Zhi Huang

Yan Cui, Jacob S. Leiby, Wenhui Lei et al.

Integrating molecular, morphological, and clinical data is essential for basic and translational biomedical research, yet systematic frameworks for jointly modeling these modalities remain limited. Here we present Haiku, a tri-modal contrastive learning model trained on multiplexed immunofluorescence (mIF). It comprises 26.7 million spatial proteomics patches from 3,218 tissue sections across 1,606 patients spanning 11 organ types, with matched hematoxylin and eosin (H&E) histology and clinical metadata aligned in a shared embedding space. Haiku enables three-way cross-modal retrieval, improves downstream classification and clinical prediction tasks over unimodal baselines, and supports zero-shot biomarker inference through fusion retrieval conditioned on clinical metadata-only text descriptions. Across tasks, Haiku outperforms competing approaches, achieving cross-modal retrieval (Recall@50 up to 0.611 versus near-zero baseline), survival prediction (C-index 0.737, +7.91% relative improvement), and zero-shot biomarker inference (mean Pearson correlation 0.718 across 52 biomarkers). Furthermore, we introduce a counterfactual prediction framework in which modifying only clinical metadata while fixing tissue morphology surfaces niche-specific molecular shifts associated with breast cancer stage progression and lung cancer survival outcomes. In a lung adenocarcinoma case study, the counterfactual analysis recovers niche-specific shifts characterized by increased CD8 and granzyme B, reduced PD-L1, and decreased Ki67, broadly consistent with patterns reported for favorable outcomes. We present these counterfactual results as exploratory, hypothesis-generating signals rather than mechanistic claims. These capabilities demonstrate that tri-modal alignment via Haiku enables integrative analysis of spatial biology, bridging molecular measurements with clinical context for biological exploration.

Peixian Liang, Songhao Li, Shunsuke Koga et al.

Accurate semantic segmentation for histopathology image is crucial for quantitative tissue analysis and downstream clinical modeling. Recent segmentation foundation models have improved generalization through large-scale pretraining, yet remain poorly aligned with pathology because they treat segmentation as a static visual prediction task. Here we present VISTA-PATH, an interactive, class-aware pathology segmentation foundation model designed to resolve heterogeneous structures, incorporate expert feedback, and produce pixel-level segmentation that are directly meaningful for clinical interpretation. VISTA-PATH jointly conditions segmentation on visual context, semantic tissue descriptions, and optional expert-provided spatial prompts, enabling precise multi-class segmentation across heterogeneous pathology images. To support this paradigm, we curate VISTA-PATH Data, a large-scale pathology segmentation corpus comprising over 1.6 million image-mask-text triplets spanning 9 organs and 93 tissue classes. Across extensive held-out and external benchmarks, VISTA-PATH consistently outperforms existing segmentation foundation models. Importantly, VISTA-PATH supports dynamic human-in-the-loop refinement by propagating sparse, patch-level bounding-box annotation feedback into whole-slide segmentation. Finally, we show that the high-fidelity, class-aware segmentation produced by VISTA-PATH is a preferred model for computational pathology. It improve tissue microenvironment analysis through proposed Tumor Interaction Score (TIS), which exhibits strong and significant associations with patient survival. Together, these results establish VISTA-PATH as a foundation model that elevates pathology image segmentation from a static prediction to an interactive and clinically grounded representation for digital pathology. Source code and demo can be found at https://github.com/zhihuanglab/VISTA-PATH.

Xiangru Tang, Zhuoyun Yu, Jiapeng Chen et al.

Virtual cell modeling represents an emerging frontier at the intersection of artificial intelligence and biology, aiming to predict quantities such as responses to diverse perturbations quantitatively. However, autonomously building computational models for virtual cells is challenging due to the complexity of biological systems, the heterogeneity of data modalities, and the need for domain-specific expertise across multiple disciplines. Here, we introduce CellForge, an agentic system that leverages a multi-agent framework that transforms presented biological datasets and research objectives directly into optimized computational models for virtual cells. More specifically, given only raw single-cell multi-omics data and task descriptions as input, CellForge outputs both an optimized model architecture and executable code for training virtual cell models and inference. The framework integrates three core modules: Task Analysis for presented dataset characterization and relevant literature retrieval, Method Design, where specialized agents collaboratively develop optimized modeling strategies, and Experiment Execution for automated generation of code. The agents in the Design module are separated into experts with differing perspectives and a central moderator, and have to collaboratively exchange solutions until they achieve a reasonable consensus. We demonstrate CellForge's capabilities in single-cell perturbation prediction, using six diverse datasets that encompass gene knockouts, drug treatments, and cytokine stimulations across multiple modalities. CellForge consistently outperforms task-specific state-of-the-art methods. Overall, CellForge demonstrates how iterative interaction between LLM agents with differing perspectives provides better solutions than directly addressing a modeling challenge. Our code is publicly available at https://github.com/gersteinlab/CellForge.

