Multiple instance learning (MIL) models have achieved remarkable success in analyzing whole slide images (WSIs) for disease classification problems. However, with regard to gigapixel WSI classification problems, current MIL models are often incapable of differentiating a WSI with extremely small tumor lesions. This minute tumor-to-normal area ratio in a MIL bag inhibits the attention mechanism from properly weighting the areas corresponding to minor tumor lesions. To overcome this challenge, we propose salient instance inference MIL (SiiMIL), a weakly-supervised MIL model for WSI classification. Our method initially learns representations of normal WSIs, and it then compares the normal WSIs representations with all the input patches to infer the salient instances of the input WSI. Finally, it employs attention-based MIL to perform the slide-level classification based on the selected patches of the WSI. Our experiments imply that SiiMIL can accurately identify tumor instances, which could only take up less than 1% of a WSI, so that the ratio of tumor to normal instances within a bag can increase by two to four times. It is worth mentioning that it performs equally well for large tumor lesions. As a result, SiiMIL achieves a significant improvement in performance over the state-of-the-art MIL methods.
Prostate cancer is the most common cancer in men worldwide and the second leading cause of cancer death in the United States. One of the prognostic features in prostate cancer is the Gleason grading of histopathology images. The Gleason grade is assigned based on tumor architecture on Hematoxylin and Eosin (H&E) stained whole slide images (WSI) by the pathologists. This process is time-consuming and has known interobserver variability. In the past few years, deep learning algorithms have been used to analyze histopathology images, delivering promising results for grading prostate cancer. However, most of the algorithms rely on the fully annotated datasets which are expensive to generate. In this work, we proposed a novel weakly-supervised algorithm to classify prostate cancer grades. The proposed algorithm consists of three steps: (1) extracting discriminative areas in a histopathology image by employing the Multiple Instance Learning (MIL) algorithm based on Transformers, (2) representing the image by constructing a graph using the discriminative patches, and (3) classifying the image into its Gleason grades by developing a Graph Convolutional Neural Network (GCN) based on the gated attention mechanism. We evaluated our algorithm using publicly available datasets, including TCGAPRAD, PANDA, and Gleason 2019 challenge datasets. We also cross validated the algorithm on an independent dataset. Results show that the proposed model achieved state-of-the-art performance in the Gleason grading task in terms of accuracy, F1 score, and cohen-kappa. The code is available at https://github.com/NabaviLab/Prostate-Cancer.
Graph convolutional neural networks have shown significant potential in natural and histopathology images. However, their use has only been studied in a single magnification or multi-magnification with late fusion. In order to leverage the multi-magnification information and early fusion with graph convolutional networks, we handle different embedding spaces at each magnification by introducing the Multi-Scale Relational Graph Convolutional Network (MS-RGCN) as a multiple instance learning method. We model histopathology image patches and their relation with neighboring patches and patches at other scales (i.e., magnifications) as a graph. To pass the information between different magnification embedding spaces, we define separate message-passing neural networks based on the node and edge type. We experiment on prostate cancer histopathology images to predict the grade groups based on the extracted features from patches. We also compare our MS-RGCN with multiple state-of-the-art methods with evaluations on several source and held-out datasets. Our method outperforms the state-of-the-art on all of the datasets and image types consisting of tissue microarrays, whole-mount slide regions, and whole-slide images. Through an ablation study, we test and show the value of the pertinent design features of the MS-RGCN.
