The development of computational pathology lies in the consensus that pathological characteristics of tumors are significant guidance for cancer diagnostics. Most existing research focuses on the inner-contextual information within each WSI yet ignores the possible inter-correlations between slides. As the development of tumors is a continuous process involving a series of histological, morphological, and genetic changes that accumulate over time, the similarities and differences between WSIs across various stages, grades, locations and patients should potentially contribute to the representation of WSIs and deserve to be taken into account in WSI modeling. To verify the advancement of introducing the slide inter-correlations into the representation learning of WSIs, we proposed a generic WSI analysis pipeline SlideGCD that can be adapted to any existing Multiple Instance Learning (MIL) frameworks and improve their performance. With the new paradigm, the prior knowledge of cancer development can participate in the end-to-end workflow, which concurrently initializes and refines the slide representation, as a guide for message passing in the slide-based graph. Extensive comparisons and experiments are conducted to validate the effectiveness and robustness of the proposed pipeline across 4 different tasks, including cancer subtyping, cancer staging, survival prediction, and gene mutation prediction, with 7 representative SOTA WSI analysis frameworks as backbones.
Whole Slide Image (WSI) classification has very significant applications in clinical pathology, e.g., tumor identification and cancer diagnosis. Currently, most research attention is focused on Multiple Instance Learning (MIL) using static datasets. One of the most obvious weaknesses of these methods is that they cannot efficiently preserve and utilize previously learned knowledge. With any new data arriving, classification models are required to be re-trained on both previous and current new data. To overcome this shortcoming and break through traditional vision modality, this paper proposes the first Vision-Language-based framework with Queryable Prototype Multiple Instance Learning (QPMIL-VL) specially designed for incremental WSI classification. This framework mainly consists of two information processing branches: one is for generating bag-level features by prototype-guided aggregation of instance features, while the other is for enhancing class features through a combination of class ensemble, tunable vector and class similarity loss. The experiments on four public WSI datasets demonstrate that our QPMIL-VL framework is effective for incremental WSI classification and often significantly outperforms other compared methods, achieving state-of-the-art (SOTA) performance. Our source code is publicly available at https://github.com/can-can-ya/QPMIL-VL.
Whole slide image (WSI) classification is a crucial problem for cancer diagnostics in clinics and hospitals. A WSI, acquired at gigapixel size, is commonly tiled into patches and processed by multiple-instance learning (MIL) models. Previous MIL-based models designed for this problem have only been evaluated on individual tasks for specific organs, and the ability to handle multiple tasks within a single model has not been investigated. In this study, we propose MECFormer, a generative Transformer-based model designed to handle multiple tasks within one model. To leverage the power of learning multiple tasks simultaneously and to enhance the model's effectiveness in focusing on each individual task, we introduce an Expert Consultation Network, a projection layer placed at the beginning of the Transformer-based model. Additionally, to enable flexible classification, autoregressive decoding is incorporated by a language decoder for WSI classification. Through extensive experiments on five datasets involving four different organs, one cancer classification task, and four cancer subtyping tasks, MECFormer demonstrates superior performance compared to individual state-of-the-art multiple-instance learning models.
Multiple Instance Learning (MIL) is widely used in medical imaging classification to reduce the labeling effort. While only bag labels are available for training, one typically seeks predictions at both bag and instance levels (classification and localization tasks, respectively). Early MIL methods treated the instances in a bag independently. Recent methods account for global and local dependencies among instances. Although they have yielded excellent results in classification, their performance in terms of localization is comparatively limited. We argue that these models have been designed to target the classification task, while implications at the instance level have not been deeply investigated. Motivated by a simple observation -- that neighboring instances are likely to have the same label -- we propose a novel, principled, and flexible mechanism to model local dependencies. It can be used alone or combined with any mechanism to model global dependencies (e.g., transformers). A thorough empirical validation shows that our module leads to state-of-the-art performance in localization while being competitive or superior in classification. Our code is at https://github.com/Franblueee/SmMIL.
