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Applications · Health / Medicine

Jie Peng, Jenna Ballard, Mohan Zhang, Sukwon Yun, Jiayi Xin, Qi Long, Yanyong Zhang, Tianlong Chen

Medical multi-modal learning requires an effective fusion capability of various heterogeneous modalities.One vital challenge is how to effectively fuse modalities when their data quality varies across different modalities and patients.For example, in the TCGA benchmark, the performance of the same modality can differ between types of cancer. Moreover, data collected at different times, locations, and with varying reagents can introduce inter-modal data quality differences ($i.e.$, $\textbf{Modality Batch Effect}$).In response, we propose ${\textbf{A}}$daptive ${\textbf{M}}$odality Token Re-Balan${\textbf{C}}$ing ($\texttt{AMC}$), a novel top-down dynamic multi-modal fusion approach.The core of $\texttt{AMC}$ is to quantify the significance of each modality (Top) and then fuse them according to the modality importance (Down).Specifically, we access the quality of each input modality and then replace uninformative tokens with inter-modal tokens, accordingly.The more important a modality is, the more informative tokens are retained from that modality.The self-attention will further integrate these mixed tokens to fuse multi-modal knowledge.Comprehensive experiments on both medical and general multi-modal datasets demonstrate the effectiveness and generalizability of $\texttt{AMC}$.

Applications · Health / Medicine

Thibaud Southiratn, Bonil Koo, Yijingxiu Lu, Sun Kim

Dual-target molecule generation, which focuses on discovering compounds capable of interacting with two target proteins, has garnered significant attention due to its potential for improving therapeutic efficiency, safety and resistance mitigation.Existing approaches face two critical challenges.First, by simplifying the complex dual-target optimization problem to scalarized combinations of individual objectives, they fail to capture important trade-offs between target engagement and molecular properties. Second, they typically do not integrate synthetic planning into the generative process.This highlights a need for more appropriate objective function design and synthesis-aware methodologies tailored to the dual-target molecule generation task.In this work, we propose CombiMOTS, a Pareto Monte Carlo Tree Search (PMCTS) framework that generates dual-target molecules.CombiMOTS is designed to explore a synthesizable fragment space while employing vectorized optimization constraints to encapsulate target affinity and physicochemical properties.Extensive experiments on real-world databases demonstrate that CombiMOTS produces novel dual-target molecules with high docking scores, enhanced diversity, and balanced pharmacological characteristics, showcasing its potential as a powerful tool for dual-target drug discovery.The code and data is accessible through \url{https://github.com/Tibogoss/CombiMOTS}.

Probabilistic Methods

Kyle Heuton, Frederick Muench, Shikhar Shrestha, Thomas J Stopka, Michael Hughes

Optimal allocation of scarce resources is a common problem for decision makers faced with choosing a limited number of locations for intervention. Spatiotemporal prediction models could make such decisions data-driven.A recent performance metric called fraction of bestpossible reach (BPR) measures the impact of using a model’s recommended size K subset of sites compared to the best possible top-K in hindsight. We tackle two open problems related to BPR. First, we explore *how to rank* all sites numerically given a probabilistic model that predicts event counts jointly across sites. Ranking via the per-site mean is suboptimal for BPR. Instead, we offer a better ranking for BPR backed by decision theory. Second, we explore*how to train* a probabilistic model's parameters to maximize BPR. Discrete selection of K sites implies all-zero parameter gradients which prevent standard gradient training. We overcome this barrier via advances in perturbed optimizers. We further suggest a training objective that combines likelihood with a BPR constraint to deliver high-quality top-K rankings as well as good forecasts for all sites. We demonstrate our approach on two where-to-intervene applications: mitigating opioid-related fatal overdoses for public health and monitoring endangered wildlife.