Attention-based multiple instance learning (AMIL) algorithms have proven to be successful in utilizing gigapixel whole-slide images (WSIs) for a variety of different computational pathology tasks such as outcome prediction and cancer subtyping problems. We extended an AMIL approach to the task of survival prediction by utilizing the classical Cox partial likelihood as a loss function, converting the AMIL model into a nonlinear proportional hazards model. We applied the model to tissue microarray (TMA) slides of 330 lung cancer patients. The results show that AMIL approaches can handle very small amounts of tissue from a TMA and reach similar C-index performance compared to established survival prediction methods trained with highly discriminative clinical factors such as age, cancer grade, and cancer stage
This paper presents the first attempt to learn semantic boundary detection using image-level class labels as supervision. Our method starts by estimating coarse areas of object classes through attentions drawn by an image classification network. Since boundaries will locate somewhere between such areas of different classes, our task is formulated as a multiple instance learning (MIL) problem, where pixels on a line segment connecting areas of two different classes are regarded as a bag of boundary candidates. Moreover, we design a new neural network architecture that can learn to estimate semantic boundaries reliably even with uncertain supervision given by the MIL strategy. Our network is used to generate pseudo semantic boundary labels of training images, which are in turn used to train fully supervised models. The final model trained with our pseudo labels achieves an outstanding performance on the SBD dataset, where it is as competitive as some of previous arts trained with stronger supervision.
The survival analysis on histological whole-slide images (WSIs) is one of the most important means to estimate patient prognosis. Although many weakly-supervised deep learning models have been developed for gigapixel WSIs, their potential is generally restricted by classical survival analysis rules and fully-supervised learning requirements. As a result, these models provide patients only with a completely-certain point estimation of time-to-event, and they could only learn from the labeled WSI data currently at a small scale. To tackle these problems, we propose a novel adversarial multiple instance learning (AdvMIL) framework. This framework is based on adversarial time-to-event modeling, and integrates the multiple instance learning (MIL) that is much necessary for WSI representation learning. It is a plug-and-play one, so that most existing MIL-based end-to-end methods can be easily upgraded by applying this framework, gaining the improved abilities of survival distribution estimation and semi-supervised learning. Our extensive experiments show that AdvMIL not only could often bring performance improvement to mainstream WSI survival analysis methods at a relatively low computational cost, but also enables these methods to effectively utilize unlabeled data via semi-supervised learning. Moreover, it is observed that AdvMIL could help improving the robustness of models against patch occlusion and two representative image noises. The proposed AdvMIL framework could promote the research of survival analysis in computational pathology with its novel adversarial MIL paradigm.
Video anomaly detection (VAD) -- commonly formulated as a multiple-instance learning problem in a weakly-supervised manner due to its labor-intensive nature -- is a challenging problem in video surveillance where the frames of anomaly need to be localized in an untrimmed video. In this paper, we first propose to utilize the ViT-encoded visual features from CLIP, in contrast with the conventional C3D or I3D features in the domain, to efficiently extract discriminative representations in the novel technique. We then model temporal dependencies and nominate the snippets of interest by leveraging our proposed Temporal Self-Attention (TSA). The ablation study confirms the effectiveness of TSA and ViT feature. The extensive experiments show that our proposed CLIP-TSA outperforms the existing state-of-the-art (SOTA) methods by a large margin on three commonly-used benchmark datasets in the VAD problem (UCF-Crime, ShanghaiTech Campus, and XD-Violence). Our source code is available at https://github.com/joos2010kj/CLIP-TSA.
Image-text multimodal representation learning aligns data across modalities and enables important medical applications, e.g., image classification, visual grounding, and cross-modal retrieval. In this work, we establish a connection between multimodal representation learning and multiple instance learning. Based on this connection, we propose a generic framework for constructing permutation-invariant score functions with many existing multimodal representation learning approaches as special cases. Furthermore, we use the framework to derive a novel contrastive learning approach and demonstrate that our method achieves state-of-the-art results in several downstream tasks.