Weixin Liang, Zachary Izzo, Yaohui Zhang et al. · berkeley, stanford

We present an approach for estimating the fraction of text in a large corpus which is likely to be substantially modified or produced by a large language model (LLM). Our maximum likelihood model leverages expert-written and AI-generated reference texts to accurately and efficiently examine real-world LLM-use at the corpus level. We apply this approach to a case study of scientific peer review in AI conferences that took place after the release of ChatGPT: ICLR 2024, NeurIPS 2023, CoRL 2023 and EMNLP 2023. Our results suggest that between 6.5% and 16.9% of text submitted as peer reviews to these conferences could have been substantially modified by LLMs, i.e. beyond spell-checking or minor writing updates. The circumstances in which generated text occurs offer insight into user behavior: the estimated fraction of LLM-generated text is higher in reviews which report lower confidence, were submitted close to the deadline, and from reviewers who are less likely to respond to author rebuttals. We also observe corpus-level trends in generated text which may be too subtle to detect at the individual level, and discuss the implications of such trends on peer review. We call for future interdisciplinary work to examine how LLM use is changing our information and knowledge practices.

Weixin Liang, Yaohui Zhang, Zhengxuan Wu et al. · berkeley, stanford

Scientific publishing lays the foundation of science by disseminating research findings, fostering collaboration, encouraging reproducibility, and ensuring that scientific knowledge is accessible, verifiable, and built upon over time. Recently, there has been immense speculation about how many people are using large language models (LLMs) like ChatGPT in their academic writing, and to what extent this tool might have an effect on global scientific practices. However, we lack a precise measure of the proportion of academic writing substantially modified or produced by LLMs. To address this gap, we conduct the first systematic, large-scale analysis across 950,965 papers published between January 2020 and February 2024 on the arXiv, bioRxiv, and Nature portfolio journals, using a population-level statistical framework to measure the prevalence of LLM-modified content over time. Our statistical estimation operates on the corpus level and is more robust than inference on individual instances. Our findings reveal a steady increase in LLM usage, with the largest and fastest growth observed in Computer Science papers (up to 17.5%). In comparison, Mathematics papers and the Nature portfolio showed the least LLM modification (up to 6.3%). Moreover, at an aggregate level, our analysis reveals that higher levels of LLM-modification are associated with papers whose first authors post preprints more frequently, papers in more crowded research areas, and papers of shorter lengths. Our findings suggests that LLMs are being broadly used in scientific writings.

Songhao Li, Jonathan Xu, Tiancheng Bao et al.

Agentic AI is rapidly advancing in healthcare and biomedical research. However, in medical image analysis, their performance and adoption remain limited due to the lack of a robust ecosystem, insufficient toolsets, and the absence of real-time interactive expert feedback. Here we present "TissueLab", a co-evolving agentic AI system that allows researchers to ask direct questions, automatically plan and generate explainable workflows, and conduct real-time analyses where experts can visualize intermediate results and refine them. TissueLab integrates tool factories across pathology, radiology, and spatial omics domains. By standardizing inputs, outputs, and capabilities of diverse tools, the system determines when and how to invoke them to address research and clinical questions. Across diverse tasks with clinically meaningful quantifications that inform staging, prognosis, and treatment planning, TissueLab achieves state-of-the-art performance compared with end-to-end vision-language models (VLMs) and other agentic AI systems such as GPT-5. Moreover, TissueLab continuously learns from clinicians, evolving toward improved classifiers and more effective decision strategies. With active learning, it delivers accurate results in unseen disease contexts within minutes, without requiring massive datasets or prolonged retraining. Released as a sustainable open-source ecosystem, TissueLab aims to accelerate computational research and translational adoption in medical imaging while establishing a foundation for the next generation of medical AI.

Minghui Chen, Ruinan Jin, Wenlong Deng et al.

