ICML 2026 论文列表

Deep learning in de novo protein design has achieved atomic-level fidelity. However, existing models remain largely non-deliberative: they directly synthesize molecular geometries without explicitly reasoning about which residues or interactions are functionally essential. As a result, design decisions are entangled with continuous sampling dynamics, limiting interpretability, controllability, and systematic reuse of biochemical knowledge. We introduce Proteo-R1, a reasoning-guided protein design framework that explicitly decouples molecular understanding from geometric generation. Proteo-R1 adopts a dual-expert architecture, where a multimodal large language model (LLM) serves as an understanding expert, analyzes protein sequences, structures, and textual context to identify key functional residues that govern binding and specificity. These residue-level decisions are then passed to a separate diffusion-based generation expert, which performs conditional co-design while respecting the fixed interaction anchors. This factorization mirrors how human experts approach molecular engineering: first, reasoning about critical interactions, then optimizing geometry subject to those constraints. By operationalizing reasoning as explicit residue-level commitments rather than latent textual guidance, Proteo-R1 achieves stable, interpretable, and modular integration of LLM reasoning with advanced geometric generative models. Code and demos are at https://proteor1.github.io.

Reliable medical audio diagnosis requires models that are both accurate and honest about their uncertainty. However, fine-tuned models on small, imbalanced datasets often become overconfident due to norm bias, where predictions rely on feature magnitude rather than semantic alignment. The Equiangular Tight Frame (ETF) provides a theoretical optimum for class separation and is effective for imbalanced and calibration tasks due to its maximal angular separability and geometric fairness, but existing ETF-based methods perform poorly on noisy medical data because gradient rotation is unstable and fixed ETFs cannot adapt to drifting prototypes. To address this, we propose Spherical Procrustes Alignment (SPA), which combines spherical constraints with dynamic ETF alignment. SPA uses a Spherical branch to eliminate norm bias via normalization and a Geometric branch to adapt features and align a fixed ETF with drifting prototypes via dynamic Procrustes alignment, while a self-alignment mechanisms fuses the two branches to jointly optimize logits. Experiments on ICBHI 2017 and CirCor DigiScope show that SPA achieves state-of-the-art performance and transforms pre-trained models into reliable and efficient clinical tools without extra inference cost.

Effective DNA modeling demands the integration of complex patterns such as local motifs, long-range dependencies, and periodic signals. Yet, architectures like CNNs, Transformers, and SSMs are hindered by static or time-domain-exclusive designs, which limit their representational flexibility. To address this, we introduce the **Synergistic Plasticity Unit (SPU)**, a scalable architecture that achieves multi-level plasticity through three synergistic layers. Specifically, SPU integrates a *Locus Plasticity Layer* (LPL) to capture fine-grained local motifs via token-specific convolution operations, while utilizing a *Domain Plasticity Layer* (DPL) to form multi-domain global features by concurrently modeling sequential (time) and spectral (frequency) patterns. Furthermore, it incorporates a *Saliency Plasticity Layer* (SPL) to optimize information flow through dual-axis saliency scoring. Supported by theoretical analysis, extensive empirical validation, and in-depth biological interpretation, this unified design enables SPU to achieve state-of-the-art performance with quasi-linear complexity, establishing a robust and principled paradigm for DNA modeling.

Recent medical MLLMs have made significant progress in generating step by step textual reasoning chains. However, they still struggle with complex clinical tasks that necessitate dynamic and iterative focusing on fine-grained visual regions. To close this gap, we introduce Ophiuchus, a versatile, tool-augmented framework that equips an MLLM to (i) decide when fine-grained visual evidence is needed, (ii) determine where to probe and ground within the medical image, and (iii) seamlessly weave the relevant sub-image content back into an interleaved, multimodal chain of thought for precise segmentation and diagnosis. Ophiuchus moves beyond mere tool-calling by tightly fusing the MLLM’s inherent grounding and reasoning capabilities with external tools, enabling more accurate and trustworthy decisions. The core of our method is a three-stage training strategy: cold-start SFT for basic tool selection; self-reflection fine-tuning to strengthen decision revision; and agentic tool reinforcement learning to elicit sophisticated, expert-like diagnostic behaviors. Extensive experiments show that Ophiuchus consistently outperforms both closed-source and open-source SOTA methods across diverse medical benchmarks, including VQA, detection, and reasoning-based segmentation. Our project code is available at https://github.com/SII-zyj/Ophiuchus.

