arXiv subjects

Marinka Zitnik

Publications and source records attributed to Marinka Zitnik.

At least 55 records · Page 3Linked to original sources

arXiv2025

Binding Affinity Prediction: From Conventional to Machine Learning-Based Approaches

Protein-ligand binding is the process by which a small molecule (drug or inhibitor) attaches to a target protein. Binding affinity, which characterizes the strength of biomolecular interactions, is essential for tackling diverse challenges in life sciences, including therapeutic design, protein engineering, enzyme optimization, and elucidating biological mechanisms. Much work has been devoted to predicting binding affinity over the past decades. Here, we review recent significant works, with a focus on methods, evaluation strategies, and benchmark datasets. We note growing use of both traditional machine learning and deep learning models for predicting binding affinity, accompanied by an increasing amount of data on proteins and small drug-like molecules. With improved predictive performance and the FDA's phasing out of animal testing, AI-driven in silico models, such as AI virtual cells (AIVCs), are poised to advance binding affinity prediction; reciprocally, progress in building binding affinity predictors can refine AIVCs. Future efforts in binding affinity prediction and AI-driven in silico models can enhance the simulation of temporal dynamics, cell-type specificity, and multi-omics integration to support more accurate and personalized outcomes.

q-bio.QM↗

arXiv2025

KnowGuard: Knowledge-Driven Abstention for Multi-Round Clinical Reasoning

In clinical practice, physicians refrain from making decisions when patient information is insufficient. This behavior, known as abstention, is a critical safety mechanism preventing potentially harmful misdiagnoses. Recent investigations have reported the application of large language models (LLMs) in medical scenarios. However, existing LLMs struggle with the abstentions, frequently providing overconfident responses despite incomplete information. This limitation stems from conventional abstention methods relying solely on model self-assessments, which lack systematic strategies to identify knowledge boundaries with external medical evidences. To address this, we propose \textbf{KnowGuard}, a novel \textit{investigate-before-abstain} paradigm that integrates systematic knowledge graph exploration for clinical decision-making. Our approach consists of two key stages operating on a shared contextualized evidence pool: 1) an evidence discovery stage that systematically explores the medical knowledge space through graph expansion and direct retrieval, and 2) an evidence evaluation stage that ranks evidence using multiple factors to adapt exploration based on patient context and conversation history. This two-stage approach enables systematic knowledge graph exploration, allowing models to trace structured reasoning paths and recognize insufficient medical evidence. We evaluate our abstention approach using open-ended multi-round clinical benchmarks that mimic realistic diagnostic scenarios, assessing abstention quality through accuracy-efficiency trade-offs beyond existing closed-form evaluations. Experimental evidences clearly demonstrate that KnowGuard outperforms state-of-the-art abstention approaches, improving diagnostic accuracy by 3.93\% while reducing unnecessary interaction by 7.27 turns on average.

cs.CL↗

arXiv2025

A Generative AI System for Biomedical Data Discovery with Grammar-Based Visualizations

We explore the potential for combining generative AI with grammar-based visualizations for biomedical data discovery. In our prototype, we use a multi-agent system to generate visualization specifications and apply filters. These visualizations are linked together, resulting in an interactive dashboard that is progressively constructed. Our system leverages the strengths of natural language while maintaining the utility of traditional user interfaces. Furthermore, we utilize generated interactive widgets enabling user adjustment. Finally, we demonstrate the potential utility of this system for biomedical data discovery with a case study.

