Pretraining on large-scale, in-domain datasets grants histopathology foundation models (FM) the ability to learn task-agnostic data representations, enhancing transfer learning on downstream tasks. In computational pathology, automated whole slide image analysis requires multiple instance learning (MIL) frameworks due to the gigapixel scale of the slides. The diversity among histopathology FMs has highlighted the need to design real-world challenges for evaluating their effectiveness. To bridge this gap, our work presents a novel benchmark for evaluating histopathology FMs as patch-level feature extractors within a MIL classification framework. For that purpose, we leverage the AI4SkIN dataset, a multi-center cohort encompassing slides with challenging cutaneous spindle cell neoplasm subtypes. We also define the Foundation Model - Silhouette Index (FM-SI), a novel metric to measure model consistency against distribution shifts. Our experimentation shows that extracting less biased features enhances classification performance, especially in similarity-based MIL classifiers.
We often attribute human characteristics to large language models (LLMs) and claim that they "know" certain things. LLMs have an internal probabilistic knowledge that represents information retained during training. How can we assess the veracity of this knowledge? We examine two common methods for probing the veracity of LLMs and discover several assumptions that are flawed. To address these flawed assumptions, we introduce sAwMIL (short for Sparse Aware Multiple-Instance Learning), a probing method that utilizes the internal activations of LLMs to separate statements into true, false, and neither. sAwMIL is based on multiple-instance learning and conformal prediction. We evaluate sAwMIL on 5 validity criteria across 16 open-source LLMs, including both default and chat-based variants, as well as on 3 new datasets. Among the insights we provide are: (1) the veracity signal is often concentrated in the third quarter of an LLM's depth; (2) truth and falsehood signals are not always symmetric; (3) linear probes perform better on chat models than on default models; (4) nonlinear probes may be required to capture veracity signals for some LLMs with reinforcement learning from human feedback or knowledge distillation; and (5) LLMs capture a third type of signal that is distinct from true and false and is neither true nor false. These findings provide a reliable method for verifying what LLMs "know" and how certain they are of their probabilistic internal knowledge.
Multiple instance learning (MIL) has shown significant promise in histopathology whole slide image (WSI) analysis for cancer diagnosis and prognosis. However, the inherent spatial heterogeneity of WSIs presents critical challenges, as morphologically similar tissue types are often dispersed across distant anatomical regions. Conventional MIL methods struggle to model these scattered tissue distributions and capture cross-regional spatial interactions effectively. To address these limitations, we propose a novel Multiple instance learning framework with Context-Aware Clustering (MiCo), designed to enhance cross-regional intra-tissue correlations and strengthen inter-tissue semantic associations in WSIs. MiCo begins by clustering instances to distill discriminative morphological patterns, with cluster centroids serving as semantic anchors. To enhance cross-regional intra-tissue correlations, MiCo employs a Cluster Route module, which dynamically links instances of the same tissue type across distant regions via feature similarity. These semantic anchors act as contextual hubs, propagating semantic relationships to refine instance-level representations. To eliminate semantic fragmentation and strengthen inter-tissue semantic associations, MiCo integrates a Cluster Reducer module, which consolidates redundant anchors while enhancing information exchange between distinct semantic groups. Extensive experiments on two challenging tasks across nine large-scale public cancer datasets demonstrate the effectiveness of MiCo, showcasing its superiority over state-of-the-art methods. The code is available at https://github.com/junjianli106/MiCo.
Pathology is essential for cancer diagnosis, with multiple instance learning (MIL) widely used for whole slide image (WSI) analysis. WSIs exhibit a natural hierarchy -- patches, regions, and slides -- with distinct semantic associations. While some methods attempt to leverage this hierarchy for improved representation, they predominantly rely on Euclidean embeddings, which struggle to fully capture semantic hierarchies. To address this limitation, we propose HyperPath, a novel method that integrates knowledge from textual descriptions to guide the modeling of semantic hierarchies of WSIs in hyperbolic space, thereby enhancing WSI classification. Our approach adapts both visual and textual features extracted by pathology vision-language foundation models to the hyperbolic space. We design an Angular Modality Alignment Loss to ensure robust cross-modal alignment, while a Semantic Hierarchy Consistency Loss further refines feature hierarchies through entailment and contradiction relationships and thus enhance semantic coherence. The classification is performed with geodesic distance, which measures the similarity between entities in the hyperbolic semantic hierarchy. This eliminates the need for linear classifiers and enables a geometry-aware approach to WSI analysis. Extensive experiments show that our method achieves superior performance across tasks compared to existing methods, highlighting the potential of hyperbolic embeddings for WSI analysis.