This paper introduces a novel cross-physiology translation task: synthesizing sleep electroencephalography (EEG) from respiration signals. To address the significant complexity gap between the two modalities, we propose a waveform-conditional generative framework that preserves fine-grained respiratory dynamics while constraining the EEG target space through discrete tokenization. Trained on over 28,000 individuals, our model achieves a 7% Mean Absolute Error in EEG spectrogram reconstruction. Beyond reconstruction, the synthesized EEG supports downstream tasks with performance comparable to ground truth EEG on age estimation (MAE 5.0 vs. 5.1 years), sex detection (AUROC 0.81 vs. 0.82), and sleep staging (Accuracy 0.84 vs. 0.88), significantly outperforming baselines trained directly on breathing. Finally, we demonstrate that the framework generalizes to contactless sensing by synthesizing EEG from wireless radio-frequency reflections, highlighting the feasibility of remote, non-contact neurological assessment during sleep.

Multi-modal neuroimaging-based psychiatric diagnosis must integrate cross-modal agreement with modality-specific complementarity, yet in real multi-site cohorts these signals are frequently entangled with site- and cohort-dependent correlations, yielding shortcut-driven predictions and limited interpretability. We propose Structured Multi-modal Graph Disentanglement (SMGD), which explicitly factorizes multi-modal graph representations into four components with distinct roles: shared diagnostic evidence, complementary diagnostic evidence, incidental cross-modal agreement, and modality-specific non-robust correlations, with the former two forming the diagnostic core and the latter two suppressed as shortcuts. SMGD is realized as geometry-driven structure learning: under a mild distributional assumption, we develop mini-batch estimable surrogate regularizers that shape subspace organization and cross-modal relations, enforcing semantic consistency through relational geometry rather than centroid coincidence while suppressing confounded dependencies. Experiments on large multi-site datasets show improved in-domain diagnosis and more reliable cross-dataset generalization in the presence of a Modality Gap, without relying on expert-crafted diagnostic biomarkers.

Survival analysis is a cornerstone of clinical research by modeling time-to-event outcomes such as metastasis, disease relapse, or patient death. Unlike standard tabular data, survival data often come with incomplete event information due to dropout, or loss to follow-up. This poses unique challenges for synthetic data generation, where it is crucial for clinical research to faithfully reproduce both the event-time distribution and the censoring mechanism. In this paper, we propose SurvDiff, an end-to-end diffusion model specifically designed for generating synthetic data in survival analysis. SurvDiff is tailored to capture the data-generating mechanism by jointly generating mixed-type covariates, event times, and right-censoring, guided by a survival-tailored loss function. The loss encodes the time-to-event structure and directly optimizes for downstream survival tasks, which ensures that SurvDiff (i) reproduces realistic event-time distributions and (ii) preserves the censoring mechanism. Across multiple datasets, we show that SurvDiff outperforms state-of-the-art generative baselines in both distributional fidelity and survival model evaluation metrics across multiple medical datasets. To the best of our knowledge, SurvDiff is the first end-to-end diffusion model explicitly designed for generating synthetic survival data.

