Yonghong He

Mingqing Wang, Zhiwei Nie, Athanasios V. Vasilakos et al.

Proteins encode diverse functions within complex three-dimensional structures, yet most deep learning representations remain highly entangled, obscuring the biophysical signals that underlie function. Here we introduce ProtDiS, a knowledge-guided framework that decomposes pretrained protein micro-environment embeddings into biologically grounded and task-relevant dimensions. Inspired by the information bottleneck principle, ProtDiS learns representations that balance informativeness and compression, yielding structural features that are more specific, independent, and information-efficient, and achieving consistent improvements across twelve downstream tasks, with the largest gains under structure-based splits. Protein- and residue-level analyses further show that ProtDiS differentiates proteins with similar folds but divergent functions and captures fine-grained biophysical signals critical. These findings suggest that knowledge-guided decomposition provides a general and interpretable approach for structuring latent spaces in protein structural modeling. The source code and implementation details are publicly available at https://github.com/AI-HPC-Research-Team/ProtDiS.

Xitong Ling, Minxi Ouyang, Yizhi Wang et al. · tsinghua

Histopathology analysis is the gold standard for medical diagnosis. Accurate classification of whole slide images (WSIs) and region-of-interests (ROIs) localization can assist pathologists in diagnosis. The gigapixel resolution of WSI and the absence of fine-grained annotations make direct classification and analysis challenging. In weakly supervised learning, multiple instance learning (MIL) presents a promising approach for WSI classification. The prevailing strategy is to use attention mechanisms to measure instance importance for classification. However, attention mechanisms fail to capture inter-instance information, and self-attention causes quadratic computational complexity. To address these challenges, we propose AMD-MIL, an agent aggregator with a mask denoise mechanism. The agent token acts as an intermediate variable between the query and key for computing instance importance. Mask and denoising matrices, mapped from agents-aggregated value, dynamically mask low-contribution representations and eliminate noise. AMD-MIL achieves better attention allocation by adjusting feature representations, capturing micro-metastases in cancer, and improving interpretability. Extensive experiments on CAMELYON-16, CAMELYON-17, TCGA-KIDNEY, and TCGA-LUNG show AMD-MIL's superiority over state-of-the-art methods.

Jiawen Li, Yuxuan Chen, Hongbo Chu et al.

Histopathological whole slide images (WSIs) classification has become a foundation task in medical microscopic imaging processing. Prevailing approaches involve learning WSIs as instance-bag representations, emphasizing significant instances but struggling to capture the interactions between instances. Additionally, conventional graph representation methods utilize explicit spatial positions to construct topological structures but restrict the flexible interaction capabilities between instances at arbitrary locations, particularly when spatially distant. In response, we propose a novel dynamic graph representation algorithm that conceptualizes WSIs as a form of the knowledge graph structure. Specifically, we dynamically construct neighbors and directed edge embeddings based on the head and tail relationships between instances. Then, we devise a knowledge-aware attention mechanism that can update the head node features by learning the joint attention score of each neighbor and edge. Finally, we obtain a graph-level embedding through the global pooling process of the updated head, serving as an implicit representation for the WSI classification. Our end-to-end graph representation learning approach has outperformed the state-of-the-art WSI analysis methods on three TCGA benchmark datasets and in-house test sets. Our code is available at https://github.com/WonderLandxD/WiKG.

Renao Yan, Qiehe Sun, Cheng Jin et al. · tsinghua

In computational pathology, whole-slide image (WSI) classification presents a formidable challenge due to its gigapixel resolution and limited fine-grained annotations. Multiple-instance learning (MIL) offers a weakly supervised solution, yet refining instance-level information from bag-level labels remains challenging. While most of the conventional MIL methods use attention scores to estimate instance importance scores (IIS) which contribute to the prediction of the slide labels, these often lead to skewed attention distributions and inaccuracies in identifying crucial instances. To address these issues, we propose a new approach inspired by cooperative game theory: employing Shapley values to assess each instance's contribution, thereby improving IIS estimation. The computation of the Shapley value is then accelerated using attention, meanwhile retaining the enhanced instance identification and prioritization. We further introduce a framework for the progressive assignment of pseudo bags based on estimated IIS, encouraging more balanced attention distributions in MIL models. Our extensive experiments on CAMELYON-16, BRACS, TCGA-LUNG, and TCGA-BRCA datasets show our method's superiority over existing state-of-the-art approaches, offering enhanced interpretability and class-wise insights. Our source code is available at https://github.com/RenaoYan/PMIL.

