ICML 2026 Papers

Diagnosing rare diseases remains a persistent challenge, often hindered by cognitive anchoring: once clinicians settle on a common diagnosis, they often discount alternative explanations, including rare conditions. To address this, we propose a cognitive-aware counterfactual reasoning framework using a Denoising Masked AutoEncoder (DMAE) to simulate what-if diagnostic scenarios that probe clinicians’ initial assumptions. Our model jointly learns (1) the true distribution of diseases and symptoms, and (2) human diagnostic behavior, revealing critical gaps between medically possible and clinically considered diagnoses. By strategically perturbing latent patient representations, it generates contrastive counterfactuals that highlight rare yet plausible diseases that cognitive bias often obscures. Unlike traditional decision-support tools, our system suggests rare diseases not because they are statistically dominant, but because they are systematically under-considered relative to the observed evidence and learned diagnostic behavior. Across four public and three private rare-disease datasets, our approach outperforms standard machine learning classifiers in detecting rare conditions while maintaining strong performance on common diagnoses. Beyond boosting accuracy, the counterfactual evidence encourages hypothesis-driven reasoning and supports clinical learning.

The *de novo* generation of high-affinity epitopes tailored to specific major histocompatibility complex (MHC) proteins is a pivotal challenge in computational immunotherapy. However, current methods struggle to effectively integrate the MHC context into the generation process, and often fail to guarantee high binding affinity due to the neglect of discriminative signals from non-binders. To bridge these gaps, we present **EpiCoCo**, a probabilistic framework for **Epi**tope generation via MHC-context **Co**-modeling and **Co**ntrastive affinity learning. EpiCoCo treats the pMHC complex as a dynamic, co-adaptive system by operating on the joint E(3) graph. In addition, we introduce Contrastive Affinity Guidance (CAG), an inference mechanism that leverages the gradient difference between learned high- and low-affinity distributions. CAG actively drives the generation trajectory towards high-affinity manifolds while utilizing repulsive signals to filter out candidates with poor binding potential. Extensive evaluations demonstrate that EpiCoCo achieves a mean binding free energy of -45.20 REU, a 23% improvement over the state-of-the-art, while maintaining high structural plausibility. The results validate that context co-modeling and negative-informed guidance are essential for generating valid, high-potency immunotherapeutics.

The rise of large language models (LLMs) has shifted time series analysis from narrow analytics to general-purpose reasoning. Yet, existing benchmarks cover only a small set of health time series modalities and tasks, failing to reflect the diverse domains and extensive temporal dependencies inherent in real-world physiological modeling. To bridge these gaps, we introduce HEARTS (Health Reasoning over Time Series), a unified benchmark for evaluating hierarchical reasoning capabilities of LLMs over general health time series. HEARTS integrates 16 real-world datasets across 12 health domains and 20 signal modalities, and defines a comprehensive taxonomy of 110 tasks grouped into four core capabilities: Perception, Inference, Generation, and Deduction. Evaluating 14 state-of-the-art LLMs on more than 20K test samples reveals intriguing findings. First, LLMs substantially underperform specialized models, and their performance is only weakly related to general reasoning scores. Moreover, LLMs often rely on simple heuristics and struggle with multi-step temporal reasoning. Finally, performance declines with increasing temporal complexity, with similar failure modes within model families, indicating that scaling alone is insufficient. By making these gaps measurable, HEARTS provides a standardized testbed and living benchmark for developing next-generation LLM agents capable of reasoning over diverse health signals.

According to the reformulated Learned Helplessness theory, repeated exposure to uncontrollable negative events can foster a depressogenic attributional style—increasing susceptibility to depression yet remaining a tractable target for cognitive therapy. Computational research on attributional cognition, however, is hampered by the lack of large-scale datasets and robust evaluation protocols. In this work, we introduce the Attributional Style Transfer Dataset (ASTD) along with dedicated evaluation metrics, the first benchmark designed to model, assess, and reframe attributional explanations at scale. Constructed via a Prevent–Filter–Validate pipeline that integrates LLM-based generation with specialist validation, ASTD contains 42,000 real-world events paired with psychologically grounded attributions spanning seven styles. Using this dataset, we address two key challenges: (1) scalable assessment of attributional style via both supervised classifiers and zero/few-shot LLMs; and (2) attributional reframing and evaluation, where we propose automatic evaluation metrics to quantify psychological validity. Furthermore, we leverage our proposed metrics to construct a preference dataset, fine-tuning LLMs with Direct Preference Optimization (DPO) and achieving substantial gains in reframing quality. Together, our dataset, metrics, and methodology offer a new paradigm for understanding and modeling attributional style, with direct implications for scalable and adaptive mental health interventions.

