Quantifying Explainers of Graph Neural Networks in Computational Pathology

Explainability of deep learning methods is imperative to facilitate their clinical adoption in digital pathology. However, popular deep learning methods and explainability techniques (explainers) based on pixel-wise processing disregard biological entities' notion, thus complicating comprehension by pathologists. In this work, we address this by adopting biological entity-based graph processing and graph explainers enabling explanations accessible to pathologists. In this context, a major challenge becomes to discern meaningful explainers, particularly in a standardized and quantifiable fashion. To this end, we propose herein a set of novel quantitative metrics based on statistics of class separability using pathologically measurable concepts to characterize graph explainers. We employ the proposed metrics to evaluate three types of graph explainers, namely the layer-wise relevance propagation, gradient-based saliency, and graph pruning approaches, to explain Cell-Graph representations for Breast Cancer Subtyping. The proposed metrics are also applicable in other domains by using domain-specific intuitive concepts. We validate the qualitative and quantitative findings on the BRACS dataset, a large cohort of breast cancer RoIs, by expert pathologists.

Anomaly Detection on X-Rays Using Self-Supervised Aggregation Learning

Deep anomaly detection models using a supervised mode of learning usually work under a closed set assumption and suffer from overfitting to previously seen rare anomalies at training, which hinders their applicability in a real scenario. In addition, obtaining annotations for X-rays is very time consuming and requires extensive training of radiologists. Hence, training anomaly detection in a fully unsupervised or self-supervised fashion would be advantageous, allowing a significant reduction of time spent on the report by radiologists. In this paper, we present SALAD, an end-to-end deep self-supervised methodology for anomaly detection on X-Ray images. The proposed method is based on an optimization strategy in which a deep neural network is encouraged to represent prototypical local patterns of the normal data in the embedding space. During training, we record the prototypical patterns of normal training samples via a memory bank. Our anomaly score is then derived by measuring similarity to a weighted combination of normal prototypical patterns within a memory bank without using any anomalous patterns. We present extensive experiments on the challenging NIH Chest X-rays and MURA dataset, which indicate that our algorithm improves state-of-the-art methods by a wide margin.

CNN-Based Ultrasound Image Reconstruction for Ultrafast Displacement Tracking

Thanks to its capability of acquiring full-view frames at multiple kilohertz, ultrafast ultrasound imaging unlocked the analysis of rapidly changing physical phenomena in the human body, with pioneering applications such as ultrasensitive flow imaging in the cardiovascular system or shear-wave elastography. The accuracy achievable with these motion estimation techniques is strongly contingent upon two contradictory requirements: a high quality of consecutive frames and a high frame rate. Indeed, the image quality can usually be improved by increasing the number of steered ultrafast acquisitions, but at the expense of a reduced frame rate and possible motion artifacts. To achieve accurate motion estimation at uncompromised frame rates and immune to motion artifacts, the proposed approach relies on single ultrafast acquisitions to reconstruct high-quality frames and on only two consecutive frames to obtain 2-D displacement estimates. To this end, we deployed a convolutional neural network-based image reconstruction method combined with a speckle tracking algorithm based on cross-correlation. Numerical and in vivo experiments, conducted in the context of plane-wave imaging, demonstrate that the proposed approach is capable of estimating displacements in regions where the presence of side lobe and grating lobe artifacts prevents any displacement estimation with a state-of-the-art technique that rely on conventional delay-and-sum beamforming. The proposed approach may therefore unlock the full potential of ultrafast ultrasound, in applications such as ultrasensitive cardiovascular motion and flow analysis or shear-wave elastography.

CNN-Based Image Reconstruction Method for Ultrafast Ultrasound Imaging

Ultrafast ultrasound (US) revolutionized biomedical imaging with its capability of acquiring full-view frames at over 1 kHz, unlocking breakthrough modalities such as shear-wave elastography and functional US neuroimaging. Yet, it suffers from strong diffraction artifacts, mainly caused by grating lobes, side lobes, or edge waves. Multiple acquisitions are typically required to obtain a sufficient image quality, at the cost of a reduced frame rate. To answer the increasing demand for high-quality imaging from single-shot acquisitions, we propose a two-step convolutional neural network (CNN)-based image reconstruction method, compatible with real-time imaging. A low-quality estimate is obtained by means of a backprojection-based operation, akin to conventional delay-and-sum beamforming, from which a high-quality image is restored using a residual CNN with multi-scale and multi-channel filtering properties, trained specifically to remove the diffraction artifacts inherent to ultrafast US imaging. To account for both the high dynamic range and the radio frequency property of US images, we introduce the mean signed logarithmic absolute error (MSLAE) as training loss function. Experiments were conducted with a linear transducer array, in single plane wave (PW) imaging. Trainings were performed on a simulated dataset, crafted to contain a wide diversity of structures and echogenicities. Extensive numerical evaluations demonstrate that the proposed approach can reconstruct images from single PWs with a quality similar to that of gold-standard synthetic aperture imaging, on a dynamic range in excess of 60 dB. In vitro and in vivo experiments show that trainings performed on simulated data translate well to experimental settings.