Survival prediction using whole slide images (WSIs) can be formulated as a multiple instance learning (MIL) problem. However, existing MIL methods often fail to explicitly capture pathological heterogeneity within WSIs, both globally -- through long-tailed morphological distributions, and locally through -- tile-level prediction uncertainty. Optimal transport (OT) provides a principled way of modeling such heterogeneity by incorporating marginal distribution constraints. Building on this insight, we propose OTSurv, a novel MIL framework from an optimal transport perspective. Specifically, OTSurv formulates survival predictions as a heterogeneity-aware OT problem with two constraints: (1) global long-tail constraint that models prior morphological distributions to avert both mode collapse and excessive uniformity by regulating transport mass allocation, and (2) local uncertainty-aware constraint that prioritizes high-confidence patches while suppressing noise by progressively raising the total transport mass. We then recast the initial OT problem, augmented by these constraints, into an unbalanced OT formulation that can be solved with an efficient, hardware-friendly matrix scaling algorithm. Empirically, OTSurv sets new state-of-the-art results across six popular benchmarks, achieving an absolute 3.6% improvement in average C-index. In addition, OTSurv achieves statistical significance in log-rank tests and offers high interpretability, making it a powerful tool for survival prediction in digital pathology. Our codes are available at https://github.com/Y-Research-SBU/OTSurv.
Accurately predicting gene mutations, mutation subtypes and their exons in lung cancer is critical for personalized treatment planning and prognostic assessment. Faced with regional disparities in medical resources and the high cost of genomic assays, using artificial intelligence to infer these mutations and exon variants from routine histopathology images could greatly facilitate precision therapy. Although some prior studies have shown that deep learning can accelerate the prediction of key gene mutations from lung cancer pathology slides, their performance remains suboptimal and has so far been limited mainly to early screening tasks. To address these limitations, we have assembled PathGene, which comprises histopathology images paired with next-generation sequencing reports from 1,576 patients at the Second Xiangya Hospital, Central South University, and 448 TCGA-LUAD patients. This multi-center dataset links whole-slide images to driver gene mutation status, mutation subtypes, exon, and tumor mutational burden (TMB) status, with the goal of leveraging pathology images to predict mutations, subtypes, exon locations, and TMB for early genetic screening and to advance precision oncology. Unlike existing datasets, we provide molecular-level information related to histopathology images in PathGene to facilitate the development of biomarker prediction models. We benchmarked 11 multiple-instance learning methods on PathGene for mutation, subtype, exon, and TMB prediction tasks. These experimental methods provide valuable alternatives for early genetic screening of lung cancer patients and assisting clinicians to quickly develop personalized precision targeted treatment plans for patients. Code and data are available at https://github.com/panliangrui/NIPS2025/.
Pathologists comprehensive evaluation of donor liver biopsies provides crucial information for accepting or discarding potential grafts. However, rapidly and accurately obtaining these assessments intraoperatively poses a significant challenge for pathologists. Features in donor liver biopsies, such as portal tract fibrosis, total steatosis, macrovesicular steatosis, and hepatocellular ballooning are correlated with transplant outcomes, yet quantifying these indicators suffers from substantial inter- and intra-observer variability. To address this, we introduce DLiPath, the first benchmark for comprehensive donor liver assessment based on a histopathology image dataset. We collected and publicly released 636 whole slide images from 304 donor liver patients at the Department of Pathology, the Third Xiangya Hospital, with expert annotations for key pathological features (including cholestasis, portal tract fibrosis, portal inflammation, total steatosis, macrovesicular steatosis, and hepatocellular ballooning). We selected nine state-of-the-art multiple-instance learning (MIL) models based on the DLiPath dataset as baselines for extensive comparative analysis. The experimental results demonstrate that several MIL models achieve high accuracy across donor liver assessment indicators on DLiPath, charting a clear course for future automated and intelligent donor liver assessment research. Data and code are available at https://github.com/panliangrui/ACM_MM_2025.