Spatial transcriptomics (ST) links gene expression with tissue morphology but remains expensive and low-throughput, motivating surrogates that infer expression from routine histology. Whole-slide H&E-to-ST inference pairs a gigapixel image with gene measurements at a sparse, irregular set of locations, making multiscale modeling challenging without incurring dense-grid overhead or quadratic token mixing. We propose HiST, a hierarchical sparse transformer that treats measured locations as a lattice-indexed sparse field and builds a dyadic encoder--decoder directly on the active tissue footprint. HiST combines sparse window attention for local geometric correspondence with resolution-changing operators for rapid multiscale context integration. For a fixed window size, the dominant runtime and memory scale with the number of observed locations rather than the dense slide area. To mitigate slide-specific acquisition variation, HiST adds a bottlenecked global conditioning pathway via a \emph{slide calibration token} that summarizes slide-level context and conditions local representations. On a multi-organ benchmark spanning diverse tissues and acquisition sources, HiST improves predictive performance over recent baselines while reducing runtime and peak memory.

The longitudinal management of blinding fundus diseases constitutes a Partially Observable Markov Decision Process (POMDP) necessitating a critical precision-risk trade-off between intervention and over-treatment, as true pathology is often obscured in static observations. However, existing paradigms fail to address this complexity. Traditional vision models remain uninterpretable and memoryless, and while Vision-Language Models (VLMs) excel in semantic understanding, they rely on unsafe open-loop text reasoning lacking the anatomical grounding essential for clinical safety. Furthermore, robust learning is hindered by the scarcity of process supervision in sparse clinical records. To bridge this gap, we introduce the Logic-Constrained Abductive Data Engine. Operating on a ``Propose-and-Verify'' paradigm, it validates MLLM-proposed biomarkers against clinical and temporal logic to reconstruct dense pathological states from sparse outcomes. Building on this foundation, we propose ORBIT, the first ophthalmic Prognostic World Model. Uniquely, ORBIT employs counterfactual visual foresight to imagine anatomical futures under different treatments, anchoring decisions in Closed-Loop Anatomical Verification rather than linguistic probabilities. Experiments demonstrate that ORBIT effectively captures disease evolution and establishes a new paradigm for human-in-the-loop longitudinal decision support and anatomically grounded treatment planning.

Single-cell foundation models trained on millions of cells can learn gene expression patterns across diverse contexts. However, for predicting genetic perturbation effects they often underperform simple regression models. We hypothesize two potential limitations: targets defined on dropout-prone absolute expression, and pretraining objectives that reconstruct static co-expression rather than encoding how genes co-regulate under expression changes. We introduce $\textbf{scDEBART}$, a perturbation-specific pretraining framework that predicts log fold-changes (logFC) conditioned on basal expression, thereby learning how gene sets co-vary across expression-change contexts at scale. To obtain reliable estimates of expression change under technical sparsity, we compute logFC from scVI-denoised expression and restrict pretraining to genes with robust detection. Pretrained on 6.28 million expression-change profiles from 66.6 million human cells and fine-tuned on five Perturb-seq datasets, scDEBART achieves mean enrichment factor (EF) of 11.96, 4-7$\times$ higher than scGPT and GEARS (mean EF 1.74-2.99), and 71.4\% top-1 accuracy for reverse perturbation identification compared to near-zero accuracy for prior models. In cross-modal transfer to drug perturbations (SCIPLEX), the model shows dose-dependent improvement in directional alignment (cosine similarity 0.04→0.30) with above-random DEG enrichment (EF 2.91-4.32), suggesting partial transfer of learned regulatory patterns across modalities. Overall, these results indicate that large-scale pretraining on scVI-denoised expression-change profiles provides a useful inductive bias for perturbation prediction.