Qiehe Sun, Jiawen Li, Jin Xu et al.

Due to its superior efficiency in utilizing annotations and addressing gigapixel-sized images, multiple instance learning (MIL) has shown great promise as a framework for whole slide image (WSI) classification in digital pathology diagnosis. However, existing methods tend to focus on advanced aggregators with different structures, often overlooking the intrinsic features of H\&E pathological slides. To address this limitation, we introduced two pathological priors: nuclear heterogeneity of diseased cells and spatial correlation of pathological tiles. Leveraging the former, we proposed a data augmentation method that utilizes stain separation during extractor training via a contrastive learning strategy to obtain instance-level representations. We then described the spatial relationships between the tiles using an adjacency matrix. By integrating these two views, we designed a multi-instance framework for analyzing H\&E-stained tissue images based on pathological inductive bias, encompassing feature extraction, filtering, and aggregation. Extensive experiments on the Camelyon16 breast dataset and TCGA-NSCLC Lung dataset demonstrate that our proposed framework can effectively handle tasks related to cancer detection and differentiation of subtypes, outperforming state-of-the-art medical image classification methods based on MIL. The code will be released later.

Xitong Ling, Yuanyuan Lei, Jiawen Li et al.

Advances in optical microscopy scanning have significantly contributed to computational pathology (CPath) by converting traditional histopathological slides into whole slide images (WSIs). This development enables comprehensive digital reviews by pathologists and accelerates AI-driven diagnostic support for WSI analysis. Recent advances in foundational pathology models have increased the need for benchmarking tasks. The Camelyon series is one of the most widely used open-source datasets in computational pathology. However, the quality, accessibility, and clinical relevance of the labels have not been comprehensively evaluated. In this study, we reprocessed 1,399 WSIs and labels from the Camelyon-16 and Camelyon-17 datasets, removing low-quality slides, correcting erroneous labels, and providing expert pixel annotations for tumor regions in the previously unreleased test set. Based on the sizes of re-annotated tumor regions, we upgraded the binary cancer screening task to a four-class task: negative, micro-metastasis, macro-metastasis, and Isolated Tumor Cells (ITC). We reevaluated pre-trained pathology feature extractors and multiple instance learning (MIL) methods using the cleaned dataset, providing a benchmark that advances AI development in histopathology.

Xinrui Chen, Haoli Bai, Tao Yuan et al.

Layer pruning has emerged as a widely used technique for compressing large language models (LLMs). However, existing layer pruning approaches often incur substantial performance degradation. We identify the majority of this degradation to a single yet previously overlooked issue: \textit{the mismatch of activation magnitudes at the pruning interface}. The pre-interface activations exhibit significantly different scales from the post-interface ones, causing the distributional shift as it propagates through the remaining layers. To address this issue, we introduce \textsc{LinearPatch}, a lightweight and plug-and-play technique that fuses two operations into one matrix multiply at the pruning interface: (i) a Hadamard transformation that suppresses massive outliers at particular tokens and (ii) a channel-wise scaling that aligns activation statistics. On LLaMA-3-8B, \textsc{LinearPatch} preserves up to \textbf{94.15\%} of the original model's performance when pruning 5 out of 32 layers, outperforming the previous state of the art by \textbf{4\%}. The patch can be further refined with 5K unlabeled samples via memory-efficient offline distillation, pushing the retention to 95.16\% within only 30 minutes on a single GPU. Code is available at https://github.com/chenxinrui-tsinghua/LinearPatch.

Qilai Zhang, Jiawen Li, Peiran Liao et al.