Multiple Instance Learning (MIL) is a cornerstone approach in computational pathology (CPath) for generating clinically meaningful slide-level embeddings from gigapixel tissue images. However, MIL often struggles with small, weakly supervised clinical datasets. In contrast to fields such as NLP and conventional computer vision, where transfer learning is widely used to address data scarcity, the transferability of MIL models remains poorly understood. In this study, we systematically evaluate the transfer learning capabilities of pretrained MIL models by assessing 11 models across 21 pretraining tasks for morphological and molecular subtype prediction. Our results show that pretrained MIL models, even when trained on different organs than the target task, consistently outperform models trained from scratch. Moreover, pretraining on pancancer datasets enables strong generalization across organs and tasks, outperforming slide foundation models while using substantially less pretraining data. These findings highlight the robust adaptability of MIL models and demonstrate the benefits of leveraging transfer learning to boost performance in CPath. Lastly, we provide a resource which standardizes the implementation of MIL models and collection of pretrained model weights on popular CPath tasks, available at https://github.com/mahmoodlab/MIL-Lab
Pre-trained encoders for offline feature extraction followed by multiple instance learning (MIL) aggregators have become the dominant paradigm in computational pathology (CPath), benefiting cancer diagnosis and prognosis. However, performance limitations arise from the absence of encoder fine-tuning for downstream tasks and disjoint optimization with MIL. While slide-level supervised end-to-end (E2E) learning is an intuitive solution to this issue, it faces challenges such as high computational demands and suboptimal results. These limitations motivate us to revisit E2E learning. We argue that prior work neglects inherent E2E optimization challenges, leading to performance disparities compared to traditional two-stage methods. In this paper, we pioneer the elucidation of optimization challenge caused by sparse-attention MIL and propose a novel MIL called ABMILX. It mitigates this problem through global correlation-based attention refinement and multi-head mechanisms. With the efficient multi-scale random patch sampling strategy, an E2E trained ResNet with ABMILX surpasses SOTA foundation models under the two-stage paradigm across multiple challenging benchmarks, while remaining computationally efficient (<10 RTX3090 hours). We show the potential of E2E learning in CPath and calls for greater research focus in this area. The code is https://github.com/DearCaat/E2E-WSI-ABMILX.
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.
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.
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.
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.
Accurate tumor detection in digital pathology whole-slide images (WSIs) is crucial for cancer diagnosis and treatment planning. Multiple Instance Learning (MIL) has emerged as a widely used approach for weakly-supervised tumor detection with large-scale data without the need for manual annotations. However, traditional MIL methods often depend on classification tasks that require tumor-free cases as negative examples, which are challenging to obtain in real-world clinical workflows, especially for surgical resection specimens. We address this limitation by reformulating tumor detection as a regression task, estimating tumor percentages from WSIs, a clinically available target across multiple cancer types. In this paper, we provide an analysis of the proposed weakly-supervised regression framework by applying it to multiple organs, specimen types and clinical scenarios. We characterize the robustness of our framework to tumor percentage as a noisy regression target, and introduce a novel concept of amplification technique to improve tumor detection sensitivity when learning from small tumor regions. Finally, we provide interpretable insights into the model's predictions by analyzing visual attention and logit maps. Our code is available at https://github.com/DIAGNijmegen/tumor-percentage-mil-regression.
