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Applications · Health / Medicine

Haoran liu, Xiaoli Lin, Jing Hu, Yu Zou, Xiaolong Zhang

Polypharmacology provides a powerful strategy for treating complex diseases, but identifying molecules that simultaneously satisfy coupled constraints across multiple biological targets remains difficult. Existing methods typically model protein pockets in isolation and struggle to jointly account for multiple heterogeneous binding sites when designing a single shared ligand. To address these limitations, we propose a pocket-structure-centric generative framework for polypharmacology. This framework introduces a novel protein topological representation that selectively masks ligand-irrelevant residues while explicitly modeling backbone folding geometry and inter-residue spatial proximity within binding pockets. In addition, structural representations are jointly fused with amino acid and nucleotide sequences to capture their complementary information across targets. Experiments on COVID-19, schizophrenia, and tumor targets show that this framework generates valid candidates with significantly improved binding affinities compared to state-of-the-art methods.

Applications · Health / Medicine

Yuchen Hua, Xingang Peng, Jianzhu Ma, Muhan Zhang

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.

Applications · Health / Medicine

Zitao Chen, Jiatong Ji, Yinjun Jia, Wei-Ying Ma, Yanyan Lan

Recent advances in 3D molecular modeling have achieved high-fidelity structural synthesis, yet these models often lack an explicit and manipulable representation space. To address this, MolFLAE introduced a fixed-dimensional, E(3)-equivariant latent space, providing a novel framework for molecular editing independent of atom counts. However, because its latent space was primarily optimized for geometric reconstruction, it remains semantically shallow and inadequate for comprehensive representation learning. In this work, we propose **MolAlign3D**, which evolves this architecture into a unified semantic-generative engine. By anchoring MolFLAE’s manipulable latents with embeddings from a pre-trained molecular encoder, we yield a manifold that is both semantically dense and geometrically precise. Experiments show that MolAlign3D achieves high-fidelity molecular reconstruction and attains comparable performance on molecular property prediction benchmarks. Notably, the integration of rich semantic priors significantly enhances zero-shot molecular manipulation, including atom-number editing and latent-space interpolation, outperforming prior fixed-dimensional equivariant latent baseline.

Applications · Health / Medicine

Zekai Chen, Xunkai Li, Sirui Zhang, Henan Sun, Jia Li, Qiangqiang Dai, Hongchao Qin, Zhenjun Li, Bing Zhou, Rong-Hua Li 等

De novo ligand design is a fundamental task that seeks to generate protein or molecule candidates that can effectively dock with protein receptors and achieve strong binding affinity entirely from scratch. It holds paramount significance for a wide spectrum of biomedical applications. However, most existing studies are constrained by the \textbf{Pseudo De Novo}, \textbf{Limited Docking Modeling}, and \textbf{Inflexible Ligand Type}. To address these issues, we propose MagicDock, a forward-looking framework grounded in the progressive pipeline and differentiable surface modeling. (1) We adopt a well-designed gradient inversion framework. To begin with, general docking knowledge of receptors and ligands is incorporated into the backbone model. Subsequently, the docking knowledge is instantiated as reverse gradient flows by binding prediction, which iteratively guide the de novo generation of ligands. (2) We emphasize differentiable surface modeling in the \textit{generation process}, leveraging learnable 3D point-cloud representations to precisely capture docking details, thereby ensuring that the generated ligands preserve docking validity through interpretable spatial fingerprints. (3) We introduce customized designs for different ligand types and integrate them into a unified gradient inversion framework with flexible triggers, thereby ensuring broad applicability. Moreover, we provide sufficient theoretical guarantees for MagicDock. Extensive experiments across 9 scenarios demonstrate that MagicDock achieves average improvements of 7.0\% and 7.4\% over SOTA baselines specialized for protein or molecule ligand design, respectively.

Applications · Health / Medicine

Qiang Zhou, Hanzhen Zhu, Pan Wang, Rui Tu, Huaizhi Qu, Zhuoran Wang, Xin Hu, Lei Li, Tianlong Chen, Jingtong Hu

According to the reformulated version of the Learned Helplessness theory, an individual who experiences uncontrollable negative events may subsequently develop a negative attributional style, thereby exhibiting greater susceptibility to depressive symptoms. This depressogenic attributional style not only contributes to depressive symptoms but also represents a malleable target for cognitive therapy. Despite its theoretical and practical significance, computational research on attributional cognition remains underexplored due to the lack of large-scale, high-quality 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.

Applications · Health / Medicine

Hongxin Xiang, Pengsen Ma, Yunkang Cao, Di Yu, Haowen Chen, Xinyu Yang, xiangxiang Zeng

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 \textsc{OpticalDNA}, a vision-based framework that reframes genomic modeling as OCR-style document understanding. \textsc{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, \textsc{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, \textsc{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.