Automated Detection of Cortical Lesions in Multiple Sclerosis Patients with 7T MRI

The automated detection of cortical lesions (CLs) in patients with multiple sclerosis (MS) is a challenging task that, despite its clinical relevance, has received very little attention. Accurate detection of the small and scarce lesions requires specialized sequences and high or ultra-high field MRI. For supervised training based on multimodal structural MRI at 7T, two experts generated ground truth segmentation masks of 60 patients with 2014 CLs. We implemented a simplified 3D U-Net with three resolution levels (3D U-Net-). By increasing the complexity of the task (adding brain tissue segmentation), while randomly dropping input channels during training, we improved the performance compared to the baseline. Considering a minimum lesion size of 0.75 {\mu}L, we achieved a lesion-wise cortical lesion detection rate of 67% and a false positive rate of 42%. However, 393 (24%) of the lesions reported as false positives were post-hoc confirmed as potential or definite lesions by an expert. This indicates the potential of the proposed method to support experts in the tedious process of CL manual segmentation.

Structure Preserving Stain Normalization of Histopathology Images Using Self-Supervised Semantic Guidance

Although generative adversarial network (GAN) based style transfer is state of the art in histopathology color-stain normalization, they do not explicitly integrate structural information of tissues. We propose a self-supervised approach to incorporate semantic guidance into a GAN based stain normalization framework and preserve detailed structural information. Our method does not require manual segmentation maps which is a significant advantage over existing methods. We integrate semantic information at different layers between a pre-trained semantic network and the stain color normalization network. The proposed scheme outperforms other color normalization methods leading to better classification and segmentation performance.

Divide-and-Rule: Self-Supervised Learning for Survival Analysis in Colorectal Cancer

With the long-term rapid increase in incidences of colorectal cancer (CRC), there is an urgent clinical need to improve risk stratification. The conventional pathology report is usually limited to only a few histopathological features. However, most of the tumor microenvironments used to describe patterns of aggressive tumor behavior are ignored. In this work, we aim to learn histopathological patterns within cancerous tissue regions that can be used to improve prognostic stratification for colorectal cancer. To do so, we propose a self-supervised learning method that jointly learns a representation of tissue regions as well as a metric of the clustering to obtain their underlying patterns. These histopathological patterns are then used to represent the interaction between complex tissues and predict clinical outcomes directly. We furthermore show that the proposed approach can benefit from linear predictors to avoid overfitting in patient outcomes predictions. To this end, we introduce a new well-characterized clinicopathological dataset, including a retrospective collective of 374 patients, with their survival time and treatment information. Histomorphological clusters obtained by our method are evaluated by training survival models. The experimental results demonstrate statistically significant patient stratification, and our approach outperformed the state-of-the-art deep clustering methods.

Benefitting from Bicubically Down-Sampled Images for Learning Real-World Image Super-Resolution

Super-resolution (SR) has traditionally been based on pairs of high-resolution images (HR) and their low-resolution (LR) counterparts obtained artificially with bicubic downsampling. However, in real-world SR, there is a large variety of realistic image degradations and analytically modeling these realistic degradations can prove quite difficult. In this work, we propose to handle real-world SR by splitting this ill-posed problem into two comparatively more well-posed steps. First, we train a network to transform real LR images to the space of bicubically downsampled images in a supervised manner, by using both real LR/HR pairs and synthetic pairs. Second, we take a generic SR network trained on bicubically downsampled images to super-resolve the transformed LR image. The first step of the pipeline addresses the problem by registering the large variety of degraded images to a common, well understood space of images. The second step then leverages the already impressive performance of SR on bicubically downsampled images, sidestepping the issues of end-to-end training on datasets with many different image degradations. We demonstrate the effectiveness of our proposed method by comparing it to recent methods in real-world SR and show that our proposed approach outperforms the state-of-the-art works in terms of both qualitative and quantitative results, as well as results of an extensive user study conducted on several real image datasets.

HACT-Net: A Hierarchical Cell-to-Tissue Graph Neural Network for Histopathological Image Classification

Cancer diagnosis, prognosis, and therapeutic response prediction are heavily influenced by the relationship between the histopathological structures and the function of the tissue. Recent approaches acknowledging the structure-function relationship, have linked the structural and spatial patterns of cell organization in tissue via cell-graphs to tumor grades. Though cell organization is imperative, it is insufficient to entirely represent the histopathological structure. We propose a novel hierarchical cell-to-tissue-graph (HACT) representation to improve the structural depiction of the tissue. It consists of a low-level cell-graph, capturing cell morphology and interactions, a high-level tissue-graph, capturing morphology and spatial distribution of tissue parts, and cells-to-tissue hierarchies, encoding the relative spatial distribution of the cells with respect to the tissue distribution. Further, a hierarchical graph neural network (HACT-Net) is proposed to efficiently map the HACT representations to histopathological breast cancer subtypes. We assess the methodology on a large set of annotated tissue regions of interest from H\&E stained breast carcinoma whole-slides. Upon evaluation, the proposed method outperformed recent convolutional neural network and graph neural network approaches for breast cancer multi-class subtyping. The proposed entity-based topological analysis is more inline with the pathological diagnostic procedure of the tissue. It provides more command over the tissue modelling, therefore encourages the further inclusion of pathological priors into task-specific tissue representation.

Towards Explainable Graph Representations in Digital Pathology

Explainability of machine learning (ML) techniques in digital pathology (DP) is of great significance to facilitate their wide adoption in clinics. Recently, graph techniques encoding relevant biological entities have been employed to represent and assess DP images. Such paradigm shift from pixel-wise to entity-wise analysis provides more control over concept representation. In this paper, we introduce a post-hoc explainer to derive compact per-instance explanations emphasizing diagnostically important entities in the graph. Although we focus our analyses to cells and cellular interactions in breast cancer subtyping, the proposed explainer is generic enough to be extended to other topological representations in DP. Qualitative and quantitative analyses demonstrate the efficacy of the explainer in generating comprehensive and compact explanations.