Recent studies highlight the promise of LLM-based prompt optimization, especially with TextGrad, which automates differentiation'' via texts and backpropagates textual feedback. This approach facilitates training in various real-world applications that do not support numerical gradient propagation or loss calculation. In this paper, we systematically explore the potential and challenges of incorporating textual gradient into Federated Learning (FL). Our contributions are fourfold. Firstly, we introduce a novel FL paradigm, Federated Textual Gradient (FedTextGrad), that allows clients to upload locally optimized prompts derived from textual gradients, while the server aggregates the received prompts. Unlike traditional FL frameworks, which are designed for numerical aggregation, FedTextGrad is specifically tailored for handling textual data, expanding the applicability of FL to a broader range of problems that lack well-defined numerical loss functions. Secondly, building on this design, we conduct extensive experiments to explore the feasibility of FedTextGrad. Our findings highlight the importance of properly tuning key factors (e.g., local steps) in FL training. Thirdly, we highlight a major challenge in FedTextGrad aggregation: retaining essential information from distributed prompt updates. Last but not least, in response to this issue, we improve the vanilla variant of FedTextGrad by providing actionable guidance to the LLM when summarizing client prompts by leveraging the Uniform Information Density principle. Through this principled study, we enable the adoption of textual gradients in FL for optimizing LLMs, identify important issues, and pinpoint future directions, thereby opening up a new research area that warrants further investigation.

Sheng Wang, Ruiming Wu, Charles Herndon et al.

Diagnosing a whole-slide image is an interactive, multi-stage process of changing magnification and moving between fields. Although recent pathology foundation models demonstrated superior performances, practical agentic systems that decide what field to examine next, adjust magnification, and deliver explainable diagnoses are still lacking. Such limitation is largely bottlenecked by data: scalable, clinically aligned supervision of expert viewing behavior that is tacit and experience-based, not documented in textbooks or internet, and therefore absent from LLM training. Here we introduce a framework designed to address this challenge through three key breakthroughs. First, the AI Session Recorder seamlessly integrates with standard whole-slide image viewers to unobtrusively record routine navigation and convert the viewer logs into standardized behavioral commands and bounding boxes. Second, a lightweight human-in-the-loop review turns AI-drafted rationales for behavioral commands into the Pathology-CoT dataset, a form of paired "where to look" and "why it matters", enabling six-fold faster labeling compared to manual constructing such Chain-of-Thought dataset. Using this behavioral data, we build Pathology-o3, a two-stage agent that first proposes important ROIs and then performs behavior-guided reasoning. On the gastrointestinal lymph-node metastasis detection task, our method achieved 100 recall on the internal validation from Stanford Medicine and 97.6 recall on an independent external validation from Sweden, exceeding the state-of-the-art OpenAI o3 model and generalizing across backbones. To our knowledge, Pathology-CoT constitutes one of the first behavior-grounded agentic systems in pathology. Turning everyday viewer logs into scalable, expert-validated supervision, our framework makes agentic pathology practical and establishes a path to human-aligned, upgradeable clinical AI.

Jacob S. Leiby, Jialu Yao, Pan Lu et al.

Immunohistochemistry (IHC) provides information on protein expression in tissue sections and is commonly used to support pathology diagnosis and disease triage. While AI models for H\&E-stained slides show promise, their applicability to IHC is limited due to domain-specific variations. Here we introduce HPA10M, a dataset that contains 10,495,672 IHC images from the Human Protein Atlas with comprehensive metadata included, and encompasses 45 normal tissue types and 20 major cancer types. Based on HPA10M, we trained iSight, a multi-task learning framework for automated IHC staining assessment. iSight combines visual features from whole-slide images with tissue metadata through a token-level attention mechanism, simultaneously predicting staining intensity, location, quantity, tissue type, and malignancy status. On held-out data, iSight achieved 85.5\% accuracy for location, 76.6\% for intensity, and 75.7\% for quantity, outperforming fine-tuned foundation models (PLIP, CONCH) by 2.5--10.2\%. In addition, iSight demonstrates well-calibrated predictions with expected calibration errors of 0.0150-0.0408. Furthermore, in a user study with eight pathologists evaluating 200 images from two datasets, iSight outperformed initial pathologist assessments on the held-out HPA dataset (79\% vs 68\% for location, 70\% vs 57\% for intensity, 68\% vs 52\% for quantity). Inter-pathologist agreement also improved after AI assistance in both held-out HPA (Cohen's $κ$ increased from 0.63 to 0.70) and Stanford TMAD datasets (from 0.74 to 0.76), suggesting expert--AI co-assessment can improve IHC interpretation. This work establishes a foundation for AI systems that can improve IHC diagnostic accuracy and highlights the potential for integrating iSight into clinical workflows to enhance the consistency and reliability of IHC assessment.