Applications · Health / Medicine

Lingzhao Meng, Shuai Guo, Weishan Zhang, Zengxiang Li, Han Yu, Nan Liu, Daniel Ting, Yuru Liu, Tao Chen, Shudong Wang

Group fairness can ensure equitable performance across different demographic subgroups for medical image analysis. However, the current fine-tuned foundation models (FMs) exhibit significant subgroup disparity. One-shot federated learning (OFL) can potentially mitigate this by leveraging cross-institutional data diversity within a single communication round. But heterogeneous distributions across medical institutions may cause OFL local models to diverge severely, resulting in parameter conflicts that amplify disparity upon aggregation. To address these challenges, we propose Fair-FedMOE, a group-fair OFL framework for medical FMs. During local training, Fairness-aware Expert Routing routes samples to group-specific experts via learnable prototypes, enabling subgroup-specialized learning to capture group-specific features without inter-group interference. During model aggregation, Prototype-guided Differential Aggregation computes personalized weights based on prototype similarity and applies differentiated aggregation strategies to filter conflicting updates. We propose RES-AUC, a Rawlsian justice-inspired metric based on worst-group performance that remains stable as groups increase. Comprehensive experiments on diverse retinal datasets covering different modalities and diseases, using retinal-specific and general-purpose FMs, show consistent fairness gains without sacrificing accuracy. Code available at https://anonymous.4open.science/r/Fair-FedMOE-2624.

Applications · Health / Medicine

Marius Knorr, Robert Müller, Jan Bremer, Nils Schweingruber

Fast Healthcare Interoperability Resources (FHIR) is the dominant standard for interoperable exchange of healthcare data. In FHIR, electronic health records form a directed graph of resources. Answering clinically meaningful questions over FHIR requires agents to perform multi-step reasoning, filtering, and aggregation across multiple resource types. Prior work shows that even tool-augmented LLM agents (retrieval, code execution, multi-turn planning) often select the wrong resources or violate traversal constraints. We study this problem in the context of FHIR-AgentBench, a benchmark for realistic question answering over real-world hospital data, and frame reasoning on FHIR as a sequential decision-making problem over a queryable structured graph. We implement a multi-turn CodeAct agent and post-train it with reinforcement learning using a custom harness and tools. A LLM Judge provides execution-grounded rewards. Compared to prompt-based, closed-model baselines, RL post-training improves performance while enforcing data-integrity constraints. Empirically, our approach improves answer correctness from 50% (o4-mini) to 64% on FHIR-AgentBench using a smaller and cheaper Qwen 2.5-7B model. We present an end-to-end post-training pipeline (environment building, harness construction, model training and custom evaluation) that reliably improves multi-turn reasoning over structured clinical graphs.

Applications · Health / Medicine

Yang Song, Yixuan Zhang, Lingfa Meng, Tongyuan Hu, Haizhou Shi, Hao Wang, Samir Bhatt, Hengguan Huang

Reliable microbiome-based diagnosis is critical for precision medicine at scale in inflammatory diseases, yet current post-training pipelines in LLMs often overlook the interaction structure that governs microbial ecosystems. In inflammatory bowel disease (IBD), disease signals arise not only from species-level abundance shifts but also from latent microbe–microbe cross-talk. We propose iLoRA, a parameter-efficient Bayesian LoRA framework that infers latent interaction graphs from microbiome inputs and integrates them into adaptation, enabling joint clinical prediction and interaction discovery. Unlike correlation-based post hoc analysis, iLoRA models microbial interactions as latent variables learned end-to-end, yielding uncertainty-aware estimates of cross-talk. We evaluate iLoRA on (i) interactive question answering with human-annotated interaction graphs to quantify structural recovery and (ii) gut microbiome cohorts for IBD diagnosis. Across both domains, iLoRA consistently improves accuracy over strong LoRA baselines while producing interpretable interaction graphs consistent with annotated relations and conventional microbiome association networks.

Applications · Health / Medicine

Ziquan Wei, Tingting Dan, Guorong Wu

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 human-environment interaction modeling limits the capacity for personalized disease modeling and clinical decision support. To address this limitation, we propose a generative model with human-environment interaction 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 human-environment interaction (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.

Applications · Health / Medicine

Luke Nightingale, Joseph Tuersley, Scott Warchal, Andrea Cairoli, Jacob Howes, Cameron Shand, Andrew Powell, Darren Green, Amy Strange, Michael Howell

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.

