Conventional Time Series Classification (TSC) methods are often black boxes that obscure inherent interpretation of their decision-making processes. In this work, we leverage Multiple Instance Learning (MIL) to overcome this issue, and propose a new framework called MILLET: Multiple Instance Learning for Locally Explainable Time series classification. We apply MILLET to existing deep learning TSC models and show how they become inherently interpretable without compromising (and in some cases, even improving) predictive performance. We evaluate MILLET on 85 UCR TSC datasets and also present a novel synthetic dataset that is specially designed to facilitate interpretability evaluation. On these datasets, we show MILLET produces sparse explanations quickly that are of higher quality than other well-known interpretability methods. To the best of our knowledge, our work with MILLET, which is available on GitHub (https://github.com/JAEarly/MILTimeSeriesClassification), is the first to develop general MIL methods for TSC and apply them to an extensive variety of domains
In the application of Multiple Instance Learning (MIL) methods for Whole Slide Image (WSI) classification, attention mechanisms often focus on a subset of discriminative instances, which are closely linked to overfitting. To mitigate overfitting, we present Attention-Challenging MIL (ACMIL). ACMIL combines two techniques based on separate analyses for attention value concentration. Firstly, UMAP of instance features reveals various patterns among discriminative instances, with existing attention mechanisms capturing only some of them. To remedy this, we introduce Multiple Branch Attention (MBA) to capture more discriminative instances using multiple attention branches. Secondly, the examination of the cumulative value of Top-K attention scores indicates that a tiny number of instances dominate the majority of attention. In response, we present Stochastic Top-K Instance Masking (STKIM), which masks out a portion of instances with Top-K attention values and allocates their attention values to the remaining instances. The extensive experimental results on three WSI datasets with two pre-trained backbones reveal that our ACMIL outperforms state-of-the-art methods. Additionally, through heatmap visualization and UMAP visualization, this paper extensively illustrates ACMIL's effectiveness in suppressing attention value concentration and overcoming the overfitting challenge. The source code is available at \url{https://github.com/dazhangyu123/ACMIL}.
Predicting patient features from single-cell data can help identify cellular states implicated in health and disease. Linear models and average cell type expressions are typically favored for this task for their efficiency and robustness, but they overlook the rich cell heterogeneity inherent in single-cell data. To address this gap, we introduce MixMIL, a framework integrating Generalized Linear Mixed Models (GLMM) and Multiple Instance Learning (MIL), upholding the advantages of linear models while modeling cell state heterogeneity. By leveraging predefined cell embeddings, MixMIL enhances computational efficiency and aligns with recent advancements in single-cell representation learning. Our empirical results reveal that MixMIL outperforms existing MIL models in single-cell datasets, uncovering new associations and elucidating biological mechanisms across different domains.
For classifying digital whole slide images in the absence of pixel level annotation, typically multiple instance learning methods are applied. Due to the generic applicability, such methods are currently of very high interest in the research community, however, the issue of data augmentation in this context is rarely explored. Here we investigate linear and multilinear interpolation between feature vectors, a data augmentation technique, which proved to be capable of improving the generalization performance classification networks and also for multiple instance learning. Experiments, however, have been performed on only two rather small data sets and one specific feature extraction approach so far and a strong dependence on the data set has been identified. Here we conduct a large study incorporating 10 different data set configurations, two different feature extraction approaches (supervised and self-supervised), stain normalization and two multiple instance learning architectures. The results showed an extraordinarily high variability in the effect of the method. We identified several interesting aspects to bring light into the darkness and identified novel promising fields of research.
Multiple Instance Learning (MIL) has been widely used in weakly supervised whole slide image (WSI) classification. Typical MIL methods include a feature embedding part, which embeds the instances into features via a pre-trained feature extractor, and an MIL aggregator that combines instance embeddings into predictions. Most efforts have typically focused on improving these parts. This involves refining the feature embeddings through self-supervised pre-training as well as modeling the correlations between instances separately. In this paper, we proposed a sparsely coding MIL (SC-MIL) method that addresses those two aspects at the same time by leveraging sparse dictionary learning. The sparse dictionary learning captures the similarities of instances by expressing them as sparse linear combinations of atoms in an over-complete dictionary. In addition, imposing sparsity improves instance feature embeddings by suppressing irrelevant instances while retaining the most relevant ones. To make the conventional sparse coding algorithm compatible with deep learning, we unrolled it into a sparsely coded module leveraging deep unrolling. The proposed SC module can be incorporated into any existing MIL framework in a plug-and-play manner with an acceptable computational cost. The experimental results on multiple datasets demonstrated that the proposed SC module could substantially boost the performance of state-of-the-art MIL methods. The codes are available at \href{https://github.com/sotiraslab/SCMIL.git}{https://github.com/sotiraslab/SCMIL.git}.
