Objective: Ulcerative colitis (UC), characterized by chronic inflammation with alternating remission-relapse cycles, requires precise histological healing (HH) evaluation to improve clinical outcomes. To overcome the limitations of annotation-intensive deep learning methods and suboptimal multi-instance learning (MIL) in HH prediction, we propose VIGIL, the first vision-language guided MIL framework integrating white light endoscopy (WLE) and endocytoscopy (EC). Methods:VIGIL begins with a dual-branch MIL module KS-MIL based on top-K typical frames selection and similarity metric adaptive learning to learn relationships among frame features effectively. By integrating the diagnostic report text and specially designed multi-level alignment and supervision between image-text pairs, VIGIL establishes joint image-text guidance during training to capture richer disease-related semantic information. Furthermore, VIGIL employs a multi-modal masked relation fusion (MMRF) strategy to uncover the latent diagnostic correlations of two endoscopic image representations. Results:Comprehensive experiments on a real-world clinical dataset demonstrate VIGIL's superior performance, achieving 92.69\% accuracy and 94.79\% AUC, outperforming existing state-of-the-art methods. Conclusion: The proposed VIGIL framework successfully establishes an effective vision-language guided MIL paradigm for UC HH prediction, reducing annotation burdens while improving prediction reliability. Significance: The research outcomes provide new insights for non-invasive UC diagnosis and hold theoretical significance and clinical value for advancing intelligent healthcare development.
Whole slide image (WSI) classification has emerged as a powerful tool in computational pathology, but remains constrained by domain shifts, e.g., due to different organs, diseases, or institution-specific variations. To address this challenge, we propose an Attention-based Generative Latent Replay Continual Learning framework (AGLR-CL), in a multiple instance learning (MIL) setup for domain incremental WSI classification. Our method employs Gaussian Mixture Models (GMMs) to synthesize WSI representations and patch count distributions, preserving knowledge of past domains without explicitly storing original data. A novel attention-based filtering step focuses on the most salient patch embeddings, ensuring high-quality synthetic samples. This privacy-aware strategy obviates the need for replay buffers and outperforms other buffer-free counterparts while matching the performance of buffer-based solutions. We validate AGLR-CL on clinically relevant biomarker detection and molecular status prediction across multiple public datasets with diverse centers, organs, and patient cohorts. Experimental results confirm its ability to retain prior knowledge and adapt to new domains, offering an effective, privacy-preserving avenue for domain incremental continual learning in WSI classification.
Multiple instance learning (MIL) is a promising approach for weakly supervised classification in pathology using whole slide images (WSIs). However, conventional MIL methods such as Attention-Based Deep Multiple Instance Learning (ABMIL) typically disregard spatial interactions among patches that are crucial to pathological diagnosis. Recent advancements, such as Transformer based MIL (TransMIL), have incorporated spatial context and inter-patch relationships. However, it remains unclear whether explicitly modeling patch relationships yields similar performance gains in ABMIL, which relies solely on Multi-Layer Perceptrons (MLPs). In contrast, TransMIL employs Transformer-based layers, introducing a fundamental architectural shift at the cost of substantially increased computational complexity. In this work, we enhance the ABMIL framework by integrating interaction-aware representations to address this question. Our proposed model, Global ABMIL (GABMIL), explicitly captures inter-instance dependencies while preserving computational efficiency. Experimental results on two publicly available datasets for tumor subtyping in breast and lung cancers demonstrate that GABMIL achieves up to a 7 percentage point improvement in AUPRC and a 5 percentage point increase in the Kappa score over ABMIL, with minimal or no additional computational overhead. These findings underscore the importance of incorporating patch interactions within MIL frameworks. Our code is available at \href{https://github.com/tueimage/GABMIL}{\texttt{GABMIL}}.