Genomic language models (gLMs) achieve strong performance across genomic prediction tasks, but their internal biological representations remain poorly understood. Sparse autoencoders (SAEs) have emerged as an interpretability tool in vision and natural language models, yet their applicability to gLMs remains unexplored. We present a systematic study of SAE-based interpretability for gLMs, introducing a diverse benchmark of human genomic annotations and a suite of genome-tailored interpretability metrics. Using Evo2 as a primary case study, we show that SAE features, particularly those from intermediate layers, are more interpretable than raw model embeddings across 42/55 (76%) of our genomic concept evaluations, with 26 of them having an F1 score greater than 0.7. We further find that interpretability depends on SAE training data properties such as evolutionary proximity and context length. Finally, to organize semantically related genomic concepts learned by an SAE, we develop a graph-based representation method that outperforms the baseline approach of using SAE model weights. We demonstrate how our framework can extend SAEs as a powerful approach for not only better understanding gLMs but also for adopting them in disease-driven genomic explorations.

Recent advances in $\textit{de novo}$ protein binder design have enabled increasing experimental validation, yet reported $\textit{in silico}$ metrics remain difficult to interpret or compare across studies due to non-standardized evaluation protocols. We introduce $\textbf{ProtDBench}$, a standardized and throughput-aware evaluation framework for protein binder design. ProtDBench defines unified benchmark tasks, evaluation protocols, and success criteria, enabling systematic analysis of how evaluation design influences observed performance. Using a large wet-lab annotated dataset, we analyze commonly used structure prediction models as evaluation verifiers, revealing substantial verifier-dependent bias and limited agreement under identical filtering protocols. We then benchmark representative open-source generative binder design methods across ten diverse protein targets under a fixed evaluation protocol. Beyond per-sequence success rates, ProtDBench incorporates throughput-aware metrics based on a fixed 24-hour budget, as well as cluster-level success criteria to account for structural diversity. Together, these results expose systematic differences induced by filtering rules, success definitions, and throughput-aware evaluation between computational efficiency, success rate, and structural diversity. Overall, ProtDBench provides a fair and reproducible evaluation pipeline that supports systematic and controlled comparison of protein binder design methods under realistic evaluation settings.

Structure-Based Drug Design (SBDD) aims to discover bioactive ligands. Conventional approaches construct probability paths separately in Euclidean and probabilistic spaces for continuous atomic coordinates and discrete chemical categories, leading to a mismatch with the underlying statistical manifolds. We address this issue by representing molecules using composite exponential-family distributions, where coordinates and categories are represented within a unified natural parameter space to evolve synchronously along exponential geodesics under the Fisher-Rao metric. To avoid the instantaneous trajectory collapse induced by geodesics directly targeting Dirac distributions, we propose Evolving Exponential Geodesic Flow for SBDD (EvoEGF-Mol), which replaces static Dirac targets with dynamically concentrating distributions and is trained with a progressive-parameter-refinement architecture. Our model approaches a reference-level PoseBusters passing rate (93.4%) on CrossDock, demonstrating remarkable geometric precision and interaction fidelity, while achieving superior performance over baseline methods on real-world MolGenBench tasks for bioactive scaffold recovery. Code is available at https://github.com/BLEACH366/EvoEGF-Mol.

Integrating language models (LMs) in healthcare systems holds great promise for improving medical workflows and decision-making. However, a critical barrier to their global adoption is the lack of reliable evaluation of their trustworthiness in multilingual healthcare settings. Existing LMs are predominantly trained in high-resource languages, making them ill-equipped to handle the complexity and diversity of healthcare queries in mid- and low-resource languages, which poses significant challenges for deployment in global healthcare contexts where linguistic diversity is essential. In this work, we present CLINIC, a Comprehensive Multilingual Benchmark to evaluate the trustworthiness of language models in healthcare. CLINIC systematically benchmarks LMs across five key dimensions of trustworthiness: truthfulness, fairness, safety, robustness, and privacy, operationalized through 18 diverse tasks spanning 15 languages and covering a wide range of critical healthcare topics. Our extensive evaluation reveals that LMs struggle with factual correctness, demonstrate bias across demographic and linguistic groups, and remain susceptible to privacy breaches and adversarial attacks. By highlighting these shortcomings, CLINIC lays the foundation for enhancing the global reach and safety of LMs in healthcare across diverse languages.