Applications · Health / Medicine

Yash Shah, Camila Gonzalez, MohammadHassan Abbasi, Qingyu Zhao, Kilian M Pohl, Ehsan Adeli

Confounders are extraneous variables that affect both the input and the target, resulting in spurious correlations and biased predictions. There are recent advances in dealing with or removing confounders in traditional models, such as metadata normalization (MDN), where the distribution of the learned features is adjusted based on the study confounders. However, in the context of continual learning, where a model learns continuously from new data over time without forgetting, learning feature representations that are invariant to confounders remains a significant challenge. To remove their influence from intermediate feature representations, we introduce the Recursive MDN (R-MDN) layer, which can be integrated into any deep learning architecture, including vision transformers, and at any model stage. R-MDN performs statistical regression via the recursive least squares algorithm to maintain and continually update an internal model state with respect to changing distributions of data and confounding variables. Our experiments demonstrate that R-MDN promotes equitable predictions across population groups, both within static learning and across different stages of continual learning, by reducing catastrophic forgetting caused by confounder effects changing over time.

Applications · Health / Medicine

Feng Wu, Tsai Hor Chan, Fuying Wang, Guosheng Yin, Lequan Yu

Various data modalities are common in real-world applications. (e.g., EHR, medical images and clinical notes in healthcare). Thus, it is essential to develop multimodal learning methods to aggregate information from multiple modalities. The main challenge is appropriately aligning and fusing the representations of different modalities into a joint distribution. Existing methods mainly rely on concatenation or the Kronecker product, oversimplifying interactions structure between modalities and indicating a need to model more complex interactions. Additionally, the joint distribution of latent representations with higher-order interactions is underexplored. Copula is a powerful statistical structure in modelling the interactions between variables, as it bridges the joint distribution and marginal distributions of multiple variables. In this paper, we propose a novel copula modelling-driven multimodal learning framework, which focuses on learning the joint distribution of various modalities to capture the complex interaction among them. The key idea is interpreting the copula model as a tool to align the marginal distributions of the modalities efficiently. By assuming a Gaussian mixture distribution for each modality and a copula model on the joint distribution, our model can also generate accurate representations for missing modalities. Extensive experiments on public MIMIC datasets demonstrate the superior performance of our model over other competitors. The code is anonymously available at https://github.com/HKU-MedAI/CMCM.

Applications · Health / Medicine

Etowah Adams, Liam Bai, Minji Lee, Yiyang Yu, Mohammed AlQuraishi

Protein language models (pLMs) are powerful predictors of protein structure and function, learning through unsupervised training on millions of protein sequences. pLMs are thought to capture common motifs in protein sequences, but the specifics of pLM features are not well understood. Identifying these features would not only shed light on how pLMs work, but potentially uncover novel protein biology––studying the model to study the biology. Motivated by this, we train sparse autoencoders (SAEs) on the residual stream of a pLM, ESM-2. By characterizing SAE features, we determine that pLMs use a combination of generic features and family-specific features to represent a protein. In addition, we demonstrate how known sequence determinants of properties such as thermostability and subcellular localization can be identified by linear probing of SAE features. For predictive features without known functional associations, we hypothesize their role in unknown mechanisms and provide visualization tools to aid their interpretation. Our study gives a better understanding of the limitations of pLMs, and demonstrates how SAE features can be used to help generate hypotheses for biological mechanisms. We release our code, model weights, and feature visualizer.

Applications · Health / Medicine

Hongru Hu, Shuwen Zhang, Yongin Choi, Venkat Malladi, Gerald Quon

Single-cell RNA sequencing (scRNA-seq) enables high-resolution exploration of cellular diversity and gene regulation, yet analyzing such data remains challenging due to technical and methodological limitations. Existing task-specific deep generative models like Variational Auto-Encoder (VAE) and its variants struggle to incorporate external biological knowledge, while transformer-based foundational large Language Models (LLMs or large LaMs) face limitations in computational cost and applicability to tabular gene expression data. Here, we introduce sciLaMA (single-cell interpretable Language Model Adapter), a novel representation learning framework that bridges these gaps by integrating static gene embeddings from multimodal LaMs with scRNA-seq tabular data through a paired-VAE architecture. Our approach generates context-aware representations for both cells and genes and outperforms state-of-the-art methods in key single-cell downstream tasks, including batch effect correction, cell clustering, and cell-state-specific gene marker and module identification, while maintaining computational efficiency. sciLaMA offers a computationally efficient, unified framework for comprehensive single-cell data analysis and biologically interpretable gene module discovery.