Multiple Instance Learning (MIL) has emerged as the best solution for Whole Slide Image (WSI) classification. It consists of dividing each slide into patches, which are treated as a bag of instances labeled with a global label. MIL includes two main approaches: instance-based and embedding-based. In the former, each patch is classified independently, and then the patch scores are aggregated to predict the bag label. In the latter, bag classification is performed after aggregating patch embeddings. Even if instance-based methods are naturally more interpretable, embedding-based MILs have usually been preferred in the past due to their robustness to poor feature extractors. However, recently, the quality of feature embeddings has drastically increased using self-supervised learning (SSL). Nevertheless, many authors continue to endorse the superiority of embedding-based MIL. To investigate this further, we conduct 710 experiments across 4 datasets, comparing 10 MIL strategies, 6 self-supervised methods with 4 backbones, 4 foundation models, and various pathology-adapted techniques. Furthermore, we introduce 4 instance-based MIL methods never used before in the pathology domain. Through these extensive experiments, we show that with a good SSL feature extractor, simple instance-based MILs, with very few parameters, obtain similar or better performance than complex, state-of-the-art (SOTA) embedding-based MIL methods, setting new SOTA results on the BRACS and Camelyon16 datasets. Since simple instance-based MIL methods are naturally more interpretable and explainable to clinicians, our results suggest that more effort should be put into well-adapted SSL methods for WSI rather than into complex embedding-based MIL methods.
Weakly-supervised video anomaly detection (WS-VAD) using Multiple Instance Learning (MIL) suffers from label ambiguity, hindering discriminative feature learning. We propose ProDisc-VAD, an efficient framework tackling this via two synergistic components. The Prototype Interaction Layer (PIL) provides controlled normality modeling using a small set of learnable prototypes, establishing a robust baseline without being overwhelmed by dominant normal data. The Pseudo-Instance Discriminative Enhancement (PIDE) loss boosts separability by applying targeted contrastive learning exclusively to the most reliable extreme-scoring instances (highest/lowest scores). ProDisc-VAD achieves strong AUCs (97.98% ShanghaiTech, 87.12% UCF-Crime) using only 0.4M parameters, over 800x fewer than recent ViT-based methods like VadCLIP, demonstrating exceptional efficiency alongside state-of-the-art performance. Code is available at https://github.com/modadundun/ProDisc-VAD.
Multiple Instance Learning (MIL) is a popular weakly-supervised method for various applications, with a particular interest in histological whole slide image (WSI) classification. Due to the gigapixel resolution of WSI, applications of MIL in WSI typically necessitate a two-stage training scheme: first, extract features from the pre-trained backbone and then perform MIL aggregation. However, it is well-known that this suboptimal training scheme suffers from "noisy" feature embeddings from the backbone and inherent weak supervision, hindering MIL from learning rich and generalizable features. However, the most commonly used technique (i.e., dropout) for mitigating this issue has yet to be explored in MIL. In this paper, we empirically explore how effective the dropout can be in MIL. Interestingly, we observe that dropping the top-k most important instances within a bag leads to better performance and generalization even under noise attack. Based on this key observation, we propose a novel MIL-specific dropout method, termed MIL-Dropout, which systematically determines which instances to drop. Experiments on five MIL benchmark datasets and two WSI datasets demonstrate that MIL-Dropout boosts the performance of current MIL methods with a negligible computational cost. The code is available at https://github.com/ChongQingNoSubway/MILDropout.
Computer-aided Whole Slide Image (WSI) classification has the potential to enhance the accuracy and efficiency of clinical pathological diagnosis. It is commonly formulated as a Multiple Instance Learning (MIL) problem, where each WSI is treated as a bag and the small patches extracted from the WSI are considered instances within that bag. However, obtaining labels for a large number of bags is a costly and time-consuming process, particularly when utilizing existing WSIs for new classification tasks. This limitation renders most existing WSI classification methods ineffective. To address this issue, we propose a novel WSI classification problem setting, more aligned with clinical practice, termed Weakly Semi-supervised Whole slide image Classification (WSWC). In WSWC, a small number of bags are labeled, while a significant number of bags remain unlabeled. The MIL nature of the WSWC problem, coupled with the absence of patch labels, distinguishes it from typical semi-supervised image classification problems, making existing algorithms for natural images unsuitable for directly solving the WSWC problem. In this paper, we present a concise and efficient framework, named CroCo, to tackle the WSWC problem through two-level Cross Consistency supervision. CroCo comprises two heterogeneous classifier branches capable of performing both instance classification and bag classification. The fundamental idea is to establish cross-consistency supervision at both the bag-level and instance-level between the two branches during training. Extensive experiments conducted on four datasets demonstrate that CroCo achieves superior bag classification and instance classification performance compared to other comparative methods when limited WSIs with bag labels are available. To the best of our knowledge, this paper presents for the first time the WSWC problem and gives a successful resolution.