Epidemiological forecasting from surveillance data is a hard problem and hybridizing mechanistic compartmental models with neural models is a natural direction. The mechanistic structure helps keep trajectories epidemiologically plausible, while neural components can capture non-stationary, data-adaptive effects. In practice, however, many seemingly straightforward couplings fail under partial observability and continually shifting transmission dynamics driven by behavior, waning immunity, seasonality, and interventions. We catalog these failure modes and show that robust performance requires making non-stationarity explicit: we extract multi-scale structure from the observed infection series and use it as an interpretable control signal for a controlled neural ODE coupled to an epidemiological model. Concretely, we decompose infections into trend, seasonal, and residual components and use these signals to drive continuous-time latent dynamics while jointly forecasting and inferring time-varying transmission, recovery, and immunity-loss rates. Across early outbreak and multi-wave regimes, our approach attains the lowest RMSE on all five datasets (up to 57% reduction over the strongest baseline), predicts the peak within one time step on four of five, and recovers time-varying epidemiological rates within ground-truth ranges, without relying on auxiliary covariates.

Predicting transcriptional responses to genetic perturbations is a central problem in functional genomics. In practice, perturbation responses are rarely gene-independent but instead manifest as coordinated, program-level transcriptional changes among functionally related genes. However, most existing methods do not explicitly model such coordination, due to gene-wise modeling paradigms and reliance on static biological priors that cannot capture dynamic program reorganization. To address these limitations, we propose scBIG, a module-inductive perturbation prediction framework that explicitly models coordinated gene programs. scBIG induces coherent gene programs from data via Gene-Relation Clustering, captures inter-program interactions through a Gene-Cluster-Aware Encoder, and preserves modular coordination using structure-aware alignment objectives. These structured representations are then modeled using conditional flow matching to enable flexible and generalizable perturbation prediction. Extensive experiments on multiple single-cell perturbation benchmarks show that scBIG consistently outperforms state-of-the-art methods, particularly on unseen and combinatorial perturbation settings, achieving an average improvement of 6.7% over the strongest baselines. The code is available at https://github.com/ttruan2426-dot/scBIG.

Precision oncology requires forecasting clinical events and trajectories, yet modeling sparse, multi-modal clinical time series remains a critical challenge. We introduce TwinWeaver, an open-source framework that serializes longitudinal patient histories into text, enabling unified event prediction as well as forecasting with large language models, and use it to build Genie Digital Twin (GDT) on 93,054 patients across 20 cancer types. In benchmarks, GDT significantly reduces forecasting errors, achieving a median Mean Absolute Scaled Error (MASE) of 0.87 compared to 0.97 for the strongest time-series baseline ($p<0.001$). Furthermore, GDT improves risk stratification, achieving an average concordance index (C-index) of 0.703 across survival, progression, and therapy switching tasks, surpassing the best baseline of 0.662. GDT also generalizes to out-of-distribution clinical trials, matching trained baselines at zero-shot and surpassing them with fine-tuning, achieving a median MASE of 0.75–0.88 and outperforming the strongest baseline in event prediction with an average C-index of 0.672 versus 0.648. Finally, TwinWeaver enables an interpretable clinical reasoning extension, providing a scalable and transparent foundation for longitudinal clinical modeling.

Biomedical imaging data presents enormous potential for deep learning models to predict invaluable properties, such as diseases and drug effects. However, unavoidable alterations of the technical conditions cause *batch effects*: variations between groups of samples that are not due to any biological signal of interest. Batch effects greatly hinder the generalization abilities of deep learning models, preventing their practical use in the real world. Unsupervised Domain Adaptation (UDA) methods have been proposed to mitigate batch effects, but they usually assume that the data is comprised of only one source domain and one target domain, whereas biological datasets are comprised of multiple domains, both at training and at inference time. While Batch Normalization–based test-time and meta-learning adaptation methods offer a promising mechanism for domain alignment, we show that existing approaches exhibit degraded performance under the usual inference scenarios of small target batch sizes and label shift. We address these limitations by leveraging negative control samples, which are consistently present in every experimental batch in biological datasets, as stable context for adaptation. We propose CS-ARM-BN, a meta-learning BN adaptation method that uses controls both during training and inference to stabilize domain statistics. We perform a suite of experiments of Mechanism-Of-Action (MoA) classification, a crucial task for drug discovery, on the large JUMP-CP imaging dataset. Our experiments show that CS-ARM-BN substantially improves robustness to batch size and class distribution shifts, enabling practical use of deep learning models for biomedical images.