cs.HC↗

arXiv2025

Artificial Intelligence for Science in Quantum, Atomistic, and Continuum Systems

Advances in artificial intelligence (AI) are fueling a new paradigm of discoveries in natural sciences. Today, AI has started to advance natural sciences by improving, accelerating, and enabling our understanding of natural phenomena at a wide range of spatial and temporal scales, giving rise to a new area of research known as AI for science (AI4Science). Being an emerging research paradigm, AI4Science is unique in that it is an enormous and highly interdisciplinary area. Thus, a unified and technical treatment of this field is needed yet challenging. This work aims to provide a technically thorough account of a subarea of AI4Science; namely, AI for quantum, atomistic, and continuum systems. These areas aim at understanding the physical world from the subatomic (wavefunctions and electron density), atomic (molecules, proteins, materials, and interactions), to macro (fluids, climate, and subsurface) scales and form an important subarea of AI4Science. A unique advantage of focusing on these areas is that they largely share a common set of challenges, thereby allowing a unified and foundational treatment. A key common challenge is how to capture physics first principles, especially symmetries, in natural systems by deep learning methods. We provide an in-depth yet intuitive account of techniques to achieve equivariance to symmetry transformations. We also discuss other common technical challenges, including explainability, out-of-distribution generalization, knowledge transfer with foundation and large language models, and uncertainty quantification. To facilitate learning and education, we provide categorized lists of resources that we found to be useful. We strive to be thorough and unified and hope this initial effort may trigger more community interests and efforts to further advance AI4Science.

cs.LG↗

arXiv2025

Multimodal Medical Code Tokenizer

Foundation models trained on patient electronic health records (EHRs) require tokenizing medical data into sequences of discrete vocabulary items. Existing tokenizers treat medical codes from EHRs as isolated textual tokens. However, each medical code is defined by its textual description, its position in ontological hierarchies, and its relationships to other codes, such as disease co-occurrences and drug-treatment associations. Medical vocabularies contain more than 600,000 codes with critical information for clinical reasoning. We introduce MedTok, a multimodal medical code tokenizer that uses the text descriptions and relational context of codes. MedTok processes text using a language model encoder and encodes the relational structure with a graph encoder. It then quantizes both modalities into a unified token space, preserving modality-specific and cross-modality information. We integrate MedTok into five EHR models and evaluate it on operational and clinical tasks across in-patient and out-patient datasets, including outcome prediction, diagnosis classification, drug recommendation, and risk stratification. Swapping standard EHR tokenizers with MedTok improves AUPRC across all EHR models, by 4.10% on MIMIC-III, 4.78% on MIMIC-IV, and 11.32% on EHRShot, with the largest gains in drug recommendation. Beyond EHR modeling, we demonstrate using MedTok tokenizer with medical QA systems. Our results demonstrate the potential of MedTok as a unified tokenizer for medical codes, improving tokenization for medical foundation models.

cs.CL↗

arXiv2025

TrialBench: Multi-Modal Artificial Intelligence-Ready Clinical Trial Datasets

Clinical trials are pivotal for developing new medical treatments but typically carry risks such as patient mortality and enrollment failure that waste immense efforts spanning over a decade. Applying artificial intelligence (AI) to predict key events in clinical trials holds great potential for providing insights to guide trial designs. However, complex data collection and question definition requiring medical expertise have hindered the involvement of AI thus far. This paper tackles these challenges by presenting a comprehensive suite of 23 meticulously curated AI-ready datasets covering multi-modal input features and 8 crucial prediction challenges in clinical trial design, encompassing prediction of trial duration, patient dropout rate, serious adverse event, mortality rate, trial approval outcome, trial failure reason, drug dose finding, design of eligibility criteria. Furthermore, we provide basic validation methods for each task to ensure the datasets' usability and reliability. We anticipate that the availability of such open-access datasets will catalyze the development of advanced AI approaches for clinical trial design, ultimately advancing clinical trial research and accelerating medical solution development.