In the last years, the weakly supervised paradigm of multiple instance learning (MIL) has become very popular in many different areas. A paradigmatic example is computational pathology, where the lack of patch-level labels for whole-slide images prevents the application of supervised models. Probabilistic MIL methods based on Gaussian Processes (GPs) have obtained promising results due to their excellent uncertainty estimation capabilities. However, these are general-purpose MIL methods that do not take into account one important fact: in (histopathological) images, the labels of neighboring patches are expected to be correlated. In this work, we extend a state-of-the-art GP-based MIL method, which is called VGPMIL-PR, to exploit such correlation. To do so, we develop a novel coupling term inspired by the statistical physics Ising model. We use variational inference to estimate all the model parameters. Interestingly, the VGPMIL-PR formulation is recovered when the weight that regulates the strength of the Ising term vanishes. The performance of the proposed method is assessed in two real-world problems of prostate cancer detection. We show that our model achieves better results than other state-of-the-art probabilistic MIL methods. We also provide different visualizations and analysis to gain insights into the influence of the novel Ising term. These insights are expected to facilitate the application of the proposed model to other research areas.
Multiple Instance Learning (MIL) is a sub-domain of classification problems with positive and negative labels and a "bag" of inputs, where the label is positive if and only if a positive element is contained within the bag, and otherwise is negative. Training in this context requires associating the bag-wide label to instance-level information, and implicitly contains a causal assumption and asymmetry to the task (i.e., you can't swap the labels without changing the semantics). MIL problems occur in healthcare (one malignant cell indicates cancer), cyber security (one malicious executable makes an infected computer), and many other tasks. In this work, we examine five of the most prominent deep-MIL models and find that none of them respects the standard MIL assumption. They are able to learn anti-correlated instances, i.e., defaulting to "positive" labels until seeing a negative counter-example, which should not be possible for a correct MIL model. We suspect that enhancements and other works derived from these models will share the same issue. In any context in which these models are being used, this creates the potential for learning incorrect models, which creates risk of operational failure. We identify and demonstrate this problem via a proposed "algorithmic unit test", where we create synthetic datasets that can be solved by a MIL respecting model, and which clearly reveal learning that violates MIL assumptions. The five evaluated methods each fail one or more of these tests. This provides a model-agnostic way to identify violations of modeling assumptions, which we hope will be useful for future development and evaluation of MIL models.
In recent years, we witness the explosion of false and unconfirmed information (i.e., rumors) that went viral on social media and shocked the public. Rumors can trigger versatile, mostly controversial stance expressions among social media users. Rumor verification and stance detection are different yet relevant tasks. Fake news debunking primarily focuses on determining the truthfulness of news articles, which oversimplifies the issue as fake news often combines elements of both truth and falsehood. Thus, it becomes crucial to identify specific instances of misinformation within the articles. In this research, we investigate a novel task in the field of fake news debunking, which involves detecting sentence-level misinformation. One of the major challenges in this task is the absence of a training dataset with sentence-level annotations regarding veracity. Inspired by the Multiple Instance Learning (MIL) approach, we propose a model called Weakly Supervised Detection of Misinforming Sentences (WSDMS). This model only requires bag-level labels for training but is capable of inferring both sentence-level misinformation and article-level veracity, aided by relevant social media conversations that are attentively contextualized with news sentences. We evaluate WSDMS on three real-world benchmarks and demonstrate that it outperforms existing state-of-the-art baselines in debunking fake news at both the sentence and article levels.
Whole-slide image analysis via the means of computational pathology often relies on processing tessellated gigapixel images with only slide-level labels available. Applying multiple instance learning-based methods or transformer models is computationally expensive as, for each image, all instances have to be processed simultaneously. The MLP-Mixer is an under-explored alternative model to common vision transformers, especially for large-scale datasets. Due to the lack of a self-attention mechanism, they have linear computational complexity to the number of input patches but achieve comparable performance on natural image datasets. We propose a combination of feature embedding and clustering to preprocess the full whole-slide image into a reduced prototype representation which can then serve as input to a suitable MLP-Mixer architecture. Our experiments on two public benchmarks and one inhouse malignant lymphoma dataset show comparable performance to current state-of-the-art methods, while achieving lower training costs in terms of computational time and memory load. Code is publicly available at https://github.com/butkej/ProtoMixer.