Applications · Health / Medicine

Daniel Shao, Richard Chen, Andrew Song, Joel Runevic, Ming Y. Lu, Tong Ding, Faisal Mahmood

Multiple Instance Learning (MIL) is a cornerstone approach in computational pathology for distilling embeddings from gigapixel tissue images into patient-level representations to predict clinical outcomes. However, MIL is frequently challenged by the constraints of working with small, weakly-supervised clinical datasets. Unlike fields such as natural language processing and computer vision, which effectively use transfer learning to improve model quality in data-scarce environments, the transferability of MIL models remains largely unexplored. We conduct the first comprehensive investigation into transfer learning capabilities of pretrained MIL models, evaluating 11 MIL models across 19 pretraining tasks spanning tissue subtyping, cancer grading, and molecular subtype prediction. We observe a substantial performance boost with finetuning pretrained models over training from randomly initialized weights, even with domain differences between pretraining and target tasks. Pretraining on pan-cancer datasets enables consistent generalization across organs and task types compared to single-disease pretraining. Remarkably, this pan-cancer pretraining leads to better transfer than that of a state-of-the-art slide-level foundation model, while using only 6.5\% of the training data. These findings indicate that MIL architectures exhibit robust adaptability, offering insights into the benefits of leveraging pretrained models to enhance performance in computational pathology.

Applications · Health / Medicine

Yishan Shen, Yuyang Ye, Hui Xiong, Yong Chen

Dynamic treatment regimes (DTRs) are critical to precision medicine, optimizing long-term outcomes through personalized, real-time decision-making in evolving clinical contexts, but require careful supervision for unsafe treatment risks. Existing efforts rely primarily on clinician-prescribed gold standards despite the absence of a known optimal strategy, and predominantly using structured EHR data without extracting valuable insights from clinical notes, limiting their reliability for treatment recommendations. In this work, we introduce SAFER, a calibrated risk-aware tabular-language recommendation framework for DTR that integrates both structured EHR and clinical notes, enabling them to learn from each other, and addresses inherent label uncertainty by assuming ambiguous optimal treatment solution for deceased patients. Moreover, SAFER employs conformal prediction to provide statistical guarantees, ensuring safe treatment recommendations while filtering out uncertain predictions. Experiments on two publicly available sepsis datasets demonstrate that SAFER outperforms state-of-the-art baselines across multiple recommendation metrics and counterfactual mortality rate, while offering robust formal assurances. These findings underscore SAFER’s potential as a trustworthy and theoretically grounded solution for high-stakes DTR applications.

Applications · Health / Medicine

Kai Yi, Kiarash Jamali, Sjors Scheres

The recent breakthrough of AlphaFold3 in modeling complex biomolecular interactions, including those between proteins and ligands, nucleotides, or metal ions, creates new opportunities for protein design. In so-called inverse protein folding, the objective is to find a sequence of amino acids that adopts a target protein structure. Many inverse folding methods struggle to predict sequences for complexes that contain non-protein components, and perform poorly with complexes that adopt multiple structural states. To address these challenges, we present ADFLIP (All-atom Discrete FLow matching Inverse Protein folding), a generative model based on discrete flow-matching for designing protein sequences conditioned on all-atom structural contexts. ADFLIP progressively incorporates predicted amino acid side chains as structural context during sequence generation and enables the design of dynamic protein complexes through ensemble sampling across multiple structural states. Furthermore, ADFLIP implements training-free classifier guidance sampling, which allows the incorporation of arbitrary pre-trained models to optimise the designed sequence for desired protein properties. We evaluated the performance of ADFLIP on protein complexes with small-molecule ligands, nucleotides, or metal ions, including dynamic complexes for which structure ensembles were determined by nuclear magnetic resonance (NMR). Our model achieves state-of-the-art performance in single-structure and multi-structure inverse folding tasks, demonstrating excellent potential for all-atom protein design. The code is available at https://github.com/ykiiiiii/ADFLIP .