Marine ecosystem monitoring via Passive Acoustic Monitoring (PAM) generates vast data, but deep learning often requires precise annotations and short segments. We introduce DSMIL-LocNet, a Multiple Instance Learning framework for whale call detection and localization using only bag-level labels. Our dual-stream model processes 2-30 minute audio segments, leveraging spectral and temporal features with attention-based instance selection. Tests on Antarctic whale data show longer contexts improve classification (F1: 0.8-0.9) while medium instances ensure localization precision (0.65-0.70). This suggests MIL can enhance scalable marine monitoring. Code: https://github.com/Ragib-Amin-Nihal/DSMIL-Loc
While deep learning methods have shown great promise in improving the effectiveness of prostate cancer (PCa) diagnosis by detecting suspicious lesions from trans-rectal ultrasound (TRUS), they must overcome multiple simultaneous challenges. There is high heterogeneity in tissue appearance, significant class imbalance in favor of benign examples, and scarcity in the number and quality of ground truth annotations available to train models. Failure to address even a single one of these problems can result in unacceptable clinical outcomes.We propose TRUSWorthy, a carefully designed, tuned, and integrated system for reliable PCa detection. Our pipeline integrates self-supervised learning, multiple-instance learning aggregation using transformers, random-undersampled boosting and ensembling: these address label scarcity, weak labels, class imbalance, and overconfidence, respectively. We train and rigorously evaluate our method using a large, multi-center dataset of micro-ultrasound data. Our method outperforms previous state-of-the-art deep learning methods in terms of accuracy and uncertainty calibration, with AUROC and balanced accuracy scores of 79.9% and 71.5%, respectively. On the top 20% of predictions with the highest confidence, we can achieve a balanced accuracy of up to 91%. The success of TRUSWorthy demonstrates the potential of integrated deep learning solutions to meet clinical needs in a highly challenging deployment setting, and is a significant step towards creating a trustworthy system for computer-assisted PCa diagnosis.
Multiple instance learning (MIL)-based framework has become the mainstream for processing the whole slide image (WSI) with giga-pixel size and hierarchical image context in digital pathology. However, these methods heavily depend on a substantial number of bag-level labels and solely learn from the original slides, which are easily affected by variations in data distribution. Recently, vision language model (VLM)-based methods introduced the language prior by pre-training on large-scale pathological image-text pairs. However, the previous text prompt lacks the consideration of pathological prior knowledge, therefore does not substantially boost the model's performance. Moreover, the collection of such pairs and the pre-training process are very time-consuming and source-intensive.To solve the above problems, we propose a dual-scale vision-language multiple instance learning (ViLa-MIL) framework for whole slide image classification. Specifically, we propose a dual-scale visual descriptive text prompt based on the frozen large language model (LLM) to boost the performance of VLM effectively. To transfer the VLM to process WSI efficiently, for the image branch, we propose a prototype-guided patch decoder to aggregate the patch features progressively by grouping similar patches into the same prototype; for the text branch, we introduce a context-guided text decoder to enhance the text features by incorporating the multi-granular image contexts. Extensive studies on three multi-cancer and multi-center subtyping datasets demonstrate the superiority of ViLa-MIL.
Emotions play a crucial role in human behavior and decision-making, making emotion recognition a key area of interest in human-computer interaction (HCI). This study addresses the challenges of emotion recognition by integrating facial expression analysis with electroencephalogram (EEG) signals, introducing a novel multimodal framework-Milmer. The proposed framework employs a transformer-based fusion approach to effectively integrate visual and physiological modalities. It consists of an EEG preprocessing module, a facial feature extraction and balancing module, and a cross-modal fusion module. To enhance visual feature extraction, we fine-tune a pre-trained Swin Transformer on emotion-related datasets. Additionally, a cross-attention mechanism is introduced to balance token representation across modalities, ensuring effective feature integration. A key innovation of this work is the adoption of a multiple instance learning (MIL) approach, which extracts meaningful information from multiple facial expression images over time, capturing critical temporal dynamics often overlooked in previous studies. Extensive experiments conducted on the DEAP dataset demonstrate the superiority of the proposed framework, achieving a classification accuracy of 96.72% in the four-class emotion recognition task. Ablation studies further validate the contributions of each module, highlighting the significance of advanced feature extraction and fusion strategies in enhancing emotion recognition performance. Our code are available at https://github.com/liangyubuaa/Milmer.