Applications · Health / Medicine

Haonan Zhang, Qing Wu, Xuanyu Tian, Bowen Li, Yuyao Zhang, Hongjiang Wei

Implicit Neural Representation (INR) has emerged as a powerful paradigm for continuous MRI reconstruction. However, standard unsupervised INR requires time-consuming optimization from scratch for each scan, hindering clinical deployment. This work presents IPOD, a Reference-Free Meta-Learning framework designed to learn generalized parameter initializations for INR directly from undersampled data. Distinct from conventional meta-learning that relies on fully-sampled ground truth, IPOD operates in an inverse-problem-driven manner, leveraging diverse reconstruction tasks with varying sampling patterns to capture a robust prior. Furthermore, we introduce an adaptive meta-update strategy modulated by task-specific performance to ensure optimal parameter distribution for diverse anatomical structures. Extensive experiments demonstrate that IPOD provides a superior initialization that enables rapid adaptation and achieves high-fidelity reconstruction across various imaging protocols, significantly outperforming existing INR baselines. By eliminating the dependence on reference images, IPOD offers a scalable and efficient solution for a wide range of imaging inverse problems. Code and data available at: https://anonymous.4open.science/r/iPod-2C60

Applications · Health / Medicine

ZONGHENG GUO, Tao Chen, Yang Jiao, Yi Pan, Xiao Hu, Manuela Ferrario

Current foundation model for photoplethysmography (PPG) signals is challenged by the intrinsic redundancy and noise of the signal. Standard masked modeling often yields trivial solutions while contrastive methods lack morphological precision. To address these limitations, we propose a Statistical-prior Informed Generative Masking Architecture (SIGMA-PPG), a generative foundation model featuring a prior-guided adversarial masking mechanism, where a reinforcement learning-driven teacher leverages statistical priors to create challenging learning paths that prevent overfitting to noise. We also incorporate a semantic consistency constraint via vector quantization to ensure that physiologically identical waveforms—even those altered by recording artifacts or minor perturbations—map to shared indices. This enhances codebook semantic density and eliminates redundant feature structures. Pre-trained on over 120,000 hours of data, SIGMA-PPG achieves superior average performance compared to five state-of-the-art baselines across 12 diverse downstream tasks.

Applications · Health / Medicine

Alma Andersson, Aya Ismail, Edward De Brouwer, Doron Haviv, Tommaso Biancalani, Kyunghyun Cho, Gabriele Scalia, Aicha BenTaieb, Hector Corrada Bravo

Understanding cellular phenotypes and how they respond to perturbations is critical for disease biology and therapeutic design. Single-cell RNA sequencing enables characterization at cellular resolution, yet the combinatorial space of conditions makes exhaustive experimental mapping infeasible. We introduce single-cell Concept Bottleneck Generative Models (scCBGM), a framework for interpretable and precise counterfactual editing of individual cells. scCBGM adapts concept bottleneck architectures for single-cell data through decoder skip connections and a cross-covariance penalty that promotes disentanglement without dimensional constraints. We extend the framework to flow matching models, enabling concept-guided editing in both encoding-decoding and generation regimes. To enable rigorous evaluation, we develop a synthetic benchmark with ground-truth counterfactuals. Across multiple real datasets, scCBGM demonstrates superior accuracy in zero-shot generalization and cell-level counterfactual prediction compared to state-of-the-art methods, while providing interpretable control over biological concepts.

Applications · Health / Medicine

Jiaqi Men, Hua Liu, Yiming Tang, Jinhong You, Jianghu Dong, Jiguo Cao

Accurate survival prediction in kidney transplantation is critical yet challenging due to the complex interplay between functional biomarkers and patient characteristics under censoring. To address this, we propose a functional censored quantile neural network (FunCQNet), a novel framework that integrates deep neural networks with a censoring-adjusted sequential quantile loss to approximate interaction-dependent coefficient functions. We further introduce a conformal inference approach to rigorously assess the significance of scalar-functional interactions, ensuring interpretability alongside predictive power. Extensive simulations demonstrate that FunCQNet robustly recovers functional effects under varying noise and censoring levels. When applied to kidney transplant data, the model yields precise multi-quantile predictions and reveals clinically significant, age-dependent interaction patterns between donor type and recipient survival.