Weakly supervised whole slide image (WSI) classification is challenging due to the lack of patch-level labels and high computational costs. State-of-the-art methods use self-supervised patch-wise feature representations for multiple instance learning (MIL). Recently, methods have been proposed to fine-tune the feature representation on the downstream task using pseudo labeling, but mostly focusing on selecting high-quality positive patches. In this paper, we propose to mine hard negative samples during fine-tuning. This allows us to obtain better feature representations and reduce the training cost. Furthermore, we propose a novel patch-wise ranking loss in MIL to better exploit these hard negative samples. Experiments on two public datasets demonstrate the efficacy of these proposed ideas. Our codes are available at https://github.com/winston52/HNM-WSI
Objective: Molecular testing (MT) classifies cytologically indeterminate thyroid nodules as benign or malignant with high sensitivity but low positive predictive value (PPV), only using molecular profiles, ignoring ultrasound (US) imaging and biopsy. We address this limitation by applying attention multiple instance learning (AMIL) to US images. Methods: We retrospectively reviewed 333 patients with indeterminate thyroid nodules at UCLA medical center (259 benign, 74 malignant). A multi-modal deep learning AMIL model was developed, combining US images and MT to classify the nodules as benign or malignant and enhance the malignancy risk stratification of MT. Results: The final AMIL model matched MT sensitivity (0.946) while significantly improving PPV (0.477 vs 0.448 for MT alone), indicating fewer false positives while maintaining high sensitivity. Conclusion: Our approach reduces false positives compared to MT while maintaining the same ability to identify positive cases, potentially reducing unnecessary benign thyroid resections in patients with indeterminate nodules.
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.
Reliable models are dependable and provide predictions acceptable given basic domain knowledge. Therefore, it is critical to develop and deploy reliable models, especially for healthcare applications. However, Multiple Instance Learning (MIL) models designed for Whole Slide Images (WSIs) classification in computational pathology are not evaluated in terms of reliability. Hence, in this paper we compare the reliability of MIL models with three suggested metrics and use three region-wise annotated datasets. We find the mean pooling instance (MEAN-POOL-INS) model more reliable than other networks despite its naive architecture design and computation efficiency. The code to reproduce the results is accessible at https://github.com/tueimage/MILs'R .
Prostate cancer (PCa) was the most frequently diagnosed cancer among American men in 2023. The histological grading of biopsies is essential for diagnosis, and various deep learning-based solutions have been developed to assist with this task. Existing deep learning frameworks are typically applied to individual 2D cross-sections sliced from 3D biopsy tissue specimens. This process impedes the analysis of complex tissue structures such as glands, which can vary depending on the tissue slice examined. We propose a novel digital pathology data source called a "volumetric core," obtained via the extraction and co-alignment of serially sectioned tissue sections using a novel morphology-preserving alignment framework. We trained an attention-based multiple-instance learning (ABMIL) framework on deep features extracted from volumetric patches to automatically classify the Gleason Grade Group (GGG). To handle volumetric patches, we used a modified video transformer with a deep feature extractor pretrained using self-supervised learning. We ran our morphology-preserving alignment framework to construct 10,210 volumetric cores, leaving out 30% for pretraining. The rest of the dataset was used to train ABMIL, which resulted in a 0.958 macro-average AUC, 0.671 F1 score, 0.661 precision, and 0.695 recall averaged across all five GGG significantly outperforming the 2D baselines.
Multimodal language modeling has enabled breakthroughs for representation learning, yet remains unexplored in the realm of functional brain data for pathology detection. This paper pioneers EEG-language models (ELMs) trained on clinical reports and 15000 EEGs. We propose to combine multimodal alignment in this novel domain with timeseries cropping and text segmentation, enabling an extension based on multiple instance learning to alleviate misalignment between irrelevant EEG or text segments. Our multimodal models significantly improve pathology detection compared to EEG-only models across four evaluations and for the first time enable zero-shot classification as well as retrieval of both neural signals and reports. In sum, these results highlight the potential of ELMs, representing significant progress for clinical applications.