Semi-supervised learning has become a dominant paradigm for reducing annotation costs. However, we argue that the current progress is clouded by a twofold overconfidence problem. Algorithmically, mainstream pseudo-labeling frameworks often conflate prediction confidence with uncertainty, leading to severe confirmation bias. Strategically, since multiple benchmark datasets lack dedicated validation sets, some studies use the test set for validation as well, leading to inflated performance estimates. Subsequent methods, compelled to employ the same strategy to surpass reported SOTA, trigger an arms race of overfitting. This raises concerns that the impressive numerical gains in the community may reflect overfitting rather than genuine progress. Thus, we propose a tri-space calibrated segmentation framework founded on a principled dual-axis reliability assessment engine. It explicitly decouples confidence from uncertainty and uses this signal to detect and correct confirmation bias across feature, probability, and image spaces in a collaborative manner. Across three benchmark datasets, TCSeg consistently delivers strong performance under existing evaluation protocols. More importantly, we advocate that the community report final-checkpoint results under multiple-run protocols, thereby establishing more rigorous benchmarks with a more realistic perspective. Code will be available: github.com/DirkLiii/TCSeg.

Predicting high-dimensional transcriptional responses to genetic perturbations is challenging because signals are sparse and experimental noise is severe. Existing methods often suffer from mean collapse, achieving high correlation by predicting the global average expression rather than perturbation-specific responses, which yields false positives and poor interpretability. Methods that add biological knowledge graphs typically treat them as dense, static priors shared across perturbations, propagating noise. We propose AdaPert, which counters mean collapse by extracting a sparse, perturbation-specific subgraph via differentiable node selection, then suppressing spurious variation in non-responsive genes while emphasizing differentially expressed ones. Across multiple benchmarks, AdaPert outperforms existing baselines, with the largest gains on DEG-aware metrics.

Synthesizing authentic phonocardiograms (PCG) from ubiquitous electrocardiograms (ECG) is a critical task for accessible cardiac monitoring. Existing generative models, however, struggle to capture the heart's complex electromechanical coupling, failing to meet the dual requirements of temporal precision and physiological fidelity needed for clinically relevant waveform analysis. We introduce the Temporally-Aware VAE-Diffusion model, a synergistic hybrid architecture that resolves this trade-off. Our architecture enforces tight physiological coupling through an Enhanced Condition Fusion mechanism and explicitly models long-range cardiac dynamics via Temporal Attention Blocks. On the EPHNOGRAM benchmark, our model sets a new state-of-the-art, achieving a Pearson correlation of 0.910$\pm$0.008, 95.95\% S1 detection accuracy, and a precise 12.0 ms timing error, significantly outperforming leading diffusion and Transformer baselines. Crucially, our work provides a reproducible zero-shot transfer evaluation for ECG-to-PCG synthesis. Evaluated on the synchronized PhysioNet/CinC 2016 training-a/MITHSDB subset without target-domain training, our model preserves high waveform fidelity and clinically relevant timing structure under domain shift, including on pathological recordings. These results support cross-dataset robustness of the proposed synthesis framework, while downstream diagnostic validation remains an important direction for future work.

Medical large vision-language models (Med-LVLMs) have recently achieved remarkable progress in vision–language comprehension and medical image segmentation. However, existing models still struggle to unify these two capabilities, which is essential for achieving clinically reasoning that connects visual findings with semantic interpretation. We present MedSIGHT, a unified framework that equips Med-LVLMs with structured, pixel-level understanding for grounded visual comprehension. MedSIGHT introduces a novel Region Perceiver module that produces region-centric tokens, encoding spatial information directly into representation space of the language model. We further propose a medical region codebook into the LLM vocabulary, allowing the model to generate discrete region codes as symbolic representations of anatomical and pathological regions. These codes are decoded through the Region Perceiver to reconstruct segmentation mask, achieving end-to-end spatial grounding. Lastly, MedSIGHT combines Region Perceiver, Codebook and LLM using our proposed progressive training strategy to gradually aligns these modules stably. Trained on only 72K multimodal instruction pairs, MedSIGHT achieves state-of-the-art performance across diverse imaging modalities on both medical comprehension and segmentation tasks. Code and model are publicly available at [GitHub](https://github.com/Aofei-Chang/MedSIGHT).