cs.LG↗

arXiv2025

Prompting Decision Transformers for Zero-Shot Reach-Avoid Policies

Offline goal-conditioned reinforcement learning methods have shown promise for reach-avoid tasks, where an agent must reach a target state while avoiding undesirable regions of the state space. Existing approaches typically encode avoid-region information into an augmented state space and cost function, which prevents flexible, dynamic specification of novel avoid-region information at evaluation time. They also rely heavily on well-designed reward and cost functions, limiting scalability to complex or poorly structured environments. We introduce RADT, a decision transformer model for offline, reward-free, goal-conditioned, avoid region-conditioned RL. RADT encodes goals and avoid regions directly as prompt tokens, allowing any number of avoid regions of arbitrary size to be specified at evaluation time. Using only suboptimal offline trajectories from a random policy, RADT learns reach-avoid behavior through a novel combination of goal and avoid-region hindsight relabeling. We benchmark RADT against 3 existing offline goal-conditioned RL models across 11 tasks, environments, and experimental settings. RADT generalizes in a zero-shot manner to out-of-distribution avoid region sizes and counts, outperforming baselines that require retraining. In one such zero-shot setting, RADT achieves 35.7% improvement in normalized cost over the best retrained baseline while maintaining high goal-reaching success. We apply RADT to cell reprogramming in biology, where it reduces visits to undesirable intermediate gene expression states during trajectories to desired target states, despite stochastic transitions and discrete, structured state dynamics.

cs.LG↗

arXiv2025

Repurposing Foundation Model for Generalizable Medical Time Series Classification

Medical time series (MedTS) classification suffers from poor generalizability in real-world deployment due to inter- and intra-dataset heterogeneity, such as varying numbers of channels, signal lengths, task definitions, and patient characteristics. To address this, we propose FORMED, a novel framework for repurposing a backbone foundation model, pre-trained on generic time series, to enable highly generalizable MedTS classification on unseen datasets. FORMED combines the backbone with a novel classifier comprising two components: (1) task-specific channel embeddings and label queries, dynamically sized to match any number of channels and target classes, and (2) a shared decoding attention layer, jointly trained across datasets to capture medical domain knowledge through task-agnostic feature-query interactions. After repurposing, FORMED achieves seamless adaptation to unseen MedTS datasets through lightweight label query training (0.1% of parameters), eliminating the need for full fine-tuning or architectural redesign. We evaluate FORMED on 5 diverse MedTS datasets, benchmarking against 11 Task-Specific Models (TSM) and 4 Task-Specific Adaptation (TSA) methods. Our results demonstrate FORMED's dominant performance, achieving up to 35% absolute improvement in F1-score (on ADFTD dataset) over specialized baselines. Further analysis reveals consistent generalization across varying channel configurations, time series lengths, and clinical tasks, which are key challenges in real-world deployment. By decoupling domain-invariant representation learning from task-specific adaptation, FORMED establishes a scalable and resource-efficient paradigm for foundation model repurposing in healthcare. This approach prioritizes clinical adaptability over rigid task-centric design, offering a practical pathway for real-world implementation.

cs.LG↗

arXiv2025

Composable Interventions for Language Models

Test-time interventions for language models can enhance factual accuracy, mitigate harmful outputs, and improve model efficiency without costly retraining. But despite a flood of new methods, different types of interventions are largely developing independently. In practice, multiple interventions must be applied sequentially to the same model, yet we lack standardized ways to study how interventions interact. We fill this gap by introducing composable interventions, a framework to study the effects of using multiple interventions on the same language models, featuring new metrics and a unified codebase. Using our framework, we conduct extensive experiments and compose popular methods from three emerging intervention categories -- Knowledge Editing, Model Compression, and Machine Unlearning. Our results from 310 different compositions uncover meaningful interactions: compression hinders editing and unlearning, composing interventions hinges on their order of application, and popular general-purpose metrics are inadequate for assessing composability. Taken together, our findings showcase clear gaps in composability, suggesting a need for new multi-objective interventions. All of our code is public: https://github.com/hartvigsen-group/composable-interventions.

