Confocal fluorescence microscopy is one of the most accessible and widely used imaging techniques for the study of biological processes. Scanning confocal microscopy allows the capture of high-quality images from 3D samples, yet suffers from well-known limitations such as photobleaching and phototoxicity of specimens caused by intense light exposure, which limits its use in some applications, especially for living cells. Cellular damage can be alleviated by changing imaging parameters to reduce light exposure, often at the expense of image quality. Machine/deep learning methods for single-image super-resolution (SISR) can be applied to restore image quality by upscaling lower-resolution (LR) images to produce high-resolution images (HR). These SISR methods have been successfully applied to photo-realistic images due partly to the abundance of publicly available data. In contrast, the lack of publicly available data partly limits their application and success in scanning confocal microscopy. In this paper, we introduce a large scanning confocal microscopy dataset named SR-CACO-2 that is comprised of low- and high-resolution image pairs marked for three different fluorescent markers. It allows the evaluation of performance of SISR methods on three different upscaling levels (X2, X4, X8). SR-CACO-2 contains the human epithelial cell line Caco-2 (ATCC HTB-37), and it is composed of 22 tiles that have been translated in the form of 9,937 image patches for experiments with SISR methods. Given the new SR-CACO-2 dataset, we also provide benchmarking results for 15 state-of-the-art methods that are representative of the main SISR families. Results show that these methods have limited success in producing high-resolution textures, indicating that SR-CACO-2 represents a challenging problem. Our dataset, code and pretrained weights are available: https://github.com/sbelharbi/sr-caco-2.

Given the emergence of deep learning, digital pathology has gained popularity for cancer diagnosis based on histology images. Deep weakly supervised object localization (WSOL) models can be trained to classify histology images according to cancer grade and identify regions of interest (ROIs) for interpretation, using inexpensive global image-class annotations. A WSOL model initially trained on some labeled source image data can be adapted using unlabeled target data in cases of significant domain shifts caused by variations in staining, scanners, and cancer type. In this paper, we focus on source-free (unsupervised) domain adaptation (SFDA), a challenging problem where a pre-trained source model is adapted to a new target domain without using any source domain data for privacy and efficiency reasons. SFDA of WSOL models raises several challenges in histology, most notably because they are not intended to adapt for both classification and localization tasks. In this paper, 4 state-of-the-art SFDA methods, each one representative of a main SFDA family, are compared for WSOL in terms of classification and localization accuracy. They are the SFDA-Distribution Estimation, Source HypOthesis Transfer, Cross-Domain Contrastive Learning, and Adaptively Domain Statistics Alignment. Experimental results on the challenging Glas (smaller, breast cancer) and Camelyon16 (larger, colon cancer) histology datasets indicate that these SFDA methods typically perform poorly for localization after adaptation when optimized for classification.

Using deep learning models to diagnose cancer from histology data presents several challenges. Cancer grading and localization of regions of interest (ROIs) in these images normally relies on both image- and pixel-level labels, the latter requiring a costly annotation process. Deep weakly-supervised object localization (WSOL) methods provide different strategies for low-cost training of deep learning models. Using only image-class annotations, these methods can be trained to classify an image, and yield class activation maps (CAMs) for ROI localization. This paper provides a review of state-of-art DL methods for WSOL. We propose a taxonomy where these methods are divided into bottom-up and top-down methods according to the information flow in models. Although the latter have seen limited progress, recent bottom-up methods are currently driving much progress with deep WSOL methods. Early works focused on designing different spatial pooling functions. However, these methods reached limited localization accuracy, and unveiled a major limitation -- the under-activation of CAMs which leads to high false negative localization. Subsequent works aimed to alleviate this issue and recover complete object. Representative methods from our taxonomy are evaluated and compared in terms of classification and localization accuracy on two challenging histology datasets. Overall, the results indicate poor localization performance, particularly for generic methods that were initially designed to process natural images. Methods designed to address the challenges of histology data yielded good results. However, all methods suffer from high false positive/negative localization. Four key challenges are identified for the application of deep WSOL methods in histology -- under/over activation of CAMs, sensitivity to thresholding, and model selection.

Weakly supervised object localization (WSOL) models aim to locate objects of interest in an image after being trained only on data with coarse image level labels. Deep learning models for WSOL rely typically on convolutional attention maps with no constraints on the regions of interest which allows them to select any region, making them vulnerable to false positive regions. This issue occurs in many application domains, e.g., medical image analysis, where interpretability is central to the prediction. In order to improve the localization reliability, we propose a deep learning framework for WSOL with pixel level localization. It is composed of two sequential sub-networks: a localizer that localizes regions of interest; followed by a classifier that classifies them. Within its end-to-end training, we incorporate the prior knowledge stating that in an agnostic-class setup an image is more likely to contain relevant --object of interest-- and irrelevant regions --noise--. Based on the conditional entropy (CE) measured at the classifier, the localizer is driven to spot relevant regions (low CE), and irrelevant regions (high CE). Our framework is able to recover large discriminative regions using our recursive erasing algorithm that we incorporate within the backpropagation during training. Moreover, the framework handles intrinsically multi-instances. Experimental results on public datasets with medical images (GlaS colon cancer) and natural images (Caltech-UCSD Birds-200-2011, Oxford flower 102) show that, compared to state of the art WSOL methods, our framework can provide significant improvements in terms of image-level classification, pixel-level localization, and robustness to overfitting when dealing with few training samples. A public reproducible PyTorch implementation is provided in: https://github.com/sbelharbi/wsol-min-max-entropy-interpretability .