A sustainable diet represents a multi-dimensional synergy among four essential pillars: nutrition adequacy, economic affordability, cultural acceptability, and environmental respect. Despite the prevalence of population-level sustainability modeling, practical implementation relies on effective individual-level adoption. This transition is often hindered by inter-individual heterogeneity, posing a formidable challenge in aligning sustainable diet requirements with individual preferences. To address this issue, we propose a personalized sustainable diet recommendation model based on a constraint-aware decision-making mechanism, where sustainability is incorporated through learnable constraints rather than modeled as user preferences. To systematically evaluate the proposed approach, we construct a sustainable diet dataset named SusDiet with about 150k recipes, characterized by broad coverage of sustainability indicators across four dimensions. Experimental results on this dataset show that our method promotes more sustainable choices without compromising individual preference. This work establishes a framework for aligning individual dietary choices with planetary health, offering quantitative evidence to guide future sustainable diet interventions and policy-making for sustainable development.

Phenotypic screening experiments produce many microscope images of cells under diverse perturbations, with biologically significant responses often subtle or difficult to identify visually. A central challenge is to extract image representations that distinguish activity from controls and group phenotypically similar perturbations. In this work we propose new adaptations of contrastive loss functions that incorporate experimental metadata as learned class vectors, and a geometrically inspired variant, called SPC, where class vectors are confined to the unit sphere and updated only by attractive terms (allowing more overlap of phenotypically similar classes). The approach is tested on two popular benchmarking datasets, BBBC021 and RxRx3-core; and we also evaluate performance on uncurated screens of HaCaT cells to gauge effectiveness in a realistic use-case scenario. We find we outperform prior methods across the three datasets and on a wide array of metrics measuring phenotype grouping, biological recall, drug-target interaction and mechanism-of-action inference. We also show we maintain this improved performance compared to models over 10x larger in parameter count, and that SPC can be used as an effective fine-tuning technique. The method is easy to implement and is well suited to settings with limited data or compute resources.

Large Language Models have shown strong generalization across natural language tasks but remain underexplored for longitudinal clinical profiles. In sports anti-doping, biological profiles are analyzed to support early detection of prohibited substance use and identification of anomalous biological patterns, both of which require joint modeling of temporal dynamics and metabolic relationships. We propose STT-LLM, a structural-temporal tokenization framework that adapts LLMs to longitudinal clinical analysis without modifying their backbone architectures. STT-LLM constructs biologically grounded structural-temporal embeddings and transforms them into LLM-compatible tokens via specialized tokenizers that explicitly encode pathway structure and temporal evolution. We evaluate STT-LLM on real-world longitudinal datasets from athletes, showing consistent improvements over native LLM tokenization strategies in sequence prediction and anomaly detection. In addition, we present a case study where STT-LLM provides contextual reasoning that aligns more closely with expert assessments compared to baseline models. These results highlight tokenization as a key bottleneck and opportunity for adapting LLMs to clinical data.

Patient-level sepsis prediction requires models that track clinical deterioration over time and integrate heterogeneous structured evidence from electronic health records. We present PathwayLLM, a trajectory-based framework that grounds prediction on temporal signals, graph-structured evidence, and pathway-level clinical information derived from statistical dependency discovery. PathwayLLM follows a three-stage design. First, each observation window is encoded from multiple structured views, including physiological measurements, temporal dynamics, a heterogeneous patient-diagnosis-medication graph, and dependency-derived pathway signals. Second, these representations are injected into a pretrained language model as auxiliary contextual embeddings so that risk prediction and evidence-conditioned explanations can be learned jointly. Third, a Clinical Trajectory LSTM with Deterioration Attention aggregates window-level representations to highlight critical deterioration points and produce patient-level risk scores. On MIMIC-IV (15,410 ICU patients; 8.45% sepsis prevalence), PathwayLLM achieves AUROC 0.891 and AUPRC 0.724, outperforming strong time-series and pretrained baselines. External validation on eICU achieves AUROC 0.842 zero-shot and 0.867 after light fine-tuning. Ablation studies indicate that trajectory aggregation and structured clinical signals are key contributors, and clinician review suggests coherent, interpretable, and clinically relevant explanations.