cs.LG↗

arXiv2025

TxAgent: An AI Agent for Therapeutic Reasoning Across a Universe of Tools

Precision therapeutics require multimodal adaptive models that generate personalized treatment recommendations. We introduce TxAgent, an AI agent that leverages multi-step reasoning and real-time biomedical knowledge retrieval across a toolbox of 211 tools to analyze drug interactions, contraindications, and patient-specific treatment strategies. TxAgent evaluates how drugs interact at molecular, pharmacokinetic, and clinical levels, identifies contraindications based on patient comorbidities and concurrent medications, and tailors treatment strategies to individual patient characteristics. It retrieves and synthesizes evidence from multiple biomedical sources, assesses interactions between drugs and patient conditions, and refines treatment recommendations through iterative reasoning. It selects tools based on task objectives and executes structured function calls to solve therapeutic tasks that require clinical reasoning and cross-source validation. The ToolUniverse consolidates 211 tools from trusted sources, including all US FDA-approved drugs since 1939 and validated clinical insights from Open Targets. TxAgent outperforms leading LLMs, tool-use models, and reasoning agents across five new benchmarks: DrugPC, BrandPC, GenericPC, TreatmentPC, and DescriptionPC, covering 3,168 drug reasoning tasks and 456 personalized treatment scenarios. It achieves 92.1% accuracy in open-ended drug reasoning tasks, surpassing GPT-4o and outperforming DeepSeek-R1 (671B) in structured multi-step reasoning. TxAgent generalizes across drug name variants and descriptions. By integrating multi-step inference, real-time knowledge grounding, and tool-assisted decision-making, TxAgent ensures that treatment recommendations align with established clinical guidelines and real-world evidence, reducing the risk of adverse events and improving therapeutic decision-making.

cs.AI↗

arXiv2025

KGARevion: An AI Agent for Knowledge-Intensive Biomedical QA

Biomedical reasoning integrates structured, codified knowledge with tacit, experience-driven insights. Depending on the context, quantity, and nature of available evidence, researchers and clinicians use diverse strategies, including rule-based, prototype-based, and case-based reasoning. Effective medical AI models must handle this complexity while ensuring reliability and adaptability. We introduce KGARevion, a knowledge graph-based agent that answers knowledge-intensive questions. Upon receiving a query, KGARevion generates relevant triplets by leveraging the latent knowledge embedded in a large language model. It then verifies these triplets against a grounded knowledge graph, filtering out errors and retaining only accurate, contextually relevant information for the final answer. This multi-step process strengthens reasoning, adapts to different models of medical inference, and outperforms retrieval-augmented generation-based approaches that lack effective verification mechanisms. Evaluations on medical QA benchmarks show that KGARevion improves accuracy by over 5.2% over 15 models in handling complex medical queries. To further assess its effectiveness, we curated three new medical QA datasets with varying levels of semantic complexity, where KGARevion improved accuracy by 10.4%. The agent integrates with different LLMs and biomedical knowledge graphs for broad applicability across knowledge-intensive tasks. We evaluated KGARevion on AfriMed-QA, a newly introduced dataset focused on African healthcare, demonstrating its strong zero-shot generalization to underrepresented medical contexts.

cs.AI↗

arXiv2025

Invariant Tokenization of Crystalline Materials for Language Model Enabled Generation

We consider the problem of crystal materials generation using language models (LMs). A key step is to convert 3D crystal structures into 1D sequences to be processed by LMs. Prior studies used the crystallographic information framework (CIF) file stream, which fails to ensure SE(3) and periodic invariance and may not lead to unique sequence representations for a given crystal structure. Here, we propose a novel method, known as Mat2Seq, to tackle this challenge. Mat2Seq converts 3D crystal structures into 1D sequences and ensures that different mathematical descriptions of the same crystal are represented in a single unique sequence, thereby provably achieving SE(3) and periodic invariance. Experimental results show that, with language models, Mat2Seq achieves promising performance in crystal structure generation as compared with prior methods.

cs.LG↗

arXiv2025

A Causality-aware Paradigm for Evaluating Creativity of Multimodal Large Language Models