Whole slide images (WSI) are microscopy images of stained tissue slides routinely prepared for diagnosis and treatment selection in medical practice. WSI are very large (gigapixel size) and complex (made of up to millions of cells). The current state-of-the-art (SoTA) approach to classify WSI subdivides them into tiles, encodes them by pre-trained networks and applies Multiple Instance Learning (MIL) to train for specific downstream tasks. However, annotated datasets are often small, typically a few hundred to a few thousand WSI, which may cause overfitting and underperforming models. Conversely, the number of unannotated WSI is ever increasing, with datasets of tens of thousands (soon to be millions) of images available. While it has been previously proposed to use these unannotated data to identify suitable tile representations by self-supervised learning (SSL), downstream classification tasks still require full supervision because parts of the MIL architecture is not trained during tile level SSL pre-training. Here, we propose a strategy of slide level SSL to leverage the large number of WSI without annotations to infer powerful slide representations. Applying our method to The Cancer-Genome Atlas, one of the most widely used data resources in cancer research (16 TB image data), we are able to downsize the dataset to 23 MB without any loss in predictive power: we show that a linear classifier trained on top of these embeddings maintains or improves previous SoTA performances on various benchmark WSI classification tasks. Finally, we observe that training a classifier on these representations with tiny datasets (e.g. 50 slides) improved performances over SoTA by an average of +6.3 AUC points over all downstream tasks.
Whole-slide images (WSI) in computational pathology have high resolution with gigapixel size, but are generally with sparse regions of interest, which leads to weak diagnostic relevance and data inefficiency for each area in the slide. Most of the existing methods rely on a multiple instance learning framework that requires densely sampling local patches at high magnification. The limitation is evident in the application stage as the heavy computation for extracting patch-level features is inevitable. In this paper, we develop RLogist, a benchmarking deep reinforcement learning (DRL) method for fast observation strategy on WSIs. Imitating the diagnostic logic of human pathologists, our RL agent learns how to find regions of observation value and obtain representative features across multiple resolution levels, without having to analyze each part of the WSI at the high magnification. We benchmark our method on two whole-slide level classification tasks, including detection of metastases in WSIs of lymph node sections, and subtyping of lung cancer. Experimental results demonstrate that RLogist achieves competitive classification performance compared to typical multiple instance learning algorithms, while having a significantly short observation path. In addition, the observation path given by RLogist provides good decision-making interpretability, and its ability of reading path navigation can potentially be used by pathologists for educational/assistive purposes. Our code is available at: \url{https://github.com/tencent-ailab/RLogist}.
Learning good representation of giga-pixel level whole slide pathology images (WSI) for downstream tasks is critical. Previous studies employ multiple instance learning (MIL) to represent WSIs as bags of sampled patches because, for most occasions, only slide-level labels are available, and only a tiny region of the WSI is disease-positive area. However, WSI representation learning still remains an open problem due to: (1) patch sampling on a higher resolution may be incapable of depicting microenvironment information such as the relative position between the tumor cells and surrounding tissues, while patches at lower resolution lose the fine-grained detail; (2) extracting patches from giant WSI results in large bag size, which tremendously increases the computational cost. To solve the problems, this paper proposes a hierarchical-based multimodal transformer framework that learns a hierarchical mapping between pathology images and corresponding genes. Precisely, we randomly extract instant-level patch features from WSIs with different magnification. Then a co-attention mapping between imaging and genomics is learned to uncover the pairwise interaction and reduce the space complexity of imaging features. Such early fusion makes it computationally feasible to use MIL Transformer for the survival prediction task. Our architecture requires fewer GPU resources compared with benchmark methods while maintaining better WSI representation ability. We evaluate our approach on five cancer types from the Cancer Genome Atlas database and achieved an average c-index of $0.673$, outperforming the state-of-the-art multimodality methods.
Multi-Instance Learning (MIL) is a recent machine learning paradigm which is immensely useful in various real-life applications, like image analysis, video anomaly detection, text classification, etc. It is well known that most of the existing machine learning classifiers are highly vulnerable to adversarial perturbations. Since MIL is a weakly supervised learning, where information is available for a set of instances, called bag and not for every instances, adversarial perturbations can be fatal. In this paper, we have proposed two adversarial perturbation methods to analyze the effect of adversarial perturbations to interpret the vulnerability of MIL methods. Out of the two algorithms, one can be customized for every bag, and the other is a universal one, which can affect all bags in a given data set and thus has some generalizability. Through simulations, we have also shown the effectiveness of the proposed algorithms to fool the state-of-the-art (SOTA) MIL methods. Finally, we have discussed through experiments, about taking care of these kind of adversarial perturbations through a simple strategy. Source codes are available at https://github.com/InkiInki/MI-UAP.