Applications · Health / Medicine

Rina Bao, Shilong Dong, Zhenfang Chen, Sheng He, Patricia Ellen Grant, Yangming Ou

Medical Visual Question Answering (MVQA) requires AI models to answer questions related to medical images, offering significant potential to assist medical professionals in evaluating and diagnosing diseases, thereby improving early interventions. However, existing MVQA datasets primarily focus on basic questions regarding visual perception and pattern recognition, without addressing the more complex questions that are critical in clinical diagnosis and decision-making. This paper introduces a new benchmark designed for professional-level medical reasoning, simulating the decision-making process. We achieve this by collecting MRI and clinical data related to Hypoxic-Ischemic Encephalopathy, enriched with expert annotations and insights. Building on this data, we generate clinical question-answer pairs and MRI interpretations to enable comprehensive diagnosis, interpretation, and prediction of neurocognitive outcomes. Our evaluation of current large vision-language models (LVLMs) shows limited performance on this benchmark, highlighting both the challenges of the task and the importance of this benchmark for advancing medical AI. Furthermore, we propose a novel ``Clinical Graph of Thoughts" model, which integrates domain-specific medical knowledge and clinical reasoning processes with the interpretive abilities of LVLMs. The model demonstrates promising results, achieving around 15\% absolute gain on the most important neurocognitive outcome task, while the benchmark still reveals substantial opportunities for further research innovation.

Applications · Health / Medicine

Guancheng Wan, Zewen Liu, Xiaojun Shan, Max Lau, B. Aditya Prakash, Wei Jin

Effective epidemic forecasting is critical for public health strategies and efficient medical resource allocation, especially in the face of rapidly spreading infectious diseases. However, existing deep-learning methods often overlook the dynamic nature of epidemics and fail to account for the specific mechanisms of disease transmission. In response to these challenges, we introduce an innovative end-to-end framework called Epidemiology-Aware Neural ODE with Continuous Disease Transmission Graph (EARTH) in this paper. To learn continuous and regional disease transmission patterns, we first propose EANO, which seamlessly integrates the neural ODE approach with the epidemic mechanism, considering the complex spatial spread process during epidemic evolution. Additionally, we introduce GLTG to model global infection trends and leverage these signals to guide local transmission dynamically. To accommodate both the global coherence of epidemic trends and the local nuances of epidemic transmission patterns, we build a cross-attention approach to fuse the most meaningful information for forecasting. Through the smooth synergy of both components, EARTH offers a more robust and flexible approach to understanding and predicting the spread of infectious diseases. Extensive experiments show EARTH superior performance in forecasting real-world epidemics compared to state-of-the-art methods. The code is available at https://github.com/GuanchengWan/EARTH.

Applications · Health / Medicine

Yujin Oh, Pengfei Jin, Sangjoon Park, Sekeun Kim, Siyeop yoon, Jin Kim, Kyungsang Kim, Xiang Li, Quanzheng Li

Ensuring fairness in medical image segmentation is critical due to biases in imbalanced clinical data acquisition caused by demographic attributes (e.g., age, sex, race) and clinical factors (e.g., disease severity). To address these challenges, we introduce Distribution-aware Mixture of Experts (dMoE), inspired by optimal control theory. We provide a comprehensive analysis of its underlying mechanisms and clarify dMoE's role in adapting to heterogeneous distributions in medical image segmentation. Furthermore, we integrate dMoE into multiple network architectures, demonstrating its broad applicability across diverse medical image analysis tasks. By incorporating demographic and clinical factors, dMoE achieves state-of-the-art performance on two 2D benchmark datasets and a 3D in-house dataset. Our results highlight the effectiveness of dMoE in mitigating biases from imbalanced distributions, offering a promising approach to bridging control theory and medical image segmentation within fairness learning paradigms. The source code is available at https://github.com/tvseg/dMoE.

