HistoWAS: A Pathomics Framework for Large-Scale Feature-Wide Association Studies of Tissue Topology and Patient Outcomes

High-throughput "pathomic" analysis of Whole Slide Images (WSIs) offers new opportunities to study tissue characteristics and for biomarker discovery. However, the clinical relevance of the tissue characteristics at the micro- and macro-environment level is limited by the lack of tools that facilitate the measurement of the spatial interaction of individual structure characteristics and their association with clinical parameters. To address these challenges, we introduce HistoWAS (Histology-Wide Association Study), a computational framework designed to link tissue spatial organization to clinical outcomes. Specifically, HistoWAS implements (1) a feature space that augments conventional metrics with 30 topological and spatial features, adapted from Geographic Information Systems (GIS) point pattern analysis, to quantify tissue micro-architecture; and (2) an association study engine, inspired by Phenome-Wide Association Studies (PheWAS), that performs mass univariate regression for each feature with statistical correction. As a proof of concept, we applied HistoWAS to analyze a total of 102 features (72 conventional object-level features and our 30 spatial features) using 385 PAS-stained WSIs from 206 participants in the Kidney Precision Medicine Project (KPMP). The code and data have been released to https://github.com/hrlblab/histoWAS.

SCR2-ST: Combine Single Cell with Spatial Transcriptomics for Efficient Active Sampling via Reinforcement Learning

Spatial transcriptomics (ST) is an emerging technology that enables researchers to investigate the molecular relationships underlying tissue morphology. However, acquiring ST data remains prohibitively expensive, and traditional fixed-grid sampling strategies lead to redundant measurements of morphologically similar or biologically uninformative regions, thus resulting in scarce data that constrain current methods. The well-established single-cell sequencing field, however, could provide rich biological data as an effective auxiliary source to mitigate this limitation. To bridge these gaps, we introduce SCR2-ST, a unified framework that leverages single-cell prior knowledge to guide efficient data acquisition and accurate expression prediction. SCR2-ST integrates a single-cell guided reinforcement learning-based (SCRL) active sampling and a hybrid regression-retrieval prediction network SCR2Net. SCRL combines single-cell foundation model embeddings with spatial density information to construct biologically grounded reward signals, enabling selective acquisition of informative tissue regions under constrained sequencing budgets. SCR2Net then leverages the actively sampled data through a hybrid architecture combining regression-based modeling with retrieval-augmented inference, where a majority cell-type filtering mechanism suppresses noisy matches and retrieved expression profiles serve as soft labels for auxiliary supervision. We evaluated SCR2-ST on three public ST datasets, demonstrating SOTA performance in both sampling efficiency and prediction accuracy, particularly under low-budget scenarios. Code is publicly available at: https://github.com/hrlblab/SCR2ST

How Close Are We? Limitations and Progress of AI Models in Banff Lesion Scoring

The Banff Classification provides the global standard for evaluating renal transplant biopsies, yet its semi-quantitative nature, complex criteria, and inter-observer variability present significant challenges for computational replication. In this study, we explore the feasibility of approximating Banff lesion scores using existing deep learning models through a modular, rule-based framework. We decompose each Banff indicator - such as glomerulitis (g), peritubular capillaritis (ptc), and intimal arteritis (v) - into its constituent structural and inflammatory components, and assess whether current segmentation and detection tools can support their computation. Model outputs are mapped to Banff scores using heuristic rules aligned with expert guidelines, and evaluated against expert-annotated ground truths. Our findings highlight both partial successes and critical failure modes, including structural omission, hallucination, and detection ambiguity. Even when final scores match expert annotations, inconsistencies in intermediate representations often undermine interpretability. These results reveal the limitations of current AI pipelines in replicating computational expert-level grading, and emphasize the importance of modular evaluation and computational Banff grading standard in guiding future model development for transplant pathology.