For many patients, current ovarian cancer treatments offer limited clinical benefit. For some therapies, it is not possible to predict patients' responses, potentially exposing them to the adverse effects of treatment without any therapeutic benefit. As part of the automated prediction of treatment effectiveness in ovarian cancer using histopathological images (ATEC23) challenge, we evaluated the effectiveness of deep learning to predict whether a course of treatment including the antiangiogenic drug bevacizumab could contribute to remission or prevent disease progression for at least 6 months in a set of 282 histopathology whole slide images (WSIs) from 78 ovarian cancer patients. Our approach used a pretrained Hierarchical Image Pyramid Transformer (HIPT) to extract region-level features and an attention-based multiple instance learning (ABMIL) model to aggregate features and classify whole slides. The optimal HIPT-ABMIL model had an internal balanced accuracy of 60.2% +- 2.9% and an AUC of 0.646 +- 0.033. Histopathology-specific model pretraining was found to be beneficial to classification performance, though hierarchical transformers were not, with a ResNet feature extractor achieving similar performance. Due to the dataset being small and highly heterogeneous, performance was variable across 5-fold cross-validation folds, and there were some extreme differences between validation and test set performance within folds. The model did not generalise well to tissue microarrays, with accuracy worse than random chance. It is not yet clear whether ovarian cancer WSIs contain information that can be used to accurately predict treatment response, with further validation using larger, higher-quality datasets required.
Microsatellite instability-high (MSI-H) is a tumor agnostic biomarker for immune checkpoint inhibitor therapy. However, MSI status is not routinely tested in prostate cancer, in part due to low prevalence and assay cost. As such, prediction of MSI status from hematoxylin and eosin (H&E) stained whole-slide images (WSIs) could identify prostate cancer patients most likely to benefit from confirmatory testing and becoming eligible for immunotherapy. Prostate biopsies and surgical resections from de-identified records of consecutive prostate cancer patients referred to our institution were analyzed. Their MSI status was determined by next generation sequencing. Patients before a cutoff date were split into an algorithm development set (n=4015, MSI-H 1.8%) and a paired validation set (n=173, MSI-H 19.7%) that consisted of two serial sections from each sample, one stained and scanned internally and the other at an external site. Patients after the cutoff date formed the temporal validation set (n=1350, MSI-H 2.3%). Attention-based multiple instance learning models were trained to predict MSI-H from H&E WSIs. The MSI-H predictor achieved area under the receiver operating characteristic curve values of 0.78 (95% CI [0.69-0.86]), 0.72 (95% CI [0.63-0.81]), and 0.72 (95% CI [0.62-0.82]) on the internally prepared, externally prepared, and temporal validation sets, respectively. While MSI-H status is significantly correlated with Gleason score, the model remained predictive within each Gleason score subgroup. In summary, we developed and validated an AI-based MSI-H diagnostic model on a large real-world cohort of routine H&E slides, which effectively generalized to externally stained and scanned samples and a temporally independent validation cohort. This algorithm has the potential to direct prostate cancer patients toward immunotherapy and to identify MSI-H cases secondary to Lynch syndrome.
Biomarker detection is an indispensable part in the diagnosis and treatment of low-grade glioma (LGG). However, current LGG biomarker detection methods rely on expensive and complex molecular genetic testing, for which professionals are required to analyze the results, and intra-rater variability is often reported. To overcome these challenges, we propose an interpretable deep learning pipeline, a Multi-Biomarker Histomorphology Discoverer (Multi-Beholder) model based on the multiple instance learning (MIL) framework, to predict the status of five biomarkers in LGG using only hematoxylin and eosin-stained whole slide images and slide-level biomarker status labels. Specifically, by incorporating the one-class classification into the MIL framework, accurate instance pseudo-labeling is realized for instance-level supervision, which greatly complements the slide-level labels and improves the biomarker prediction performance. Multi-Beholder demonstrates superior prediction performance and generalizability for five LGG biomarkers (AUROC=0.6469-0.9735) in two cohorts (n=607) with diverse races and scanning protocols. Moreover, the excellent interpretability of Multi-Beholder allows for discovering the quantitative and qualitative correlations between biomarker status and histomorphology characteristics. Our pipeline not only provides a novel approach for biomarker prediction, enhancing the applicability of molecular treatments for LGG patients but also facilitates the discovery of new mechanisms in molecular functionality and LGG progression.