Recently, numerous benchmarks have been developed to evaluate the logical reasoning abilities of large language models (LLMs). However, assessing the equally important creative capabilities of LLMs is challenging due to the subjective, diverse, and data-scarce nature of creativity, especially in multimodal scenarios. In this paper, we consider the comprehensive pipeline for evaluating the creativity of multimodal LLMs, with a focus on suitable evaluation platforms and methodologies. First, we find the Oogiri game, a creativity-driven task requiring humor, associative thinking, and the ability to produce unexpected responses to text, images, or both. This game aligns well with the input-output structure of modern multimodal LLMs and benefits from a rich repository of high-quality, human-annotated creative responses, making it an ideal platform for studying LLM creativity. Next, beyond using the Oogiri game for standard evaluations like ranking and selection, we propose LoTbench, an interactive, causality-aware evaluation framework, to further address some intrinsic risks in standard evaluations, such as information leakage and limited interpretability. The proposed LoTbench not only quantifies LLM creativity more effectively but also visualizes the underlying creative thought processes. Our results show that while most LLMs exhibit constrained creativity, the performance gap between LLMs and humans is not insurmountable. Furthermore, we observe a strong correlation between results from the multimodal cognition benchmark MMMU and LoTbench, but only a weak connection with traditional creativity metrics. This suggests that LoTbench better aligns with human cognitive theories, highlighting cognition as a critical foundation in the early stages of creativity and enabling the bridging of diverse concepts. https://lotbench.github.io

cs.AI↗

arXiv2024

Compositional Representation of Polymorphic Crystalline Materials

Machine learning (ML) has seen promising developments in materials science, yet its efficacy largely depends on detailed crystal structural data, which are often complex and hard to obtain, limiting their applicability in real-world material synthesis processes. An alternative, using compositional descriptors, offers a simpler approach by indicating the elemental ratios of compounds without detailed structural insights. However, accurately representing materials solely with compositional descriptors presents challenges due to polymorphism, where a single composition can correspond to various structural arrangements, creating ambiguities in its representation. To this end, we introduce PCRL, a novel approach that employs probabilistic modeling of composition to capture the diverse polymorphs from available structural information. Extensive evaluations on sixteen datasets demonstrate the effectiveness of PCRL in learning compositional representation, and our analysis highlights its potential applicability of PCRL in material discovery. The source code for PCRL is available at https://github.com/Namkyeong/PCRL.

cond-mat.mtrl-sci↗

arXiv2024

UniTS: A Unified Multi-Task Time Series Model

Although pre-trained transformers and reprogrammed text-based LLMs have shown strong performance on time series tasks, the best-performing architectures vary widely across tasks, with most models narrowly focused on specific areas, such as time series forecasting. Unifying predictive and generative time series tasks within a single model remains challenging. We introduce UniTS, a unified multi-task time series model that utilizes task tokenization to integrate predictive and generative tasks into a single framework. UniTS employs a modified transformer block to capture universal time series representations, enabling transferability from a heterogeneous, multi-domain pre-training dataset-characterized by diverse dynamic patterns, sampling rates, and temporal scales-to a wide range of downstream datasets with varied task specifications and data domains. Tested on 38 datasets across human activity sensors, healthcare, engineering, and finance, UniTS achieves superior performance compared to 12 forecasting models, 20 classification models, 18 anomaly detection models, and 16 imputation models, including adapted text-based LLMs. UniTS also demonstrates strong few-shot and prompt capabilities when applied to new domains and tasks. In single-task settings, UniTS outperforms competitive task-specialized time series models. Code and datasets are available at https://github.com/mims-harvard/UniTS.