Applications · Health / Medicine

Yaxuan Song, Jianan Fan, Tianyi Wang, Qiuyue Hu, Hang Chang, Heng Huang, Weidong Cai

Histopathology whole-slide images (WSIs) are routinely acquired in clinical practice and contain rich tissue morphology but lack direct molecular architecture and functional programs defining pathological states, whereas RNA sequencing (RNA-seq) provides genome-wide transcriptional profiles at substantial cost, thereby motivating WSI-based genome-wide transcriptomic prediction. Existing approaches for predicting gene expression from WSIs predominantly rely on deterministic regression with one-to-one mapping, limiting their ability to capture biological heterogeneity and predictive uncertainty. We propose RNA-FM, a flow-matching generative framework for genome-wide bulk RNA-seq prediction from histopathology images. RNA-FM formulates transcriptomic prediction as a continuous-time conditional transport problem, learning a velocity field that maps a simple prior to the target gene expression distribution conditioned on morphological features. By incorporating pathway-level structure, RNA-FM enables scalable, biologically interpretable, and genome-wide gene expression imputation. Extensive experiments across multiple anatomical regions, pathway-level analysis, and external validation cohorts demonstrate that RNA-FM consistently outperforms state-of-the-art approaches while effectively capturing both inter-patient and intra-tumoral heterogeneity.

Applications · Health / Medicine

Marie Brockschmidt, Maresa Schröder, Stefan Feuerriegel

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 consistently 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.

Applications · Health / Medicine

Bowen Jing, Mihir Bafna, Anisha Parsan, Heyuan Ni, David Kwabi-Addo, Bryan Bryson, Adam Klivans, Bonnie Berger

Multistate mechanisms underlie many of the complex functions observed in natural proteins. The ability to rationally design multistate proteins would have transformative implications for many areas of biotechnology, yet lies beyond the capabilities of existing deep learning frameworks for protein design. To address this gap, we introduce SwitchCraft, a versatile and programmatic framework for designing state-switching proteins based on backpropagation through compositional design constraints parameterized by structure prediction models. In silico evaluations demonstrate success on a wide range of state-switching functional primitives, from allosteric regulation of motifs to discrimination of bound ligand identities. Using these primitives, we demonstrate an in silico strategy for de novo design of fluorescent biosensors to arbitrary small molecule analytes. These results position SwitchCraft at the inception of a powerful paradigm for higher-order functional protein design.

Applications · Health / Medicine

Mingcheng Zhu, Zhiyao Luo, Yu Liu, Tingting Zhu

By processing electronic health records (EHRs) as natural language sequences, large language models (LLMs) have shown potential in clinical prediction tasks such as mortality prediction and phenotyping. However, longitudinal or highly frequent EHRs often yield excessively long token sequences that result in high computational costs and even reduced performance. Existing solutions either add modules for compression or remove less important tokens, which introduce additional inference latency or risk losing clinical information. To achieve lossless compression of token sequences without additional cost or loss of performance, we propose Medical Token-Pair Encoding (MedTPE), a layered method that extends standard tokenisation for EHR sequences. MedTPE merges frequently co-occurring medical token pairs into composite tokens, providing lossless compression while preserving the computational complexity through a dependency-aware replacement strategy. Only the embeddings of the newly introduced tokens of merely 0.5-1.0\% of the LLM’s parameters are fine-tuned via self-supervised learning. Experiments on real-world datasets for two clinical scenarios demonstrate that MedTPE reduces input token length by up to 31% and inference latency by 34-63%, while maintaining or even improving both predictive performance and output format compliance across three LLMs and four clinical prediction tasks. Furthermore, MedTPE demonstrates robustness across different input context lengths and generalisability to scientific and financial domains.

Applications · Health / Medicine

Lina Zhang, Jiarui Cui, Tonmoy Monsoor, Peizheng Li, Xinyi Peng, Chong Han, Prateik Sinha, Siyuan Dai, Jessica Pasqua, Colin McCrimmon 等

While Multimodal Large Language Models (MLLMs) have demonstrated remarkable proficiency in general video understanding, their capacity to interpret involuntary, and spatio-temporally evolving pathologic motor behaviors such as seizure semiology remains largely untested. To address this gap, we introduce Seizure-Semiology-Suite (S³), a clinically grounded dataset and benchmark for fine-grained, structured seizure semiology understanding. The dataset includes 438 seizure videos annotated with over 35,000 dense labels covering 20 ILAE-defined semiological features. Building on this dataset, we propose a seven-task hierarchical benchmark that systematically evaluates MLLMs from low-level visual perception to temporal sequencing, narrative report generation, and seizure diagnosis. To enable clinically meaningful evaluation of generated reports, we further introduce the Report Quality Index for Seizure Semiology (Seizure-RQI). Extensive baselines across 11 open-weight MLLMs reveal systematic weaknesses in laterality reasoning, temporal localization, symptom sequencing, and clinically faithful reporting. We show that seizure-specific fine-tuning substantially improves performance across tasks, and that a two-stage neuro-symbolic framework achieves an F1 score of 0.96 on epileptic versus non-epileptic seizure classification. Seizure-Semiology-Suite establishes a rigorous benchmark for evaluating multimodal models in safety-critical medical video understanding and guides the development of clinically reliable, domain-adaptive multimodal intelligence.