Introduction: Deep learning models hold great promise for digital pathology, but their opaque decision-making processes undermine trust and hinder clinical adoption. Explainable AI methods are essential to enhance model transparency and reliability. Methods: We developed HIPPO, an explainable AI framework that systematically modifies tissue regions in whole slide images to generate image counterfactuals, enabling quantitative hypothesis testing, bias detection, and model evaluation beyond traditional performance metrics. HIPPO was applied to a variety of clinically important tasks, including breast metastasis detection in axillary lymph nodes, prognostication in breast cancer and melanoma, and IDH mutation classification in gliomas. In computational experiments, HIPPO was compared against traditional metrics and attention-based approaches to assess its ability to identify key tissue elements driving model predictions. Results: In metastasis detection, HIPPO uncovered critical model limitations that were undetectable by standard performance metrics or attention-based methods. For prognostic prediction, HIPPO outperformed attention by providing more nuanced insights into tissue elements influencing outcomes. In a proof-of-concept study, HIPPO facilitated hypothesis generation for identifying melanoma patients who may benefit from immunotherapy. In IDH mutation classification, HIPPO more robustly identified the pathology regions responsible for false negatives compared to attention, suggesting its potential to outperform attention in explaining model decisions. Conclusions: HIPPO expands the explainable AI toolkit for computational pathology by enabling deeper insights into model behavior. This framework supports the trustworthy development, deployment, and regulation of weakly-supervised models in clinical and research settings, promoting their broader adoption in digital pathology.
Sensor fusion combines data from multiple sensor sources to improve reliability, robustness, and accuracy of data interpretation. The Fuzzy Integral (FI), in particular, the Choquet integral (ChI), is often used as a powerful nonlinear aggregator for fusion across multiple sensors. However, existing supervised ChI learning algorithms typically require precise training labels for each input data point, which can be difficult or impossible to obtain. Additionally, prior work on ChI fusion is often based only on the normalized fuzzy measures, which bounds the fuzzy measure values between [0, 1]. This can be limiting in cases where the underlying scales of input data sources are bipolar (i.e., between [-1, 1]). To address these challenges, this paper proposes a novel Choquet integral-based fusion framework, named Bi-MIChI (pronounced "bi-mi-kee"), which uses bi-capacities to represent the interactions between pairs of subsets of the input sensor sources on a bi-polar scale. This allows for extended non-linear interactions between the sensor sources and can lead to interesting fusion results. Bi-MIChI also addresses label uncertainty through Multiple Instance Learning, where training labels are applied to "bags" (sets) of data instead of per-instance. Our proposed Bi-MIChI framework shows effective classification and detection performance on both synthetic and real-world experiments for sensor fusion with label uncertainty. We also provide detailed analyses on the behavior of the fuzzy measures to demonstrate our fusion process.
The rapidly evolving field of digital oncopathology faces significant challenges, including the need to address diverse and complex clinical questions, often involving rare conditions, with limited availability of labeled data. These limitations hinder the development of robust AI-driven tools in the biomedical space, where accuracy in probabilistic determinations is of utmost importance. To address this, digital pathology foundation models have begun to emerge, typically developed with the size and diversity of the pre-training dataset and model parameters in mind. Here, we present CanvOI, a ViT-g/10-based foundation model designed to enhance the capabilities of digital pathology by addressing these challenges through a different approach. Considering the unique nature of oncologic histopathological images and the requirements from the embeddings to provide meaningful representations for Multiple Instance Learning (MIL) downstream models, we chose to modify the input image characteristics. By introducing larger tile sizes (380 x 380 pixels) and smaller patch sizes (10 x 10 pixels), we were able to optimize the model's performance, pushing computational resources in a new direction and achieving state-of-the-art performance on cancer-related benchmarks. CanvOI demonstrated a 1.5-7.4% improvement in averaged AUC compared to other leading foundation models built for digital pathology. Moreover, our results demonstrate that CanvOI significantly outperformed the other models, with the performance gap widening substantially when trained on just 10% of the initial cohort. This work highlights an alternative approach that, if integrated with traditional development approaches, has the potential to advance Oncology Intelligence (OI), overcome some of the current barriers and ultimately improve the clinical outcome of cancer patients.