Cytology is essential for cancer diagnostics and screening due to its minimally invasive nature. However, the development of robust deep learning models for digital cytology is challenging due to the heterogeneity in staining and preparation methods of samples, differences across organs, and the limited availability of large, diverse, annotated datasets. Developing a task-specific model for every cytology application is impractical and non-cytology-specific foundation models struggle to generalize to tasks in this domain where the emphasis is on cell morphology. To address these challenges, we introduce CytoFM, the first cytology self-supervised foundation model. Using iBOT, a self-supervised Vision Transformer (ViT) training framework incorporating masked image modeling and self-distillation, we pretrain CytoFM on a diverse collection of cytology datasets to learn robust, transferable representations. We evaluate CytoFM on multiple downstream cytology tasks, including breast cancer classification and cell type identification, using an attention-based multiple instance learning framework. Our results demonstrate that CytoFM performs better on two out of three downstream tasks than existing foundation models pretrained on histopathology (UNI) or natural images (iBOT-Imagenet). Visualizations of learned representations demonstrate our model is able to attend to cytologically relevant features. Despite a small pre-training dataset, CytoFM's promising results highlight the ability of task-agnostic pre-training approaches to learn robust and generalizable features from cytology data.
Inflammatory bowel disease (IBD) involves chronic inflammation of the digestive tract, with treatment options often burdened by adverse effects. Identifying biomarkers for personalized treatment is crucial. While immune cells play a key role in IBD, accurately identifying ulcer regions in whole slide images (WSIs) is essential for characterizing these cells and exploring potential therapeutics. Multiple instance learning (MIL) approaches have advanced WSI analysis but they lack spatial context awareness. In this work, we propose a weakly-supervised model called DomainGCN that employs a graph convolution neural network (GCN) and incorporates domain-specific knowledge of ulcer features, specifically, the presence of epithelium, lymphocytes, and debris for WSI-level ulcer prediction in IBD. We demonstrate that DomainGCN outperforms various state-of-the-art (SOTA) MIL methods and show the added value of domain knowledge.
Computational pathology, which involves analyzing whole slide images for automated cancer diagnosis, relies on multiple instance learning, where performance depends heavily on the feature extractor and aggregator. Recent Pathology Foundation Models (PFMs), pretrained on large-scale histopathology data, have significantly enhanced both the extractor and aggregator, but they lack a systematic analysis framework. In this survey, we present a hierarchical taxonomy organizing PFMs through a top-down philosophy applicable to foundation model analysis in any domain: model scope, model pretraining, and model design. Additionally, we systematically categorize PFM evaluation tasks into slide-level, patch-level, multimodal, and biological tasks, providing comprehensive benchmarking criteria. Our analysis identifies critical challenges in both PFM development (pathology-specific methodology, end-to-end pretraining, data-model scalability) and utilization (effective adaptation, model maintenance), paving the way for future directions in this promising field. Resources referenced in this survey are available at https://github.com/BearCleverProud/AwesomeWSI.