Modern machine learning pipelines, in particular those based on deep learning (DL) models, require large amounts of labeled data. For classification problems, the most common learning paradigm consists of presenting labeled examples during training, thus providing strong supervision on what constitutes positive and negative samples. This constitutes a major obstacle for the development of DL models in radiology--in particular for cross-sectional imaging (e.g., computed tomography [CT] scans)--where labels must come from manual annotations by expert radiologists at the image or slice-level. These differ from examination-level annotations, which are coarser but cheaper, and could be extracted from radiology reports using natural language processing techniques. This work studies the question of what kind of labels should be collected for the problem of intracranial hemorrhage detection in brain CT. We investigate whether image-level annotations should be preferred to examination-level ones. By framing this task as a multiple instance learning problem, and employing modern attention-based DL architectures, we analyze the degree to which different levels of supervision improve detection performance. We find that strong supervision (i.e., learning with local image-level annotations) and weak supervision (i.e., learning with only global examination-level labels) achieve comparable performance in examination-level hemorrhage detection (the task of selecting the images in an examination that show signs of hemorrhage) as well as in image-level hemorrhage detection (highlighting those signs within the selected images). Furthermore, we study this behavior as a function of the number of labels available during training. Our results suggest that local labels may not be necessary at all for these tasks, drastically reducing the time and cost involved in collecting and curating datasets.
Land cover classification (LCC), and monitoring how land use changes over time, is an important process in climate change mitigation and adaptation. Existing approaches that use machine learning with Earth observation data for LCC rely on fully-annotated and segmented datasets. Creating these datasets requires a large amount of effort, and a lack of suitable datasets has become an obstacle in scaling the use of LCC. In this study, we propose Scene-to-Patch models: an alternative LCC approach utilising Multiple Instance Learning (MIL) that requires only high-level scene labels. This enables much faster development of new datasets whilst still providing segmentation through patch-level predictions, ultimately increasing the accessibility of using LCC for different scenarios. On the DeepGlobe-LCC dataset, our approach outperforms non-MIL baselines on both scene- and patch-level prediction. This work provides the foundation for expanding the use of LCC in climate change mitigation methods for technology, government, and academia.
In digital pathology, Whole Slide Image (WSI) analysis is usually formulated as a Multiple Instance Learning (MIL) problem. Although transformer-based architectures have been used for WSI classification, these methods require modifications to adapt them to specific challenges of this type of image data. Among these challenges is the amount of memory and compute required by deep transformer models to process long inputs, such as the thousands of image patches that can compose a WSI at $\times 10$ or $\times 20$ magnification. We introduce \textit{SeqShort}, a multi-head attention-based sequence shortening layer to summarize each WSI in a fixed- and short-sized sequence of instances, that allows us to reduce the computational costs of self-attention on long sequences, and to include positional information that is unavailable in other MIL approaches. Furthermore, we show that WSI classification performance can be improved when the downstream transformer architecture has been pre-trained on a large corpus of text data, and only fine-tuning less than 0.1\% of its parameters. We demonstrate the effectiveness of our method in lymph node metastases classification and cancer subtype classification tasks, without the need of designing a WSI-specific transformer nor doing in-domain pre-training, keeping a reduced compute budget and low number of trainable parameters.
