propose PerturbedVAE, a general framework designed to resolve this signal imbalance. The framework explicitly separates perturbation-specific information from dominant invariant structure and recovers causal representations to effectively utilize such information for prediction. We further provide an identifiability analysis that characterizes the conditions under which sparse perturbation effects can be reliably recovered, thereby clarifying how the framework can be concretely specified under such conditions. Empirically, PerturbedVAE achieves state-of-the-art performance on a widely used benchmark across multiple evaluation settings, yielding significant gains on out-of-distribution combinatorial predictions and uncovering interpretable perturbation-response programs.

Proteins are inherently dynamic, with biological functions often emerging from transitions between multiple conformational states. While recent breakthroughs have largely addressed the static structure prediction problem, no systematic benchmark exists to demonstrate how well current models capture functionally relevant dynamics. We introduce ProMiSE, the first benchmark that provides both a dataset and an evaluation scheme, based on native biological assemblies and integrating major conformational change mechanisms—intrinsic, ligand-induced, and protein-induced—within a single curated dataset. We conducted a comprehensive evaluation of state-of-the-art structure prediction models, including AlphaFold3 and recent generative approaches. Our findings reveal that current models exhibit a limited ability to sample intrinsic multi-states and are often insensitive to biological context in induced scenarios. Internal representation analysis suggests that training-data exposure can shift predictions toward dominant conformational states over alternative biologically relevant states, primarily at the structure module. In contrast, results from BioEmu indicate that reducing decoding-stage bias can substantially improve multi-state sampling without major changes to upstream pair representations.

Generative modeling of three-dimensional (3D) molecules is a fundamental yet challenging problem in drug discovery and materials science. Existing approaches typically represent molecules as 3D graphs and co-generate discrete atom types with continuous atomic coordinates, leading to intrinsic learning difficulties such as heterogeneous modality entanglement and geometry–chemistry coherence constraints. We propose VecMol, a novel representation that models 3D molecules as continuous vector fields over Euclidean space, where vectors point toward nearby atoms and implicitly encode molecular structure. The vector field is parameterized by a neural field and generated using a latent diffusion model, avoiding explicit graph generation and decoupling structure learning from discrete atom instantiation. Experiments on the QM9 and GEOM-Drugs benchmarks demonstrate that VecMol achieves competitive generation quality, suggesting vector-field-based representations as a promising new direction for 3D molecular generation.

Reliable automatic seizure detection from long-term electroencephalogram recordings (EEG) remains an unsolved challenge, as current models often fail to generalize across patients or clinical settings. Manual EEG review still is the standard of care, highlighting the need for robust models and standardized evaluation. The current literature often reports high efficacy, yet these models frequently fail when deployed to unseen patient populations. To rigorously assess this generalization gap, we conducted a large-scale empirical study evaluating 28 state-of-the-art algorithmic architectures, ranging from classical feature engineering to modern Deep Learning. These algorithms were collected by organizing a competition. A strictly held-out private dataset of continuous EEG recordings from 65 subjects, totaling 4,360 hours of data, was utilized to evaluate algorithm performance. Expert neurophysiologists annotated these recordings, establishing the ground truth for seizure events. Algorithms were evaluated using event-based metrics from the SzCORE framework, including sensitivity, precision, F1-score, and false positive rate per day. Results revealed significant performance variability among state-of-the-art approaches, with the top F1 score of 32% (sensitivity 37%, precision 29%), highlighting the persistent difficulty of this task for current machine learning methodologies. Our analysis uncovered a discordance between peak performance and population-level stability. The algorithms achieving the highest aggregate F1-scores did not achieve the most consistent ranking across subjects, indicating high performance variance and susceptibility to failure on outlier patients. This independent evaluation also exposed a notable gap between self-reported efficacies and hold-out performance, underscoring the critical need for standardized, rigorous benchmarking in developing clinically viable ML models. A comparison with previous challenges and commercial systems indicates that the best algorithm in this study surpassed prior methods. Critically, the evaluation infrastructure transitions into a continuously open benchmarking platform, fostering reproducible research and accelerating the development of robust seizure detection algorithms by allowing ongoing submissions and integration of additional private datasets. Clinical centers can also adopt this platform to evaluate seizure detection algorithms on their EEG data using a standardized, reproducible framework.

Reasoning in knowledge-intensive domains remains challenging as intermediate steps are often not locally verifiable: unlike math or code, evaluating step correctness may require synthesizing clues across large external knowledge sources. As a result, subtle errors can propagate through reasoning traces, potentially never to be detected. Prior work has proposed process reward models (PRMs), including retrieval-augmented variants, but these methods operate post hoc, scoring completed trajectories, which prevents their integration into dynamic inference procedures. Here, we introduce Process Reward Agents (PRA), an inference-time method for providing domain-grounded, online, step-wise rewards to a frozen policy. In contrast to prior retrieval-augmented PRMs, PRA enables search-based decoding to rank and prune candidate trajectories at every generation step. Experiments on multiple medical reasoning benchmarks demonstrate that PRA consistently outperforms strong baselines, achieving 81.9% accuracy on MedQA with Qwen3-4B, a new state of the art at the 4B scale. Importantly, PRA generalizes to unseen frozen policy models ranging from 0.5B to 8B parameters, improving their accuracy by up to 25.7% without any policy model updates. More broadly, PRA suggests a paradigm in which frozen reasoners are decoupled from domain-specific reward modules, allowing the deployment of new backbones in complex domains without retraining. All code and data are publicly available at https://process-reward-agents.github.io/.