cs.LG↗

arXiv2024

Geometric Deep Learning for Structure-Based Drug Design: A Survey

Structure-based drug design (SBDD) leverages the three-dimensional geometry of proteins to identify potential drug candidates. Traditional approaches, rooted in physicochemical modeling and domain expertise, are often resource-intensive. Recent advancements in geometric deep learning, which effectively integrate and process 3D geometric data, alongside breakthroughs in accurate protein structure predictions from tools like AlphaFold, have significantly propelled the field forward. This paper systematically reviews the state-of-the-art in geometric deep learning for SBDD. We begin by outlining foundational tasks in SBDD, discussing prevalent 3D protein representations, and highlighting representative predictive and generative models. Next, we provide an in-depth review of key tasks, including binding site prediction, binding pose generation, de novo molecule generation, linker design, protein pocket generation, and binding affinity prediction. For each task, we present formal problem definitions, key methods, datasets, evaluation metrics, and performance benchmarks. Lastly, we explore current challenges and future opportunities in SBDD. Challenges include oversimplified problem formulations, limited out-of-distribution generalization, biosecurity concerns related to the misuse of structural data, insufficient evaluation metrics and large-scale benchmarks, and the need for experimental validation and enhanced model interpretability. Opportunities lie in leveraging multimodal datasets, integrating domain knowledge, developing comprehensive benchmarks, establishing criteria aligned with clinical outcomes, and designing foundation models to expand the scope of design tasks. We also curate \url{https://github.com/zaixizhang/Awesome-SBDD}, reflecting ongoing contributions and new datasets in SBDD.

q-bio.QM↗

arXiv2024

Multi Scale Graph Neural Network for Alzheimer's Disease

Alzheimer's disease (AD) is a complex, progressive neurodegenerative disorder characterized by extracellular A\b{eta} plaques, neurofibrillary tau tangles, glial activation, and neuronal degeneration, involving multiple cell types and pathways. Current models often overlook the cellular context of these pathways. To address this, we developed a multiscale graph neural network (GNN) model, ALZ PINNACLE, using brain omics data from donors spanning the entire aging to AD spectrum. ALZ PINNACLE is based on the PINNACLE GNN framework, which learns context-aware protein, cell type, and tissue representations within a unified latent space. ALZ PINNACLE was trained on 14,951 proteins, 206,850 protein interactions, 7 cell types, and 48 cell subtypes or states. After pretraining, we investigated the learned embedding of APOE, the largest genetic risk factor for AD, across different cell types. Notably, APOE embeddings showed high similarity in microglial, neuronal, and CD8 cells, suggesting a similar role of APOE in these cell types. Fine tuning the model on AD risk genes revealed cell type contexts predictive of the role of APOE in AD. Our results suggest that ALZ PINNACLE may provide a valuable framework for uncovering novel insights into AD neurobiology.

cs.LG↗

arXiv2024

FoldMark: Protecting Protein Generative Models with Watermarking

Protein structure is key to understanding protein function and is essential for progress in bioengineering, drug discovery, and molecular biology. Recently, with the incorporation of generative AI, the power and accuracy of computational protein structure prediction/design have been improved significantly. However, ethical concerns such as copyright protection and harmful content generation (biosecurity) pose challenges to the wide implementation of protein generative models. Here, we investigate whether it is possible to embed watermarks into protein generative models and their outputs for copyright authentication and the tracking of generated structures. As a proof of concept, we propose a two-stage method FoldMark as a generalized watermarking strategy for protein generative models. FoldMark first pretrain watermark encoder and decoder, which can minorly adjust protein structures to embed user-specific information and faithfully recover the information from the encoded structure. In the second step, protein generative models are fine-tuned with watermark-conditioned Low-Rank Adaptation (LoRA) modules to preserve generation quality while learning to generate watermarked structures with high recovery rates. Extensive experiments are conducted on open-source protein structure prediction models (e.g., ESMFold and MultiFlow) and de novo structure design models (e.g., FrameDiff and FoldFlow) and we demonstrate that our method is effective across all these generative models. Meanwhile, our watermarking framework only exerts a negligible impact on the original protein structure quality and is robust under potential post-processing and adaptive attacks.

cs.CR↗