Object recognition using single-point supervision has attracted increasing attention recently. However, the performance gap compared with fully-supervised algorithms remains large. Previous works generated class-agnostic \textbf{\textit{proposals in an image}} offline and then treated mixed candidates as a single bag, putting a huge burden on multiple instance learning (MIL). In this paper, we introduce Point-to-Box Network (P2BNet), which constructs balanced \textbf{\textit{instance-level proposal bags}} by generating proposals in an anchor-like way and refining the proposals in a coarse-to-fine paradigm. Through further research, we find that the bag of proposals, either at the image level or the instance level, is established on discrete box sampling. This leads the pseudo box estimation into a sub-optimal solution, resulting in the truncation of object boundaries or the excessive inclusion of background. Hence, we conduct a series exploration of discrete-to-continuous optimization, yielding P2BNet++ and Point-to-Mask Network (P2MNet). P2BNet++ conducts an approximately continuous proposal sampling strategy by better utilizing spatial clues. P2MNet further introduces low-level image information to assist in pixel prediction, and a boundary self-prediction is designed to relieve the limitation of the estimated boxes. Benefiting from the continuous object-aware \textbf{\textit{pixel-level perception}}, P2MNet can generate more precise bounding boxes and generalize to segmentation tasks. Our method largely surpasses the previous methods in terms of the mean average precision on COCO, VOC, SBD, and Cityscapes, demonstrating great potential to bridge the performance gap compared with fully supervised tasks.
Oncologists often rely on a multitude of data, including whole-slide images (WSIs), to guide therapeutic decisions, aiming for the best patient outcome. However, predicting the prognosis of cancer patients can be a challenging task due to tumor heterogeneity and intra-patient variability, and the complexity of analyzing WSIs. These images are extremely large, containing billions of pixels, making direct processing computationally expensive and requiring specialized methods to extract relevant information. Additionally, multiple WSIs from the same patient may capture different tumor regions, some being more informative than others. This raises a fundamental question: Should we use all WSIs to characterize the patient, or should we identify the most representative slide for prognosis? Our work seeks to answer this question by performing a comparison of various strategies for predicting survival at the WSI and patient level. The former treats each WSI as an independent sample, mimicking the strategy adopted in other works, while the latter comprises methods to either aggregate the predictions of the several WSIs or automatically identify the most relevant slide using multiple-instance learning (MIL). Additionally, we evaluate different Graph Neural Networks architectures under these strategies. We conduct our experiments using the MMIST-ccRCC dataset, which comprises patients with clear cell renal cell carcinoma (ccRCC). Our results show that MIL-based selection improves accuracy, suggesting that choosing the most representative slide benefits survival prediction.
With the rapid advancement of pathology foundation models (FMs), the representation learning of whole slide images (WSIs) attracts increasing attention. Existing studies develop high-quality patch feature extractors and employ carefully designed aggregation schemes to derive slide-level representations. However, mainstream weakly supervised slide representation learning methods, primarily based on multiple instance learning (MIL), are tailored to specific downstream tasks, which limits their generalizability. To address this issue, some studies explore unsupervised slide representation learning. However, these approaches focus solely on the visual modality of patches, neglecting the rich semantic information embedded in textual data. In this work, we propose ProAlign, a cross-modal unsupervised slide representation learning framework. Specifically, we leverage a large language model (LLM) to generate descriptive text for the prototype types present in a WSI, introducing patch-text contrast to construct initial prototype embeddings. Furthermore, we propose a parameter-free attention aggregation strategy that utilizes the similarity between patches and these prototypes to form unsupervised slide embeddings applicable to a wide range of downstream tasks. Extensive experiments on four public datasets show that ProAlign outperforms existing unsupervised frameworks and achieves performance comparable to some weakly supervised models.
In this paper, we address the challenge of few-shot classification in histopathology whole slide images (WSIs) by utilizing foundational vision-language models (VLMs) and slide-level prompt learning. Given the gigapixel scale of WSIs, conventional multiple instance learning (MIL) methods rely on aggregation functions to derive slide-level (bag-level) predictions from patch representations, which require extensive bag-level labels for training. In contrast, VLM-based approaches excel at aligning visual embeddings of patches with candidate class text prompts but lack essential pathological prior knowledge. Our method distinguishes itself by utilizing pathological prior knowledge from language models to identify crucial local tissue types (patches) for WSI classification, integrating this within a VLM-based MIL framework. Our approach effectively aligns patch images with tissue types, and we fine-tune our model via prompt learning using only a few labeled WSIs per category. Experimentation on real-world pathological WSI datasets and ablation studies highlight our method's superior performance over existing MIL- and VLM-based methods in few-shot WSI classification tasks. Our code is publicly available at https://github.com/LTS5/SLIP.