Brain tumors are the most common solid tumors in children and young adults, but the scarcity of large histopathology datasets has limited the application of computational pathology in this group. This study implements two weakly supervised multiple-instance learning (MIL) approaches on patch-features obtained from state-of-the-art histology-specific foundation models to classify pediatric brain tumors in hematoxylin and eosin whole slide images (WSIs) from a multi-center Swedish cohort. WSIs from 540 subjects (age 8.5$\pm$4.9 years) diagnosed with brain tumor were gathered from the six Swedish university hospitals. Instance (patch)-level features were obtained from WSIs using three pre-trained feature extractors: ResNet50, UNI and CONCH. Instances were aggregated using attention-based MIL (ABMIL) or clustering-constrained attention MIL (CLAM) for patient-level classification. Models were evaluated on three classification tasks based on the hierarchical classification of pediatric brain tumors: tumor category, family and type. Model generalization was assessed by training on data from two of the centers and testing on data from four other centers. Model interpretability was evaluated through attention-mapping. The highest classification performance was achieved using UNI features and AMBIL aggregation, with Matthew's correlation coefficient of 0.86$\pm$0.04, 0.63$\pm$0.04, and 0.53$\pm$0.05, for tumor category, family and type classification, respectively. When evaluating generalization, models utilizing UNI and CONCH features outperformed those using ResNet50. However, the drop in performance from the in-site to out-of-site testing was similar across feature extractors. These results show the potential of state-of-the-art computational pathology methods in diagnosing pediatric brain tumors at different hierarchical levels with fair generalizability on a multi-center national dataset.
Time to biochemical recurrence in prostate cancer is essential for prognostic monitoring of the progression of patients after prostatectomy, which assesses the efficacy of the surgery. In this work, we proposed to leverage multiple instance learning through a two-stage ``thinking fast \& slow'' strategy for the time to recurrence (TTR) prediction. The first (``thinking fast'') stage finds the most relevant WSI area for biochemical recurrence and the second (``thinking slow'') stage leverages higher resolution patches to predict TTR. Our approach reveals a mean C-index ($Ci$) of 0.733 ($\theta=0.059$) on our internal validation and $Ci=0.603$ on the LEOPARD challenge validation set. Post hoc attention visualization shows that the most attentive area contributes to the TTR prediction.
Tongue diagnosis in Traditional Chinese Medicine (TCM) is a crucial diagnostic method that can reflect an individual's health status. Traditional methods for identifying tooth-marked tongues are subjective and inconsistent because they rely on practitioner experience. We propose a novel fully automated Weakly Supervised method using Vision transformer and Multiple instance learning WSVM for tongue extraction and tooth-marked tongue recognition. Our approach first accurately detects and extracts the tongue region from clinical images, removing any irrelevant background information. Then, we implement an end-to-end weakly supervised object detection method. We utilize Vision Transformer (ViT) to process tongue images in patches and employ multiple instance loss to identify tooth-marked regions with only image-level annotations. WSVM achieves high accuracy in tooth-marked tongue classification, and visualization experiments demonstrate its effectiveness in pinpointing these regions. This automated approach enhances the objectivity and accuracy of tooth-marked tongue diagnosis. It provides significant clinical value by assisting TCM practitioners in making precise diagnoses and treatment recommendations. Code is available at https://github.com/yc-zh/WSVM.
Recent advancements in ML and DL have significantly improved Android malware detection, yet many methodologies still rely on basic static analysis, bytecode, or function call graphs that often fail to capture complex malicious behaviors. DexBERT, a pre-trained BERT-like model tailored for Android representation learning, enriches class-level representations by analyzing Smali code extracted from APKs. However, its functionality is constrained by its inability to process multiple Smali classes simultaneously. This paper introduces DetectBERT, which integrates correlated Multiple Instance Learning (c-MIL) with DexBERT to handle the high dimensionality and variability of Android malware, enabling effective app-level detection. By treating class-level features as instances within MIL bags, DetectBERT aggregates these into a comprehensive app-level representation. Our evaluation demonstrates that DetectBERT not only surpasses existing state-of-the-art detection methods but also adapts to evolving malware threats. Moreover, the versatility of the DetectBERT framework holds promising potential for broader applications in app-level analysis and other software engineering tasks, offering new avenues for research and development.