The rapid evolution of deep learning has significantly advanced the field of medical image analysis. However, despite these achievements, the further enhancement of deep learning models for medical image analysis faces a significant challenge due to the scarcity of large, well-annotated datasets. To address this issue, recent years have witnessed a growing emphasis on the development of data-efficient deep learning methods. This paper conducts a thorough review of data-efficient deep learning methods for medical image analysis. To this end, we categorize these methods based on the level of supervision they rely on, encompassing categories such as no supervision, inexact supervision, incomplete supervision, inaccurate supervision, and only limited supervision. We further divide these categories into finer subcategories. For example, we categorize inexact supervision into multiple instance learning and learning with weak annotations. Similarly, we categorize incomplete supervision into semi-supervised learning, active learning, and domain-adaptive learning and so on. Furthermore, we systematically summarize commonly used datasets for data efficient deep learning in medical image analysis and investigate future research directions to conclude this survey.
Point-level supervised temporal action localization (PTAL) aims at recognizing and localizing actions in untrimmed videos where only a single point (frame) within every action instance is annotated in training data. Without temporal annotations, most previous works adopt the multiple instance learning (MIL) framework, where the input video is segmented into non-overlapped short snippets, and action classification is performed independently on every short snippet. We argue that the MIL framework is suboptimal for PTAL because it operates on separated short snippets that contain limited temporal information. Therefore, the classifier only focuses on several easy-to-distinguish snippets instead of discovering the whole action instance without missing any relevant snippets. To alleviate this problem, we propose a novel method that localizes actions by generating and evaluating action proposals of flexible duration that involve more comprehensive temporal information. Moreover, we introduce an efficient clustering algorithm to efficiently generate dense pseudo labels that provide stronger supervision, and a fine-grained contrastive loss to further refine the quality of pseudo labels. Experiments show that our proposed method achieves competitive or superior performance to the state-of-the-art methods and some fully-supervised methods on four benchmarks: ActivityNet 1.3, THUMOS 14, GTEA, and BEOID datasets.
Breast cancer is a major concern for women's health globally, with axillary lymph node (ALN) metastasis identification being critical for prognosis evaluation and treatment guidance. This paper presents a deep learning (DL) classification pipeline for quantifying clinical information from digital core-needle biopsy (CNB) images, with one step less than existing methods. A publicly available dataset of 1058 patients was used to evaluate the performance of different baseline state-of-the-art (SOTA) DL models in classifying ALN metastatic status based on CNB images. An extensive ablation study of various data augmentation techniques was also conducted. Finally, the manual tumor segmentation and annotation step performed by the pathologists was assessed.
We tackle the complex problem of detecting and recognising anomalies in surveillance videos at the frame level, utilising only video-level supervision. We introduce the novel method AnomalyCLIP, the first to combine Large Language and Vision (LLV) models, such as CLIP, with multiple instance learning for joint video anomaly detection and classification. Our approach specifically involves manipulating the latent CLIP feature space to identify the normal event subspace, which in turn allows us to effectively learn text-driven directions for abnormal events. When anomalous frames are projected onto these directions, they exhibit a large feature magnitude if they belong to a particular class. We also introduce a computationally efficient Transformer architecture to model short- and long-term temporal dependencies between frames, ultimately producing the final anomaly score and class prediction probabilities. We compare AnomalyCLIP against state-of-the-art methods considering three major anomaly detection benchmarks, i.e. ShanghaiTech, UCF-Crime, and XD-Violence, and empirically show that it outperforms baselines in recognising video anomalies.