Whole Slide Images (WSIs) are high-resolution digital scans widely used in medical diagnostics. WSI classification is typically approached using Multiple Instance Learning (MIL), where the slide is partitioned into tiles treated as interconnected instances. While attention-based MIL methods aim to identify the most informative tiles, they often fail to fully exploit the spatial relationships among them, potentially overlooking intricate tissue structures crucial for accurate diagnosis. To address this limitation, we propose Probabilistic Spatial Attention MIL (PSA-MIL), a novel attention-based MIL framework that integrates spatial context into the attention mechanism through learnable distance-decayed priors, formulated within a probabilistic interpretation of self-attention as a posterior distribution. This formulation enables a dynamic inference of spatial relationships during training, eliminating the need for predefined assumptions often imposed by previous approaches. Additionally, we suggest a spatial pruning strategy for the posterior, effectively reducing self-attention's quadratic complexity. To further enhance spatial modeling, we introduce a diversity loss that encourages variation among attention heads, ensuring each captures distinct spatial representations. Together, PSA-MIL enables a more data-driven and adaptive integration of spatial context, moving beyond predefined constraints. We achieve state-of-the-art performance across both contextual and non-contextual baselines, while significantly reducing computational costs.
Sepsis is a life-threatening condition which requires rapid diagnosis and treatment. Traditional microbiological methods are time-consuming and expensive. In response to these challenges, deep learning algorithms were developed to identify 14 bacteria species and 3 yeast-like fungi from microscopic images of Gram-stained smears of positive blood samples from sepsis patients. A total of 16,637 Gram-stained microscopic images were used in the study. The analysis used the Cellpose 3 model for segmentation and Attention-based Deep Multiple Instance Learning for classification. Our model achieved an accuracy of 77.15% for bacteria and 71.39% for fungi, with ROC AUC of 0.97 and 0.88, respectively. The highest values, reaching up to 96.2%, were obtained for Cutibacterium acnes, Enterococcus faecium, Stenotrophomonas maltophilia and Nakaseomyces glabratus. Classification difficulties were observed in closely related species, such as Staphylococcus hominis and Staphylococcus haemolyticus, due to morphological similarity, and within Candida albicans due to high morphotic diversity. The study confirms the potential of our model for microbial classification, but it also indicates the need for further optimisation and expansion of the training data set. In the future, this technology could support microbial diagnosis, reducing diagnostic time and improving the effectiveness of sepsis treatment due to its simplicity and accessibility. Part of the results presented in this publication was covered by a patent application at the European Patent Office EP24461637.1 "A computer implemented method for identifying a microorganism in a blood and a data processing system therefor".
Spread through air spaces (STAS) represents a newly identified aggressive pattern in lung cancer, which is known to be associated with adverse prognostic factors and complex pathological features. Pathologists currently rely on time consuming manual assessments, which are highly subjective and prone to variation. This highlights the urgent need for automated and precise diag nostic solutions. 2,970 lung cancer tissue slides are comprised from multiple centers, re-diagnosed them, and constructed and publicly released three lung cancer STAS datasets: STAS CSU (hospital), STAS TCGA, and STAS CPTAC. All STAS datasets provide corresponding pathological feature diagnoses and related clinical data. To address the bias, sparse and heterogeneous nature of STAS, we propose an scale-aware multiple instance learning(SMILE) method for STAS diagnosis of lung cancer. By introducing a scale-adaptive attention mechanism, the SMILE can adaptively adjust high attention instances, reducing over-reliance on local regions and promoting consistent detection of STAS lesions. Extensive experiments show that SMILE achieved competitive diagnostic results on STAS CSU, diagnosing 251 and 319 STAS samples in CPTAC andTCGA,respectively, surpassing clinical average AUC. The 11 open baseline results are the first to be established for STAS research, laying the foundation for the future expansion, interpretability, and clinical integration of computational pathology technologies. The datasets and code are available at https://anonymous.4open.science/r/IJCAI25-1DA1.