DyMorph-B2I: Dynamic and Morphology-Guided Binary-to-Instance Segmentation for Renal Pathology

Accurate morphological quantification of renal pathology functional units relies on instance-level segmentation, yet most existing datasets and automated methods provide only binary (semantic) masks, limiting the precision of downstream analyses. Although classical post-processing techniques such as watershed, morphological operations, and skeletonization, are often used to separate semantic masks into instances, their individual effectiveness is constrained by the diverse morphologies and complex connectivity found in renal tissue. In this study, we present DyMorph-B2I, a dynamic, morphology-guided binary-to-instance segmentation pipeline tailored for renal pathology. Our approach integrates watershed, skeletonization, and morphological operations within a unified framework, complemented by adaptive geometric refinement and customizable hyperparameter tuning for each class of functional unit. Through systematic parameter optimization, DyMorph-B2I robustly separates adherent and heterogeneous structures present in binary masks. Experimental results demonstrate that our method outperforms individual classical approaches and na\"ive combinations, enabling superior instance separation and facilitating more accurate morphometric analysis in renal pathology workflows. The pipeline is publicly available at: https://github.com/ddrrnn123/DyMorph-B2I.

Img2ST-Net: Efficient High-Resolution Spatial Omics Prediction from Whole Slide Histology Images via Fully Convolutional Image-to-Image Learning

Recent advances in multi-modal AI have demonstrated promising potential for generating the currently expensive spatial transcriptomics (ST) data directly from routine histology images, offering a means to reduce the high cost and time-intensive nature of ST data acquisition. However, the increasing resolution of ST, particularly with platforms such as Visium HD achieving 8um or finer, introduces significant computational and modeling challenges. Conventional spot-by-spot sequential regression frameworks become inefficient and unstable at this scale, while the inherent extreme sparsity and low expression levels of high-resolution ST further complicate both prediction and evaluation. To address these limitations, we propose Img2ST-Net, a novel histology-to-ST generation framework for efficient and parallel high-resolution ST prediction. Unlike conventional spot-by-spot inference methods, Img2ST-Net employs a fully convolutional architecture to generate dense, HD gene expression maps in a parallelized manner. By modeling HD ST data as super-pixel representations, the task is reformulated from image-to-omics inference into a super-content image generation problem with hundreds or thousands of output channels. This design not only improves computational efficiency but also better preserves the spatial organization intrinsic to spatial omics data. To enhance robustness under sparse expression patterns, we further introduce SSIM-ST, a structural-similarity-based evaluation metric tailored for high-resolution ST analysis. We present a scalable, biologically coherent framework for high-resolution ST prediction. Img2ST-Net offers a principled solution for efficient and accurate ST inference at scale. Our contributions lay the groundwork for next-generation ST modeling that is robust and resolution-aware. The source code has been made publicly available at https://github.com/hrlblab/Img2ST-Net.

Quantitative Benchmarking of Anomaly Detection Methods in Digital Pathology

Anomaly detection has been widely studied in the context of industrial defect inspection, with numerous methods developed to tackle a range of challenges. In digital pathology, anomaly detection holds significant potential for applications such as rare disease identification, artifact detection, and biomarker discovery. However, the unique characteristics of pathology images, such as their large size, multi-scale structures, stain variability, and repetitive patterns, introduce new challenges that current anomaly detection algorithms struggle to address. In this quantitative study, we benchmark over 20 classical and prevalent anomaly detection methods through extensive experiments. We curated five digital pathology datasets, both real and synthetic, to systematically evaluate these approaches. Our experiments investigate the influence of image scale, anomaly pattern types, and training epoch selection strategies on detection performance. The results provide a detailed comparison of each method's strengths and limitations, establishing a comprehensive benchmark to guide future research in anomaly detection for digital pathology images.

IRS: Incremental Relationship-guided Segmentation for Digital Pathology

Continual learning is rapidly emerging as a key focus in computer vision, aiming to develop AI systems capable of continuous improvement, thereby enhancing their value and practicality in diverse real-world applications. In healthcare, continual learning holds great promise for continuously acquired digital pathology data, which is collected in hospitals on a daily basis. However, panoramic segmentation on digital whole slide images (WSIs) presents significant challenges, as it is often infeasible to obtain comprehensive annotations for all potential objects, spanning from coarse structures (e.g., regions and unit objects) to fine structures (e.g., cells). This results in temporally and partially annotated data, posing a major challenge in developing a holistic segmentation framework. Moreover, an ideal segmentation model should incorporate new phenotypes, unseen diseases, and diverse populations, making this task even more complex. In this paper, we introduce a novel and unified Incremental Relationship-guided Segmentation (IRS) learning scheme to address temporally acquired, partially annotated data while maintaining out-of-distribution (OOD) continual learning capacity in digital pathology. The key innovation of IRS lies in its ability to realize a new spatial-temporal OOD continual learning paradigm by mathematically modeling anatomical relationships between existing and newly introduced classes through a simple incremental universal proposition matrix. Experimental results demonstrate that the IRS method effectively handles the multi-scale nature of pathological segmentation, enabling precise kidney segmentation across various structures (regions, units, and cells) as well as OOD disease lesions at multiple magnifications. This capability significantly enhances domain generalization, making IRS a robust approach for real-world digital pathology applications.