Yinuo Xu, Yan Cui, Mingyao Li et al.

Identifying cell types and subtypes in routine histopathology is fundamental for understanding disease. Existing tile-based models capture nuclear detail but miss the broader tissue context that influences cell identity. Current human annotations are coarse-grained and uneven across studies, making fine-grained, subtype-level classification difficult. In this study, we build a marker-guided dataset from Xenium spatial transcriptomics with single-cell resolution labels for more than two million cells across eight organs and 16 classes to address the lack of high-quality annotations. Leveraging this data resource, we introduce NuClass, a pathologist workflow inspired framework for cell-wise multi-scale integration of nuclear morphology and microenvironmental context. It combines Path local, which focuses on nuclear morphology from 224x224 pixel crops, and Path global, which models the surrounding 1024x1024 pixel neighborhood, through a learnable gating module that balances local and global information. An uncertainty-guided objective directs the global path to prioritize regions where the local path is uncertain, and we provide calibrated confidence estimates and Grad-CAM maps for interpretability. Evaluated on three fully held-out cohorts, NuClass achieves up to 96 percent F1 for its best-performing class, outperforming strong baselines. Our results demonstrate that multi-scale, uncertainty-aware fusion can bridge the gap between slide-level pathological foundation models and reliable, cell-level phenotype prediction.

Mert Yuksekgonul, Federico Bianchi, Joseph Boen et al.

AI is undergoing a paradigm shift, with breakthroughs achieved by systems orchestrating multiple large language models (LLMs) and other complex components. As a result, developing principled and automated optimization methods for compound AI systems is one of the most important new challenges. Neural networks faced a similar challenge in its early days until backpropagation and automatic differentiation transformed the field by making optimization turn-key. Inspired by this, we introduce TextGrad, a powerful framework performing automatic ``differentiation'' via text. TextGrad backpropagates textual feedback provided by LLMs to improve individual components of a compound AI system. In our framework, LLMs provide rich, general, natural language suggestions to optimize variables in computation graphs, ranging from code snippets to molecular structures. TextGrad follows PyTorch's syntax and abstraction and is flexible and easy-to-use. It works out-of-the-box for a variety of tasks, where the users only provide the objective function without tuning components or prompts of the framework. We showcase TextGrad's effectiveness and generality across a diverse range of applications, from question answering and molecule optimization to radiotherapy treatment planning. Without modifying the framework, TextGrad improves the zero-shot accuracy of GPT-4o in Google-Proof Question Answering from $51\%$ to $55\%$, yields $20\%$ relative performance gain in optimizing LeetCode-Hard coding problem solutions, improves prompts for reasoning, designs new druglike small molecules with desirable in silico binding, and designs radiation oncology treatment plans with high specificity. TextGrad lays a foundation to accelerate the development of the next-generation of AI systems.

Zhi Huang, Paul Salama, Wei Shao et al.

One of the central goals in precision health is the understanding and interpretation of high-dimensional biological data to identify genes and markers associated with disease initiation, development, and outcomes. Though significant effort has been committed to harness gene expression data for multiple analyses while accounting for time-to-event modeling by including survival times, many traditional analyses have focused separately on non-negative matrix factorization (NMF) of the gene expression data matrix and survival regression with Cox proportional hazards model. In this work, Cox proportional hazards regression is integrated with NMF by imposing survival constraints. This is accomplished by jointly optimizing the Frobenius norm and partial log likelihood for events such as death or relapse. Simulation results on synthetic data demonstrated the superiority of the proposed method, when compared to other algorithms, in finding survival associated gene clusters. In addition, using human cancer gene expression data, the proposed technique can unravel critical clusters of cancer genes. The discovered gene clusters reflect rich biological implications and can help identify survival-related biomarkers. Towards the goal of precision health and cancer treatments, the proposed algorithm can help understand and interpret high-dimensional heterogeneous genomics data with accurate identification of survival-associated gene clusters.