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Classification and Disease Localization in Histopathology Using Only Global Labels: A Weakly-Supervised Approach

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 Added by Eric Tramel
 Publication date 2018
and research's language is English




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Analysis of histopathology slides is a critical step for many diagnoses, and in particular in oncology where it defines the gold standard. In the case of digital histopathological analysis, highly trained pathologists must review vast whole-slide-images of extreme digital resolution ($100,000^2$ pixels) across multiple zoom levels in order to locate abnormal regions of cells, or in some cases single cells, out of millions. The application of deep learning to this problem is hampered not only by small sample sizes, as typical datasets contain only a few hundred samples, but also by the generation of ground-truth localized annotations for training interpretable classification and segmentation models. We propose a method for disease localization in the context of weakly supervised learning, where only image-level labels are available during training. Even without pixel-level annotations, we are able to demonstrate performance comparable with models trained with strong annotations on the Camelyon-16 lymph node metastases detection challenge. We accomplish this through the use of pre-trained deep convolutional networks, feature embedding, as well as learning via top instances and negative evidence, a multiple instance learning technique from the field of semantic segmentation and object detection.



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We demonstrate the use of an extensive deep neural network to localize instances of objects in images. The EDNN is naturally able to accurately perform multi-class counting using only ground truth count values as labels. Without providing any conceptual information, object annotations, or pixel segmentation information, the neural network is able to formulate its own conceptual representation of the items in the image. Using images labelled with only the counts of the objects present,the structure of the extensive deep neural network can be exploited to perform localization of the objects within the visual field. We demonstrate that a trained EDNN can be used to count objects in images much larger than those on which it was trained. In order to demonstrate our technique, we introduce seven new data sets: five progressively harder MNIST digit-counting data sets, and two datasets of 3d-rendered rubber ducks in various situations. On most of these datasets, the EDNN achieves greater than 99% test set accuracy in counting objects.
To enable a deep learning-based system to be used in the medical domain as a computer-aided diagnosis system, it is essential to not only classify diseases but also present the locations of the diseases. However, collecting instance-level annotations for various thoracic diseases is expensive. Therefore, weakly supervised localization methods have been proposed that use only image-level annotation. While the previous methods presented the disease location as the most discriminative part for classification, this causes a deep network to localize wrong areas for indistinguishable X-ray images. To solve this issue, we propose a spatial attention method using disease masks that describe the areas where diseases mainly occur. We then apply the spatial attention to find the precise disease area by highlighting the highest probability of disease occurrence. Meanwhile, the various sizes, rotations and noise in chest X-ray images make generating the disease masks challenging. To reduce the variation among images, we employ an alignment module to transform an input X-ray image into a generalized image. Through extensive experiments on the NIH-Chest X-ray dataset with eight kinds of diseases, we show that the proposed method results in superior localization performances compared to state-of-the-art methods.
Using state-of-the-art deep learning models for cancer diagnosis presents several challenges related to the nature and availability of labeled histology images. In particular, cancer grading and localization in these images normally relies on both image- and pixel-level labels, the latter requiring a costly annotation process. In this survey, deep weakly-supervised learning (WSL) models are investigated to identify and locate diseases in histology images, without the need for pixel-level annotations. Given training data with global image-level labels, these models allow to simultaneously classify histology images and yield pixel-wise localization scores, thereby identifying the corresponding regions of interest (ROI). Since relevant WSL models have mainly been investigated within the computer vision community, and validated on natural scene images, we assess the extent to which they apply to histology images which have challenging properties, e.g. very large size, similarity between foreground/background, highly unstructured regions, stain heterogeneity, and noisy/ambiguous labels. The most relevant models for deep WSL are compared experimentally in terms of accuracy (classification and pixel-wise localization) on several public benchmark histology datasets for breast and colon cancer -- BACH ICIAR 2018, BreaKHis, CAMELYON16, and GlaS. Furthermore, for large-scale evaluation of WSL models on histology images, we propose a protocol to construct WSL datasets from Whole Slide Imaging. Results indicate that several deep learning models can provide a high level of classification accuracy, although accurate pixel-wise localization of cancer regions remains an issue for such images. Code is publicly available.
Pointwise localization allows more precise localization and accurate interpretability, compared to bounding box, in applications where objects are highly unstructured such as in medical domain. In this work, we focus on weakly supervised localization (WSL) where a model is trained to classify an image and localize regions of interest at pixel-level using only global image annotation. Typical convolutional attentions maps are prune to high false positive regions. To alleviate this issue, we propose a new deep learning method for WSL, composed of a localizer and a classifier, where the localizer is constrained to determine relevant and irrelevant regions using conditional entropy (CE) with the aim to reduce false positive regions. Experimental results on a public medical dataset and two natural datasets, using Dice index, show that, compared to state of the art WSL methods, our proposal can provide significant improvements in terms of image-level classification and pixel-level localization (low false positive) with robustness to overfitting. A public reproducible PyTorch implementation is provided in: https://github.com/sbelharbi/wsol-min-max-entropy-interpretability .
Weakly Supervised Object Localization (WSOL) methodsusually rely on fully convolutional networks in order to ob-tain class activation maps(CAMs) of targeted labels. How-ever, these networks always highlight the most discriminativeparts to perform the task, the located areas are much smallerthan entire targeted objects. In this work, we propose a novelend-to-end model to enlarge CAMs generated from classifi-cation models, which can localize targeted objects more pre-cisely. In detail, we add an additional module in traditionalclassification networks to extract foreground object propos-als from images without classifying them into specific cate-gories. Then we set these normalized regions as unrestrictedpixel-level mask supervision for the following classificationtask. We collect a set of images defined as Background ImageSet from the Internet. The number of them is much smallerthan the targeted dataset but surprisingly well supports themethod to extract foreground regions from different pictures.The region extracted is independent from classification task,where the extracted region in each image covers almost en-tire object rather than just a significant part. Therefore, theseregions can serve as masks to supervise the response mapgenerated from classification models to become larger andmore precise. The method achieves state-of-the-art results onCUB-200-2011 in terms of Top-1 and Top-5 localization er-ror while has a competitive result on ILSVRC2016 comparedwith other approaches.

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