Representation learning has driven major advances in natural image analysis by enabling models to acquire high-level semantic features. In microscopy imaging, however, it remains unclear what current representation learning methods really learn. In this work, we conduct a systematic study of representation learning for the two most widely used and broadly available microscopy data types, representing critical scales in biology: cell culture and tissue imaging. We investigate whether, in contrast to natural images, existing models fail to consistently acquire high-level, biologically meaningful features. To this end, we introduce a set of simple yet revealing baselines on curated benchmarks, including untrained models and structural representations of cellular tissue. Our results show that, surprisingly, for a considerable subset of evaluation settings, the baselines are comparable to state-of-the-art methods, demonstrating that many commonly used benchmark metrics are insufficient to assess representation quality and often mask a lack of relevant high-level abstractions. In addition, we investigate how detailed comparisons with these baselines provide ways to interpret the strengths and weaknesses of models for further improvements. Together, our results suggest that progress in representation learning for microscopy requires not only stronger models, but also benchmarks that are more indicative of what is actually learned.

The characterization of histopathology with AI promises to assist clinical decision-making, but it is currently limited due to coarse-grained annotations that miss cellular identities. To overcome this gap, we bridge histopathological images, gene expression profiles, and natural-language descriptions using *SpatialWhisperer*, a trimodal contrastive learning model. Our training integrates community-scale datasets comprising spatially resolved gene expression profiles paired with histopathology images, as well as single-cell gene expression profiles with detailed annotations. The shared gene expression modality implies a transitive relationship between images and textual annotations, which our method leverages to enable accurate zero-shot cell type annotation directly from H&E images. *SpatialWhisperer* outperforms published baselines, achieving relative AUROC gains of up to 15.9% across three benchmarks spanning 19 tissues and 20 cell types. When training with data from all three modality pairs, we observe performance gains in low-data regimes. We formalize our approach and present a sufficient condition under which this transitive alignment is induced. Our work establishes *transitive representation learning* for fine-grained interpretation of histopathology images.

Protein mutation effect prediction is fundamental to protein engineering and disease variant interpretation, yet experimentally measured mutation data remain accurate but extremely sparse. To provide scalable supplementary mutation signals, we construct a PDB-wide mutation augmentation dataset that exhaustively enumerates single-site substitutions on experimentally resolved protein structures and aligns mutation signals from physics-based energy models, protein language models, and inverse folding models. Large-scale analysis under a unified mutation preference representation reveals substantial differences in the consistency, concentration, and substitution patterns of mutation distributions across models, indicating that disagreement is pervasive and reflects conflicting inductive biases rather than random noise. Motivated by these observations, we propose an unsupervised multi-source mutation preference distillation framework that learns from relative mutation preferences while explicitly modeling cross-source disagreement. Without using any experimental mutation labels during training, our approach achieves the best overall performance among the evaluated zero-shot baselines and naive multi-source fusion strategies on ProteinGym. We release the dataset and evaluation pipeline to support reproducible studies of protein mutation effects.

Function-guided protein design is a crucial task with significant applications in drug discovery and enzyme engineering. However, the field lacks a unified and comprehensive evaluation framework. Current models are assessed using inconsistent and limited subsets of metrics, which prevents fair comparison and a clear understanding of the relationships between different evaluation criteria. To address this gap, we introduce **PDFBench**, the first comprehensive benchmark for function-guided de novo protein design. Our benchmark systematically evaluates eight state-of-the-art models on 16 metrics across two key settings: description-guided design, for which we repurpose the Mol-Instructions dataset, originally lacking quantitative benchmarking, and keyword-guided design, for which we introduce a new test set, SwissTest, created with a strict datetime cutoff to ensure data integrity. By benchmarking across a wide array of metrics and analyzing their correlations, **PDFBench** enables more reliable model comparisons and provides key insights to guide future research.