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Register a new userDeep Interpretable Classification and Weakly-Supervised Segmentation of Histology Images via Max-Min Uncertainty
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Soufiane Belharbi
Publication date
2020
fields
Informatics Engineering
and research's language is
English
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Weakly-supervised learning (WSL) has recently triggered substantial interest as it mitigates the lack of pixel-wise annotations. Given global image labels, WSL methods yield pixel-level predictions (segmentations), which enable to interpret class predictions. Despite their recent success, mostly with natural images, such methods can face important challenges when the foreground and background regions have similar visual cues, yielding high false-positive rates in segmentations, as is the case in challenging histology images. WSL training is commonly driven by standard classification losses, which implicitly maximize model confidence, and locate the discriminative regions linked to classification decisions. Therefore, they lack mechanisms for modeling explicitly non-discriminative regions and reducing false-positive rates. We propose novel regularization terms, which enable the model to seek both non-discriminative and discriminative regions, while discouraging unbalanced segmentations. We introduce high uncertainty as a criterion to localize non-discriminative regions that do not affect classifier decision, and describe it with original Kullback-Leibler (KL) divergence losses evaluating the deviation of posterior predictions from the uniform distribution. Our KL terms encourage high uncertainty of the model when the latter inputs the latent non-discriminative regions. Our loss integrates: (i) a cross-entropy seeking a foreground, where model confidence about class prediction is high; (ii) a KL regularizer seeking a background, where model uncertainty is high; and (iii) log-barrier terms discouraging unbalanced segmentations. Comprehensive experiments and ablation studies over the public GlaS colon cancer data and a Camelyon16 patch-based benchmark for breast cancer show substantial improvements over state-of-the-art WSL methods, and confirm the effect of our new regularizers.
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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 .
In the last few years, deep learning classifiers have shown promising results in image-based medical diagnosis. However, interpreting the outputs of these models remains a challenge. In cancer diagnosis, interpretability can be achieved by localizing the region of the input image responsible for the output, i.e. the location of a lesion. Alternatively, segmentation or detection models can be trained with pixel-wise annotations indicating the locations of malignant lesions. Unfortunately, acquiring such labels is labor-intensive and requires medical expertise. To overcome this difficulty, weakly-supervised localization can be utilized. These methods allow neural network classifiers to output saliency maps highlighting the regions of the input most relevant to the classification task (e.g. malignant lesions in mammograms) using only image-level labels (e.g. whether the patient has cancer or not) during training. When applied to high-resolution images, existing methods produce low-resolution saliency maps. This is problematic in applications in which suspicious lesions are small in relation to the image size. In this work, we introduce a novel neural network architecture to perform weakly-supervised segmentation of high-resolution images. The proposed model selects regions of interest via coarse-level localization, and then performs fine-grained segmentation of those regions. We apply this model to breast cancer diagnosis with screening mammography, and validate it on a large clinically-realistic dataset. Measured by Dice similarity score, our approach outperforms existing methods by a large margin in terms of localization performance of benign and malignant lesions, relatively improving the performance by 39.6% and 20.0%, respectively. Code and the weights of some of the models are available at https://github.com/nyukat/GLAM
Medical images differ from natural images in significantly higher resolutions and smaller regions of interest. Because of these differences, neural network architectures that work well for natural images might not be applicable to medical image analysis. In this work, we extend the globally-aware multiple instance classifier, a framework we proposed to address these unique properties of medical images. This model first uses a low-capacity, yet memory-efficient, network on the whole image to identify the most informative regions. It then applies another higher-capacity network to collect details from chosen regions. Finally, it employs a fusion module that aggregates global and local information to make a final prediction. While existing methods often require lesion segmentation during training, our model is trained with only image-level labels and can generate pixel-level saliency maps indicating possible malignant findings. We apply the model to screening mammography interpretation: predicting the presence or absence of benign and malignant lesions. On the NYU Breast Cancer Screening Dataset, consisting of more than one million images, our model achieves an AUC of 0.93 in classifying breasts with malignant findings, outperforming ResNet-34 and Faster R-CNN. Compared to ResNet-34, our model is 4.1x faster for inference while using 78.4% less GPU memory. Furthermore, we demonstrate, in a reader study, that our model surpasses radiologist-level AUC by a margin of 0.11. The proposed model is available online: https://github.com/nyukat/GMIC.
The rapidly emerging field of deep learning-based computational pathology has demonstrated promise in developing objective prognostic models from histology whole slide images. However, most prognostic models are either based on histology or genomics alone and do not address how histology and genomics can be integrated to develop joint image-omic prognostic models. Additionally identifying explainable morphological and molecular descriptors from these models that govern such prognosis is of interest. We used multimodal deep learning to integrate gigapixel whole slide pathology images, RNA-seq abundance, copy number variation, and mutation data from 5,720 patients across 14 major cancer types. Our interpretable, weakly-supervised, multimodal deep learning algorithm is able to fuse these heterogeneous modalities for predicting outcomes and discover prognostic features from these modalities that corroborate with poor and favorable outcomes via multimodal interpretability. We compared our model with unimodal deep learning models trained on histology slides and molecular profiles alone, and demonstrate performance increase in risk stratification on 9 out of 14 cancers. In addition, we analyze morphologic and molecular markers responsible for prognostic predictions across all cancer types. All analyzed data, including morphological and molecular correlates of patient prognosis across the 14 cancer types at a disease and patient level are presented in an interactive open-access database (http://pancancer.mahmoodlab.org) to allow for further exploration and prognostic biomarker discovery. To validate that these model explanations are prognostic, we further analyzed high attention morphological regions in WSIs, which indicates that tumor-infiltrating lymphocyte presence corroborates with favorable cancer prognosis on 9 out of 14 cancer types studied.
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