Recent genomic foundation models largely adopt large language model architectures that treat DNA as a one-dimensional token sequence. However, exhaustive sequential reading is structurally misaligned with sparse and discontinuous genomic semantics, leading to wasted computation on low-information background and preventing understanding-driven compression for long contexts. Here, we present OpticalDNA, a vision-based framework that reframes genomic modeling as Optical Character Recognition (OCR)-style document understanding. OpticalDNA renders DNA into structured visual layouts and trains an OCR-capable vision--language model with a \emph{visual DNA encoder} and a \emph{document decoder}, where the encoder produces compact, reconstructible visual tokens for high-fidelity compression. Building on this representation, OpticalDNA defines prompt-conditioned objectives over core genomic primitives—reading, region grounding, subsequence retrieval, and masked span completion—thereby learning layout-aware DNA representations that retain fine-grained genomic information under a reduced effective token budget. Across diverse genomic benchmarks, OpticalDNA consistently outperforms recent baselines; on sequences up to 450k bases, it achieves the best overall performance with nearly $20\times$ fewer effective tokens, and surpasses models with up to $985\times$ more activated parameters while tuning only 256k \emph{trainable} parameters.

Antibody expression ranking is a critical task in antibody design, yet its modelling is severely hindered by the scarcity of labeled experimental data. To address this, we propose a unified preference-based learning framework that integrates scarce quantitative expression data with large-scale weak positive supervision from immunization data. We adapt Direct Preference Optimization (DPO) to protein language models by introducing a union-masked log-likelihood approximation and IMGT-based alignment, enabling efficient training on variable-length sequences. Evaluating on a diverse internal dataset of 1254 labeled sequences and 4 million unlabeled camelid-derived antibodies, we show that our method consistently outperforms baselines on most metrics. Our results demonstrate that preference learning can effectively learn from weak supervision, providing a scalable solution for antibody expressibility optimization in data-constrained settings. Project page: https://kisoji-biotechnology-inc.github.io/Preference-Expression-Ranking/.

In single-cell research, tracing and analyzing high-throughput single-cell differentiation trajectories is crucial for understanding biological processes. Key to this is the robust modeling of hierarchical structures that govern cellular development. Traditional methods face limitations in computational cost, performance, and stability. VAE-based approaches have made strides but still require branch-specific network modules, limiting their scalability and stability, while often suffering from posterior collapse.To overcome these challenges, we introduce HDTree, a generative modeling framework designed for robust lineage inference. HDTree captures tree relationships within a hierarchical latent space using a unified hierarchical codebook and employs a quantized diffusion process to model continuous cell state transitions. By aligning the generative process with the Waddington landscape, this method not only improves stability and scalability but also enhances the biological plausibility of inferred lineages. HDTree's effectiveness is demonstrated through comparisons on both general-purpose and single-cell datasets, where it outperforms existing methods in lineage inference accuracy, reconstruction quality, and hierarchical consistency. These contributions enable accurate and efficient modeling of cellular differentiation paths, offering reliable insights for biological discovery.

Recent advances in diffusion models show promise for Structure-Based Drug Design (SBDD), which aims to generate 3D ligand molecules that bind tightly to specific protein targets. This involves jointly optimizing the ligand's 3D conformation and its binding position within the protein pocket. However, existing diffusion-based SBDD methods diffuse conformation and binding position synchronously within a high-dimensional joint space, leading to inefficient exploration and suboptimal generation quality in both aspects. To address this, we propose **DeCoDe**, a novel diffusion framework that **decouples** the diffusion processes of the binding position and molecular conformation. Our key insight is to prioritize the perturbation of the ligand's internal conformation in the early stages of the forward (noising) process, while accelerating the perturbation of its global binding position later. This design guides the reverse (denoising) process to *first coarsely position* the ligand within the pocket before *refining its detailed structure*, mimicking a more efficient, step-wise generation strategy. Extensive experiments on the CrossDocked2020 benchmark show that DeCoDe achieves significantly higher structural fidelity (with an average improvement of 18%), while maintaining competitive binding affinity and overall molecular properties compared to state-of-the-art baselines.