Multiple instance learning exhibits a powerful approach for whole slide image-based diagnosis in the absence of pixel- or patch-level annotations. In spite of the huge size of hole slide images, the number of individual slides is often rather small, leading to a small number of labeled samples. To improve training, we propose and investigate different data augmentation strategies for multiple instance learning based on the idea of linear interpolations of feature vectors (known as MixUp). Based on state-of-the-art multiple instance learning architectures and two thyroid cancer data sets, an exhaustive study is conducted considering a range of common data augmentation strategies. Whereas a strategy based on to the original MixUp approach showed decreases in accuracy, the use of a novel intra-slide interpolation method led to consistent increases in accuracy.
Image analysis and machine learning algorithms operating on multi-gigapixel whole-slide images (WSIs) often process a large number of tiles (sub-images) and require aggregating predictions from the tiles in order to predict WSI-level labels. In this paper, we present a review of existing literature on various types of aggregation methods with a view to help guide future research in the area of computational pathology (CPath). We propose a general CPath workflow with three pathways that consider multiple levels and types of data and the nature of computation to analyse WSIs for predictive modelling. We categorize aggregation methods according to the context and representation of the data, features of computational modules and CPath use cases. We compare and contrast different methods based on the principle of multiple instance learning, perhaps the most commonly used aggregation method, covering a wide range of CPath literature. To provide a fair comparison, we consider a specific WSI-level prediction task and compare various aggregation methods for that task. Finally, we conclude with a list of objectives and desirable attributes of aggregation methods in general, pros and cons of the various approaches, some recommendations and possible future directions.
Multiple Instance Learning (MIL) is a widely employed framework for learning on gigapixel whole-slide images (WSIs) from WSI-level annotations. In most MIL based analytical pipelines for WSI-level analysis, the WSIs are often divided into patches and deep features for patches (i.e., patch embeddings) are extracted prior to training to reduce the overall computational cost and cope with the GPUs' limited RAM. To overcome this limitation, we present EmbAugmenter, a data augmentation generative adversarial network (DA-GAN) that can synthesize data augmentations in the embedding space rather than in the pixel space, thereby significantly reducing the computational requirements. Experiments on the SICAPv2 dataset show that our approach outperforms MIL without augmentation and is on par with traditional patch-level augmentation for MIL training while being substantially faster.
High-resolution images are prevalent in various applications, such as autonomous driving and computer-aided diagnosis. However, training neural networks on such images is computationally challenging and easily leads to out-of-memory errors even on modern GPUs. We propose a simple method, Iterative Patch Selection (IPS), which decouples the memory usage from the input size and thus enables the processing of arbitrarily large images under tight hardware constraints. IPS achieves this by selecting only the most salient patches, which are then aggregated into a global representation for image recognition. For both patch selection and aggregation, a cross-attention based transformer is introduced, which exhibits a close connection to Multiple Instance Learning. Our method demonstrates strong performance and has wide applicability across different domains, training regimes and image sizes while using minimal accelerator memory. For example, we are able to finetune our model on whole-slide images consisting of up to 250k patches (>16 gigapixels) with only 5 GB of GPU VRAM at a batch size of 16.
Learning representations for individual instances when only bag-level labels are available is a fundamental challenge in multiple instance learning (MIL). Recent works have shown promising results using contrastive self-supervised learning (CSSL), which learns to push apart representations corresponding to two different randomly-selected instances. Unfortunately, in real-world applications such as medical image classification, there is often class imbalance, so randomly-selected instances mostly belong to the same majority class, which precludes CSSL from learning inter-class differences. To address this issue, we propose a novel framework, Iterative Self-paced Supervised Contrastive Learning for MIL Representations (ItS2CLR), which improves the learned representation by exploiting instance-level pseudo labels derived from the bag-level labels. The framework employs a novel self-paced sampling strategy to ensure the accuracy of pseudo labels. We evaluate ItS2CLR on three medical datasets, showing that it improves the quality of instance-level pseudo labels and representations, and outperforms existing MIL methods in terms of both bag and instance level accuracy. Code is available at https://github.com/Kangningthu/ItS2CLR