The two primary types of Hematoxylin and Eosin (H&E) slides in histopathology are Formalin-Fixed Paraffin-Embedded (FFPE) and Fresh Frozen (FF). FFPE slides offer high quality histopathological images but require a labor-intensive acquisition process. In contrast, FF slides can be prepared quickly, but the image quality is relatively poor. Our task is to translate FF images into FFPE style, thereby improving the image quality for diagnostic purposes. In this paper, we propose Diffusion-FFPE, a method for FF-to-FFPE histopathological image translation using a pre-trained diffusion model. Specifically, we utilize a one-step diffusion model as the generator, which we fine-tune using LoRA adapters within an adversarial learning framework. To enable the model to effectively capture both global structural patterns and local details, we introduce a multi-scale feature fusion module that leverages two VAE encoders to extract features at different image resolutions, performing feature fusion before inputting them into the UNet. Additionally, a pre-trained vision-language model for histopathology serves as the backbone for the discriminator, enhancing model performance. Our FF-to-FFPE translation experiments on the TCGA-NSCLC dataset demonstrate that the proposed approach outperforms existing methods. The code and models are released at https://github.com/QilaiZhang/Diffusion-FFPE.

Chun-Mei Feng, Yuanyang He, Jian Zou et al.

Existing test-time prompt tuning (TPT) methods focus on single-modality data, primarily enhancing images and using confidence ratings to filter out inaccurate images. However, while image generation models can produce visually diverse images, single-modality data enhancement techniques still fail to capture the comprehensive knowledge provided by different modalities. Additionally, we note that the performance of TPT-based methods drops significantly when the number of augmented images is limited, which is not unusual given the computational expense of generative augmentation. To address these issues, we introduce IT3A, a novel test-time adaptation method that utilizes a pre-trained generative model for multi-modal augmentation of each test sample from unknown new domains. By combining augmented data from pre-trained vision and language models, we enhance the ability of the model to adapt to unknown new test data. Additionally, to ensure that key semantics are accurately retained when generating various visual and text enhancements, we employ cosine similarity filtering between the logits of the enhanced images and text with the original test data. This process allows us to filter out some spurious augmentation and inadequate combinations. To leverage the diverse enhancements provided by the generation model across different modals, we have replaced prompt tuning with an adapter for greater flexibility in utilizing text templates. Our experiments on the test datasets with distribution shifts and domain gaps show that in a zero-shot setting, IT3A outperforms state-of-the-art test-time prompt tuning methods with a 5.50% increase in accuracy.

Yuxuan Chen, Jiawen Li, Huijuan Shi et al.

Bone metastasis analysis is a significant challenge in pathology and plays a critical role in determining patient quality of life and treatment strategies. The microenvironment and specific tissue structures are essential for pathologists to predict the primary bone cancer origins and primary bone cancer subtyping. By digitizing bone tissue sections into whole slide images (WSIs) and leveraging deep learning to model slide embeddings, this analysis can be enhanced. However, tumor metastasis involves complex multivariate interactions with diverse bone tissue structures, which traditional WSI analysis methods such as multiple instance learning (MIL) fail to capture. Moreover, graph neural networks (GNNs), limited to modeling pairwise relationships, are hard to represent high-order biological associations. To address these challenges, we propose a dynamic hypergraph neural network (DyHG) that overcomes the edge construction limitations of traditional graph representations by connecting multiple nodes via hyperedges. A low-rank strategy is used to reduce the complexity of parameters in learning hypergraph structures, while a Gumbel-Softmax-based sampling strategy optimizes the patch distribution across hyperedges. An MIL aggregator is then used to derive a graph-level embedding for comprehensive WSI analysis. To evaluate the effectiveness of DyHG, we construct two large-scale datasets for primary bone cancer origins and subtyping classification based on real-world bone metastasis scenarios. Extensive experiments demonstrate that DyHG significantly outperforms state-of-the-art (SOTA) baselines, showcasing its ability to model complex biological interactions and improve the accuracy of bone metastasis analysis.