Computational pathology (CPath) has significantly advanced the clinical practice of pathology. Despite the progress made, Multiple Instance Learning (MIL), a promising paradigm within CPath, continues to face challenges, particularly related to incomplete information utilization. Existing frameworks, such as those based on Convolutional Neural Networks (CNNs), attention, and selective scan space state sequential model (SSM), lack sufficient flexibility and scalability in fusing diverse features, and cannot effectively fuse diverse features. Additionally, current approaches do not adequately exploit order-related and order-independent features, resulting in suboptimal utilization of sequence information. To address these limitations, we propose a novel MIL framework called Mamba2MIL. Our framework utilizes the state space duality model (SSD) to model long sequences of patches of whole slide images (WSIs), which, combined with weighted feature selection, supports the fusion processing of more branching features and can be extended according to specific application needs. Moreover, we introduce a sequence transformation method tailored to varying WSI sizes, which enhances sequence-independent features while preserving local sequence information, thereby improving sequence information utilization. Extensive experiments demonstrate that Mamba2MIL surpasses state-of-the-art MIL methods. We conducted extensive experiments across multiple datasets, achieving improvements in nearly all performance metrics. Specifically, on the NSCLC dataset, Mamba2MIL achieves a binary tumor classification AUC of 0.9533 and an accuracy of 0.8794. On the BRACS dataset, it achieves a multiclass classification AUC of 0.7986 and an accuracy of 0.4981. The code is available at https://github.com/YuqiZhang-Buaa/Mamba2MIL.
Anomaly action detection and localization play an essential role in security and advanced surveillance systems. However, due to the tremendous amount of surveillance videos, most of the available data for the task is unlabeled or semi-labeled with the video class known, but the location of the anomaly event is unknown. In this work, we target anomaly localization in semi-supervised videos. While the mainstream direction in addressing this task is focused on segment-level multi-instance learning and the generation of pseudo labels, we aim to explore a promising yet unfulfilled direction to solve the problem by learning the temporal relations within videos in order to locate anomaly events. To this end, we propose a hierarchical transformer model designed to evaluate the significance of observed actions in anomalous videos with a divide-and-conquer strategy along the temporal axis. Our approach segments a parent video hierarchically into multiple temporal children instances and measures the influence of the children nodes in classifying the abnormality of the parent video. Evaluating our model on two well-known anomaly detection datasets, UCF-crime and ShanghaiTech, proves its ability to interpret the observed actions within videos and localize the anomalous ones. Our proposed approach outperforms previous works relying on segment-level multiple-instance learning approaches while reaching a promising performance compared to the more recent pseudo-labeling-based approaches.
Recent advancements in computational pathology and artificial intelligence have significantly improved whole slide image (WSI) classification. However, the gigapixel resolution of WSIs and the scarcity of manual annotations present substantial challenges. Multiple instance learning (MIL) is a promising weakly supervised learning approach for WSI classification. Recently research revealed employing pseudo bag augmentation can encourage models to learn various data, thus bolstering models' performance. While directly inheriting the parents' labels can introduce more noise by mislabeling in training. To address this issue, we translate the WSI classification task from weakly supervised learning to semi-weakly supervised learning, termed SWS-MIL, where adaptive pseudo bag augmentation (AdaPse) is employed to assign labeled and unlabeled data based on a threshold strategy. Using the "student-teacher" pattern, we introduce a feature augmentation technique, MergeUp, which merges bags with low-priority bags to enhance inter-category information, increasing training data diversity. Experimental results on the CAMELYON-16, BRACS, and TCGA-LUNG datasets demonstrate the superiority of our method over existing state-of-the-art approaches, affirming its efficacy in WSI classification.