Applications · Health / Medicine

Eray Erturk, Fahad Kamran, Salar Abbaspourazad, Sean Jewell, Harsh Sharma, Yujie Li, Sinead Williamson, Nicholas Foti, Joseph Futoma

Wearable devices record physiological and behavioral signals that can improve health predictions. While foundation models are increasingly used for such predictions, they have been primarily applied to low-level sensor data, despite behavioral data often being more informative due to their alignment with physiologically relevant timescales and quantities. We develop foundation models of such behavioral signals using over 2.5B hours of wearable data from 162K individuals, systematically optimizing architectures and tokenization strategies for this unique dataset. Evaluated on 57 health-related tasks, our model shows strong performance across diverse real-world applications including individual-level classification and time-varying health state prediction. The model excels in behavior-driven tasks like sleep prediction, and improves further when combined with representations of raw sensor data. These results underscore the importance of tailoring foundation model design to wearables and demonstrate the potential to enable new health applications.

Applications · Health / Medicine

Xiangxin Zhou, Mingyu Li, xiao yi, Jiahan Li, Dongyu Xue, Zaixiang Zheng, Jianzhu Ma, Quanquan Gu

Cyclic peptides offer inherent advantages in pharmaceuticals. For example, cyclic peptides are more resistant to enzymatic hydrolysis compared to linear peptides and usually exhibit excellent stability and affinity. Although deep generative models have achieved great success in linear peptide design, several challenges prevent the development of computational methods for designing diverse types of cyclic peptides. These challenges include the scarcity of 3D structural data on target proteins and associated cyclic peptide ligands, the geometric constraints that cyclization imposes, and the involvement of non-canonical amino acids in cyclization. To address the above challenges, we introduce CpSDE, which consists of two key components: AtomSDE, a generative structure prediction model based on harmonic SDE, and ResRouter, a residue type predictor. Utilizing a routed sampling algorithm that alternates between these two models to iteratively update sequences and structures, CpSDE facilitates the generation of cyclic peptides. By employing explicit all-atom and bond modeling, CpSDE overcomes existing data limitations and is proficient in designing a wide variety of cyclic peptides.Our experimental results demonstrate that the cyclic peptides designed by our method exhibit reliable stability and affinity.

Applications · Health / Medicine

Arthur Deng, Karsten Householder, Fang Wu, K. Garcia, Brian Trippe

Accurate estimation of mutational effects on protein-protein binding energies is an open problem with applications in structural biology and therapeutic design. Several deep learning predictors for this task have been proposed but, presumably due to the scarcity of binding data, these methods under-perform computationally expensive estimates based on empirical force-fields. In response, we propose a transfer-learning approach that leverages advances in protein sequence modeling and folding stability prediction for this task. The key idea is to parameterize the binding energy as the difference between the folding energy of the protein complex and the sum of the folding energies of its binding partners. We show that using a pre-trained inverse-folding model as a proxy for folding energy provides strong zero-shot performance, and can be fine-tuned with (1) copious folding energy measurements and (2) more limited binding energy measurements.The resulting predictor, StaB-ddG, is the first deep learning predictor to match the accuracy of the state-of-the-art empirical force-field method Flex ddG, while offering an over 10,000x speed-up.

