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RMDL: Recalibrated multi-instance deep learning for whole slide gastric image classification

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 Added by Shujun Wang
 Publication date 2020
and research's language is English




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The whole slide histopathology images (WSIs) play a critical role in gastric cancer diagnosis. However, due to the large scale of WSIs and various sizes of the abnormal area, how to select informative regions and analyze them are quite challenging during the automatic diagnosis process. The multi-instance learning based on the most discriminative instances can be of great benefit for whole slide gastric image diagnosis. In this paper, we design a recalibrated multi-instance deep learning method (RMDL) to address this challenging problem. We first select the discriminative instances, and then utilize these instances to diagnose diseases based on the proposed RMDL approach. The designed RMDL network is capable of capturing instance-wise dependencies and recalibrating instance features according to the importance coefficient learned from the fused features. Furthermore, we build a large whole-slide gastric histopathology image dataset with detailed pixel-level annotations. Experimental results on the constructed gastric dataset demonstrate the significant improvement on the accuracy of our proposed framework compared with other state-of-the-art multi-instance learning methods. Moreover, our method is general and can be extended to other diagnosis tasks of different cancer types based on WSIs.



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Multiple instance learning (MIL) is the preferred approach for whole slide image classification. However, most MIL approaches do not exploit the interdependencies of tiles extracted from a whole slide image, which could provide valuable cues for classification. This paper presents a novel MIL approach that exploits the spatial relationship of tiles for classifying whole slide images. To do so, a sparse map is built from tiles embeddings, and is then classified by a sparse-input CNN. It obtained state-of-the-art performance over popular MIL approaches on the classification of cancer subtype involving 10000 whole slide images. Our results suggest that the proposed approach might (i) improve the representation learning of instances and (ii) exploit the context of instance embeddings to enhance the classification performance. The code of this work is open-source at {github censored for review}.
Weak supervision learning on classification labels has demonstrated high performance in various tasks. When a few pixel-level fine annotations are also affordable, it is natural to leverage both of the pixel-level (e.g., segmentation) and image level (e.g., classification) annotation to further improve the performance. In computational pathology, however, such weak or mixed supervision learning is still a challenging task, since the high resolution of whole slide images makes it unattainable to perform end-to-end training of classification models. An alternative approach is to analyze such data by patch-base model training, i.e., using self-supervised learning to generate pixel-level pseudo labels for patches. However, such methods usually have model drifting issues, i.e., hard to converge, because the noise accumulates during the self-training process. To handle those problems, we propose a mixed supervision learning framework for super high-resolution images to effectively utilize their various labels (e.g., sufficient image-level coarse annotations and a few pixel-level fine labels). During the patch training stage, this framework can make use of coarse image-level labels to refine self-supervised learning and generate high-quality pixel-level pseudo labels. A comprehensive strategy is proposed to suppress pixel-level false positives and false negatives. Three real-world datasets with very large number of images (i.e., more than 10,000 whole slide images) and various types of labels are used to evaluate the effectiveness of mixed supervision learning. We reduced the false positive rate by around one third compared to state of the art while retaining 100% sensitivity, in the task of image-level classification.
Convolutional Neural Networks (CNN) are state-of-the-art models for many image classification tasks. However, to recognize cancer subtypes automatically, training a CNN on gigapixel resolution Whole Slide Tissue Images (WSI) is currently computationally impossible. The differentiation of cancer subtypes is based on cellular-level visual features observed on image patch scale. Therefore, we argue that in this situation, training a patch-level classifier on image patches will perform better than or similar to an image-level classifier. The challenge becomes how to intelligently combine patch-level classification results and model the fact that not all patches will be discriminative. We propose to train a decision fusion model to aggregate patch-level predictions given by patch-level CNNs, which to the best of our knowledge has not been shown before. Furthermore, we formulate a novel Expectation-Maximization (EM) based method that automatically locates discriminative patches robustly by utilizing the spatial relationships of patches. We apply our method to the classification of glioma and non-small-cell lung carcinoma cases into subtypes. The classification accuracy of our method is similar to the inter-observer agreement between pathologists. Although it is impossible to train CNNs on WSIs, we experimentally demonstrate using a comparable non-cancer dataset of smaller images that a patch-based CNN can outperform an image-based CNN.
Existing deep learning methods for diagnosis of gastric cancer commonly use convolutional neural network. Recently, the Visual Transformer has attracted great attention because of its performance and efficiency, but its applications are mostly in the field of computer vision. In this paper, a multi-scale visual transformer model, referred to as GasHis-Transformer, is proposed for Gastric Histopathological Image Classification (GHIC), which enables the automatic classification of microscopic gastric images into abnormal and normal cases. The GasHis-Transformer model consists of two key modules: A global information module and a local information module to extract histopathological features effectively. In our experiments, a public hematoxylin and eosin (H&E) stained gastric histopathological dataset with 280 abnormal and normal images are divided into training, validation and test sets by a ratio of 1 : 1 : 2. The GasHis-Transformer model is applied to estimate precision, recall, F1-score and accuracy on the test set of gastric histopathological dataset as 98.0%, 100.0%, 96.0% and 98.0%, respectively. Furthermore, a critical study is conducted to evaluate the robustness of GasHis-Transformer, where ten different noises including four adversarial attack and six conventional image noises are added. In addition, a clinically meaningful study is executed to test the gastrointestinal cancer identification performance of GasHis-Transformer with 620 abnormal images and achieves 96.8% accuracy. Finally, a comparative study is performed to test the generalizability with both H&E and immunohistochemical stained images on a lymphoma image dataset and a breast cancer dataset, producing comparable F1-scores (85.6% and 82.8%) and accuracies (83.9% and 89.4%), respectively. In conclusion, GasHisTransformer demonstrates high classification performance and shows its significant potential in the GHIC task.
Automated whole slide image (WSI) tagging has become a growing demand due to the increasing volume and diversity of WSIs collected nowadays in histopathology. Various methods have been studied to classify WSIs with single tags but none of them focuses on labeling WSIs with multiple tags. To this end, we propose a novel end-to-end trainable deep neural network named Patch Transformer which can effectively predict multiple slide-level tags from WSI patches based on both the correlations and the uniqueness between the tags. Specifically, the proposed method learns patch characteristics considering 1) patch-wise relations through a patch transformation module and 2) tag-wise uniqueness for each tagging task through a multi-tag attention module. Extensive experiments on a large and diverse dataset consisting of 4,920 WSIs prove the effectiveness of the proposed model.
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