Whole slide image (WSI) classification is a critical task in computational pathology. However, the gigapixel-size of such images remains a major challenge for the current state of deep-learning. Current methods rely on multiple-instance learning (MIL) models with frozen feature extractors. Given the the high number of instances in each image, MIL methods have long assumed independence and permutation-invariance of patches, disregarding the tissue structure and correlation between patches. Recent works started studying this correlation between instances but the computational workload of such a high number of tokens remained a limiting factor. In particular, relative position of patches remains unaddressed. We propose to apply a straightforward encoding module, namely a RoFormer layer , relying on memory-efficient exact self-attention and relative positional encoding. This module can perform full self-attention with relative position encoding on patches of large and arbitrary shaped WSIs, solving the need for correlation between instances and spatial modeling of tissues. We demonstrate that our method outperforms state-of-the-art MIL models on three commonly used public datasets (TCGA-NSCLC, BRACS and Camelyon16)) on weakly supervised classification tasks. Code is available at https://github.com/Sanofi-Public/DDS-RoFormerMIL
Composed image retrieval which combines a reference image and a text modifier to identify the desired target image is a challenging task, and requires the model to comprehend both vision and language modalities and their interactions. Existing approaches focus on holistic multi-modal interaction modeling, and ignore the composed and complimentary property between the reference image and text modifier. In order to better utilize the complementarity of multi-modal inputs for effective information fusion and retrieval, we move the multi-modal understanding to fine-granularity at concept-level, and learn the multi-modal concept alignment to identify the visual location in reference or target images corresponding to text modifier. Toward the end, we propose a NEUral COncept REasoning (NEUCORE) model which incorporates multi-modal concept alignment and progressive multimodal fusion over aligned concepts. Specifically, considering that text modifier may refer to semantic concepts not existing in the reference image and requiring to be added into the target image, we learn the multi-modal concept alignment between the text modifier and the concatenation of reference and target images, under multiple-instance learning framework with image and sentence level weak supervision. Furthermore, based on aligned concepts, to form discriminative fusion features of the input modalities for accurate target image retrieval, we propose a progressive fusion strategy with unified execution architecture instantiated by the attended language semantic concepts. Our proposed approach is evaluated on three datasets and achieves state-of-the-art results.
Whole Slide Images (WSIs) present a challenging computer vision task due to their gigapixel size and presence of numerous artefacts. Yet they are a valuable resource for patient diagnosis and stratification, often representing the gold standard for diagnostic tasks. Real-world clinical datasets tend to come as sets of heterogeneous WSIs with labels present at the patient-level, with poor to no annotations. Weakly supervised attention-based multiple instance learning approaches have been developed in recent years to address these challenges, but can fail to resolve both long and short-range dependencies. Here we propose an end-to-end multi-stain self-attention graph (MUSTANG) multiple instance learning pipeline, which is designed to solve a weakly-supervised gigapixel multi-image classification task, where the label is assigned at the patient-level, but no slide-level labels or region annotations are available. The pipeline uses a self-attention based approach by restricting the operations to a highly sparse k-Nearest Neighbour Graph of embedded WSI patches based on the Euclidean distance. We show this approach achieves a state-of-the-art F1-score/AUC of 0.89/0.92, outperforming the widely used CLAM model. Our approach is highly modular and can easily be modified to suit different clinical datasets, as it only requires a patient-level label without annotations and accepts WSI sets of different sizes, as the graphs can be of varying sizes and structures. The source code can be found at https://github.com/AmayaGS/MUSTANG.
Although multiple instance learning (MIL) methods are widely used for automatic tumor detection on whole slide images (WSI), they suffer from the extreme class imbalance within the small tumor WSIs. This occurs when the tumor comprises only a few isolated cells. For early detection, it is of utmost importance that MIL algorithms can identify small tumors, even when they are less than 1% of the size of the WSI. Existing studies have attempted to address this issue using attention-based architectures and instance selection-based methodologies, but have not yielded significant improvements. This paper proposes cross-attention-based salient instance inference MIL (CASiiMIL), which involves a novel saliency-informed attention mechanism, to identify breast cancer lymph node micro-metastasis on WSIs without the need for any annotations. Apart from this new attention mechanism, we introduce a negative representation learning algorithm to facilitate the learning of saliency-informed attention weights for improved sensitivity on tumor WSIs. The proposed model outperforms the state-of-the-art MIL methods on two popular tumor metastasis detection datasets, and demonstrates great cross-center generalizability. In addition, it exhibits excellent accuracy in classifying WSIs with small tumor lesions. Moreover, we show that the proposed model has excellent interpretability attributed to the saliency-informed attention weights. We strongly believe that the proposed method will pave the way for training algorithms for early tumor detection on large datasets where acquiring fine-grained annotations is practically impossible.