The growing volume of high-resolution Whole Slide Images in digital histopathology poses significant storage, transmission, and computational efficiency challenges. Standard compression methods, such as JPEG, reduce file sizes but often fail to preserve fine-grained phenotypic details critical for downstream tasks. In this work, we repurpose autoencoders (AEs) designed for Latent Diffusion Models as an efficient learned compression framework for pathology images. We systematically benchmark three AE models with varying compression levels and evaluate their reconstruction ability using pathology foundation models. We introduce a fine-tuning strategy to further enhance reconstruction fidelity that optimizes a pathology-specific learned perceptual metric. We validate our approach on downstream tasks, including segmentation, patch classification, and multiple instance learning, showing that replacing images with AE-compressed reconstructions leads to minimal performance degradation. Additionally, we propose a K-means clustering-based quantization method for AE latents, improving storage efficiency while maintaining reconstruction quality. We provide the weights of the fine-tuned autoencoders at https://huggingface.co/collections/StonyBrook-CVLab/pathology-fine-tuned-aes-67d45f223a659ff2e3402dd0.
Whole-slide image classification represents a key challenge in computational pathology and medicine. Attention-based multiple instance learning (MIL) has emerged as an effective approach for this problem. However, the effect of attention mechanism architecture on model performance is not well-documented for biomedical imagery. In this work, we compare different methods and implementations of MIL, including deep learning variants. We introduce a new method using higher-dimensional feature spaces for deep MIL. We also develop a novel algorithm for whole-slide image classification where extreme machine learning is combined with attention-based MIL to improve sensitivity and reduce training complexity. We apply our algorithms to the problem of detecting circulating rare cells (CRCs), such as erythroblasts, in peripheral blood. Our results indicate that nonlinearities play a key role in the classification, as removing them leads to a sharp decrease in stability in addition to a decrease in average area under the curve (AUC) of over 4%. We also demonstrate a considerable increase in robustness of the model with improvements of over 10% in average AUC when higher-dimensional feature spaces are leveraged. In addition, we show that extreme learning machines can offer clear improvements in terms of training efficiency by reducing the number of trained parameters by a factor of 5 whilst still maintaining the average AUC to within 1.5% of the deep MIL model. Finally, we discuss options of enriching the classical computing framework with quantum algorithms in the future. This work can thus help pave the way towards more accurate and efficient single-cell diagnostics, one of the building blocks of precision medicine.
Bag-based Multiple Instance Learning (MIL) approaches have emerged as the mainstream methodology for Whole Slide Image (WSI) classification. However, most existing methods adopt a segmented training strategy, which first extracts features using a pre-trained feature extractor and then aggregates these features through MIL. This segmented training approach leads to insufficient collaborative optimization between the feature extraction network and the MIL network, preventing end-to-end joint optimization and thereby limiting the overall performance of the model. Additionally, conventional methods typically extract features from all patches of fixed size, ignoring the multi-scale observation characteristics of pathologists. This not only results in significant computational resource waste when tumor regions represent a minimal proportion (as in the Camelyon16 dataset) but may also lead the model to suboptimal solutions. To address these limitations, this paper proposes an end-to-end multi-scale WSI classification framework that integrates multi-scale feature extraction with multiple instance learning. Specifically, our approach includes: (1) a semantic feature filtering module to reduce interference from non-lesion areas; (2) a multi-scale feature extraction module to capture pathological information at different levels; and (3) a multi-scale fusion MIL module for global modeling and feature integration. Through an end-to-end training strategy, we simultaneously optimize both the feature extractor and MIL network, ensuring maximum compatibility between them. Experiments were conducted on three cross-center datasets (DigestPath2019, BCNB, and UBC-OCEAN). Results demonstrate that our proposed method outperforms existing state-of-the-art approaches in terms of both accuracy (ACC) and AUC metrics.