MagNet: Multi-Level Attention Graph Network for Predicting High-Resolution Spatial Transcriptomics

The rapid development of spatial transcriptomics (ST) offers new opportunities to explore the gene expression patterns within the spatial microenvironment. Current research integrates pathological images to infer gene expression, addressing the high costs and time-consuming processes to generate spatial transcriptomics data. However, as spatial transcriptomics resolution continues to improve, existing methods remain primarily focused on gene expression prediction at low-resolution spot levels. These methods face significant challenges, especially the information bottleneck, when they are applied to high-resolution HD data. To bridge this gap, this paper introduces MagNet, a multi-level attention graph network designed for accurate prediction of high-resolution HD data. MagNet employs cross-attention layers to integrate features from multi-resolution image patches hierarchically and utilizes a GAT-Transformer module to aggregate neighborhood information. By integrating multilevel features, MagNet overcomes the limitations posed by low-resolution inputs in predicting high-resolution gene expression. We systematically evaluated MagNet and existing ST prediction models on both a private spatial transcriptomics dataset and a public dataset at three different resolution levels. The results demonstrate that MagNet achieves state-of-the-art performance at both spot level and high-resolution bin levels, providing a novel methodology and benchmark for future research and applications in high-resolution HD-level spatial transcriptomics. Code is available at https://github.com/Junchao-Zhu/MagNet.

CASC-AI: Consensus-aware Self-corrective AI Agents for Noise Cell Segmentation

Multi-class cell segmentation in high-resolution gigapixel whole slide images (WSI) is crucial for various clinical applications. However, training such models typically requires labor-intensive, pixel-wise annotations by domain experts. Recent efforts have democratized this process by involving lay annotators without medical expertise. However, conventional non-agent-based approaches struggle to handle annotation noise adaptively, as they lack mechanisms to mitigate false positives (FP) and false negatives (FN) at both the image-feature and pixel levels. In this paper, we propose a consensus-aware self-corrective AI agent that leverages the Consensus Matrix to guide its learning process. The Consensus Matrix defines regions where both the AI and annotators agree on cell and non-cell annotations, which are prioritized with stronger supervision. Conversely, areas of disagreement are adaptively weighted based on their feature similarity to high-confidence agreement regions, with more similar regions receiving greater attention. Additionally, contrastive learning is employed to separate features of noisy regions from those of reliable agreement regions by maximizing their dissimilarity. This paradigm enables the AI to iteratively refine noisy labels, enhancing its robustness. Validated on one real-world lay-annotated cell dataset and two simulated noisy datasets, our method demonstrates improved segmentation performance, effectively correcting FP and FN errors and showcasing its potential for training robust models on noisy datasets. The official implementation and cell annotations are publicly available at https://github.com/ddrrnn123/CASC-AI.

KPIs 2024 Challenge: Advancing Glomerular Segmentation from Patch- to Slide-Level

Chronic kidney disease (CKD) is a major global health issue, affecting over 10% of the population and causing significant mortality. While kidney biopsy remains the gold standard for CKD diagnosis and treatment, the lack of comprehensive benchmarks for kidney pathology segmentation hinders progress in the field. To address this, we organized the Kidney Pathology Image Segmentation (KPIs) Challenge, introducing a dataset that incorporates preclinical rodent models of CKD with over 10,000 annotated glomeruli from 60+ Periodic Acid Schiff (PAS)-stained whole slide images. The challenge includes two tasks, patch-level segmentation and whole slide image segmentation and detection, evaluated using the Dice Similarity Coefficient (DSC) and F1-score. By encouraging innovative segmentation methods that adapt to diverse CKD models and tissue conditions, the KPIs Challenge aims to advance kidney pathology analysis, establish new benchmarks, and enable precise, large-scale quantification for disease research and diagnosis.