Applications · Health / Medicine

Minqi Yu, Jinduo Liu, Junzhong Ji

Deep models are increasingly used to analyze brain graphs for the diagnosis and understanding of brain diseases. However, due to the multi-site data aggregation and individual differences, brain graph datasets exhibit widespread distribution shifts, which impair the model’s generalization ability to the test set, thereby limiting the performance of existing methods. To address these issues, we propose a Causally Invariance-aware Augmentation for brain Graph Contrastive Learning, called CIA-GCL. This method first generates a brain graph by extracting node features based on the topological structure. Then, a learnable brain invariant subgraph is identified based on a causal decoupling approach to capture the maximum label-related invariant information with invariant learning. Around this invariant subgraph, we design a novel invariance-aware augmentation strategy to generate meaningful augmented samples for graph contrast learning. Finally, the extracted invariant subgraph is utilized for brain disease classification, effectively mitigating distribution shifts while also identifying critical local graph structures, enhancing the model’s interpretability. Experiments on three real-world brain disease datasets demonstrate that our method achieves state-of-the-art performance, effectively generalizes to multi-site brain datasets, and provides certain interpretability.

Applications · Health / Medicine

Sophia Tang, Yinuo Zhang, Pranam Chatterjee, PhD

We present **PepTune**, a multi-objective discrete diffusion model for simultaneous generation and optimization of therapeutic peptide SMILES. Built on the Masked Discrete Language Model (MDLM) framework, PepTune ensures valid peptide structures with a novel bond-dependent masking schedule and invalid loss function. To guide the diffusion process, we introduce **Monte Carlo Tree Guidance (MCTG)**, an inference-time multi-objective guidance algorithm that balances exploration and exploitation to iteratively refine Pareto-optimal sequences. MCTG integrates classifier-based rewards with search-tree expansion, overcoming gradient estimation challenges and data sparsity. Using PepTune, we generate diverse, chemically-modified peptides simultaneously optimized for multiple therapeutic properties, including target binding affinity, membrane permeability, solubility, hemolysis, and non-fouling for various disease-relevant targets. In total, our results demonstrate that MCTG for masked discrete diffusion is a powerful and modular approach for multi-objective sequence design in discrete state spaces.

Applications · Health / Medicine

Jiarui Lu, Xiaoyin Chen, Stephen Lu, Aurelie Lozano, Vijil Chenthamarakshan, Payel Das, Jian Tang

Protein dynamics play a crucial role in protein biological functions and properties, and their traditional study typically relies on time-consuming molecular dynamics (MD) simulations conducted in silico. Recent advances in generative modeling, particularly denoising diffusion models, have enabled efficient accurate protein structure prediction and conformation sampling by learning distributions over crystallographic structures. However, effectively integrating physical supervision into these data-driven approaches remains challenging, as standard energy-based objectives often lead to intractable optimization. In this paper, we introduce Energy-based Alignment (EBA), a method that aligns generative models with feedback from physical models, efficiently calibrating them to appropriately balance conformational states based on their energy differences. Experimental results on the MD ensemble benchmark demonstrate that EBA achieves state-of-the-art performance in generating high-quality protein ensembles. By improving the physical plausibility of generated structures, our approach enhances model predictions and holds promise for applications in structural biology and drug discovery.

Applications · Health / Medicine

Chuang Liu, Hongyan Xu, Yichao Cao, Xiu Su, Zhe Qu, Tianfa Li, Shan An, Haogang Zhu

Medical imaging faces significant challenges in single-domain generalization (SDG) due to the diversity of imaging devices and the variability among data collection centers. To address these challenges, we propose \textbf{TinyMIG}, a framework designed to transfer generalization capabilities from vision foundation models to medical imaging SDG. TinyMIG aims to enable lightweight specialized models to mimic the strong generalization capabilities of foundation models in terms of both global feature distribution and local fine-grained details during training. Specifically, for global feature distribution, we propose a Global Distribution Consistency Learning strategy that mimics the prior distributions of the foundation model layer by layer. For local fine-grained details, we further design a Localized Representation Alignment method, which promotes semantic alignment and generalization distillation between the specialized model and the foundation model. These mechanisms collectively enable the specialized model to achieve robust performance in diverse medical imaging scenarios. Extensive experiments on large-scale benchmarks demonstrate that TinyMIG, with extremely low computational cost, significantly outperforms state-of-the-art models, showcasing its superior SDG capabilities. All the code and model weights will be publicly available.