Manually annotating nuclei from the gigapixel Hematoxylin and Eosin (H&E)-stained Whole Slide Images (WSIs) is a laborious and costly task, meaning automated algorithms for cell nuclei instance segmentation and classification could alleviate the workload of pathologists and clinical researchers and at the same time facilitate the automatic extraction of clinically interpretable features. But due to high intra- and inter-class variability of nuclei morphological and chromatic features, as well as H&E-stains susceptibility to artefacts, state-of-the-art algorithms cannot correctly detect and classify instances with the necessary performance. In this work, we hypothesise context and attention inductive biases in artificial neural networks (ANNs) could increase the generalization of algorithms for cell nuclei instance segmentation and classification. We conduct a thorough survey on context and attention methods for cell nuclei instance segmentation and classification from H&E-stained microscopy imaging, while providing a comprehensive discussion of the challenges being tackled with context and attention. Besides, we illustrate some limitations of current approaches and present ideas for future research. As a case study, we extend both a general instance segmentation and classification method (Mask-RCNN) and a tailored cell nuclei instance segmentation and classification model (HoVer-Net) with context- and attention-based mechanisms, and do a comparative analysis on a multi-centre colon nuclei identification and counting dataset. Although pathologists rely on context at multiple levels while paying attention to specific Regions of Interest (RoIs) when analysing and annotating WSIs, our findings suggest translating that domain knowledge into algorithm design is no trivial task, but to fully exploit these mechanisms, the scientific understanding of these methods should be addressed.

The success of supervised deep learning models in medical image segmentation relies on detailed annotations. However, labor-intensive manual labeling is costly and inefficient, especially in dense object segmentation. To this end, we propose a self-supervised learning based approach with a Prior Self-activation Module (PSM) that generates self-activation maps from the input images to avoid labeling costs and further produce pseudo masks for the downstream task. To be specific, we firstly train a neural network using self-supervised learning and utilize the gradient information in the shallow layers of the network to generate self-activation maps. Afterwards, a semantic-guided generator is then introduced as a pipeline to transform visual representations from PSM to pixel-level semantic pseudo masks for downstream tasks. Furthermore, a two-stage training module, consisting of a nuclei detection network and a nuclei segmentation network, is adopted to achieve the final segmentation. Experimental results show the effectiveness on two public pathological datasets. Compared with other fully-supervised and weakly-supervised methods, our method can achieve competitive performance without any manual annotations.

Two major causes of death in the United States and worldwide are stroke and myocardial infarction. The underlying cause of both is thrombi released from ruptured or eroded unstable atherosclerotic plaques that occlude vessels in the heart (myocardial infarction) or the brain (stroke). Clinical studies show that plaque composition plays a more important role than lesion size in plaque rupture or erosion events. To determine the plaque composition, various cell types in 3D cardiovascular immunofluorescent images of plaque lesions are counted. However, counting these cells manually is expensive, time-consuming, and prone to human error. These challenges of manual counting motivate the need for an automated approach to localize and count the cells in images. The purpose of this study is to develop an automatic approach to accurately detect and count cells in 3D immunofluorescent images with minimal annotation effort. In this study, we used a weakly supervised learning approach to train the HoVer-Net segmentation model using point annotations to detect nuclei in fluorescent images. The advantage of using point annotations is that they require less effort as opposed to pixel-wise annotation. To train the HoVer-Net model using point annotations, we adopted a popularly used cluster labeling approach to transform point annotations into accurate binary masks of cell nuclei. Traditionally, these approaches have generated binary masks from point annotations, leaving a region around the object unlabeled (which is typically ignored during model training). However, these areas may contain important information that helps determine the boundary between cells. Therefore, we used the entropy minimization loss function in these areas to encourage the model to output more confident predictions on the unlabeled areas. Our comparison studies indicate that the HoVer-Net model trained using our weakly ...

Cell nuclei detection is a challenging research topic because of limitations in cellular image quality and diversity of nuclear morphology, i.e. varying nuclei shapes, sizes, and overlaps between multiple cell nuclei. This has been a topic of enduring interest with promising recent success shown by deep learning methods. These methods train Convolutional Neural Networks (CNNs) with a training set of input images and known, labeled nuclei locations. Many such methods are supplemented by spatial or morphological processing. Using a set of canonical cell nuclei shapes, prepared with the help of a domain expert, we develop a new approach that we call Shape Priors with Convolutional Neural Networks (SP-CNN). We further extend the network to introduce a shape prior (SP) layer and then allowing it to become trainable (i.e. optimizable). We call this network tunable SP-CNN (TSP-CNN). In summary, we present new network structures that can incorporate 'expected behavior' of nucleus shapes via two components: learnable layers that perform the nucleus detection and a fixed processing part that guides the learning with prior information. Analytically, we formulate two new regularization terms that are targeted at: 1) learning the shapes, 2) reducing false positives while simultaneously encouraging detection inside the cell nucleus boundary. Experimental results on two challenging datasets reveal that the proposed SP-CNN and TSP-CNN can outperform state-of-the-art alternatives.

Detection of cell nuclei in microscopic images is a challenging research topic, because of limitations in cellular image quality and diversity of nuclear morphology, i.e. varying nuclei shapes, sizes, and overlaps between multiple cell nuclei. This has been a topic of enduring interest with promising recent success shown by deep learning methods. These methods train for example convolutional neural networks (CNNs) with a training set of input images and known, labeled nuclei locations. Many of these methods are supplemented by spatial or morphological processing. We develop a new approach that we call Shape Priors with Convolutional Neural Networks (SP-CNN) to perform significantly enhanced nuclei detection. A set of canonical shapes is prepared with the help of a domain expert. Subsequently, we present a new network structure that can incorporate `expected behavior' of nucleus shapes via two components: {\em learnable} layers that perform the nucleus detection and a {\em fixed} processing part that guides the learning with prior information. Analytically, we formulate a new regularization term that is targeted at penalizing false positives while simultaneously encouraging detection inside cell nucleus boundary. Experimental results on a challenging dataset reveal that SP-CNN is competitive with or outperforms several state-of-the-art methods.

Imagine unleashing the power of artificial intelligence to automate a critical component of biomedical research, expediting life-saving research in the treatment of almost every disease from rare disorders to the common cold. This could soon be a reality, thanks to the fourth Data Science Bowl, a 90-day competition in which, for the very first time, participants trained deep learning models to examine images of cells and identify nuclei, regardless of the experimental setup--and without human intervention. Algorithms developed in this competition could save researchers hundreds of thousands of hours of effort per year. This year, the competition brought together nearly 18,000 global participants, the most ever for the Data Science Bowl. Collectively, they submitted more than 68,000 algorithms and worked an estimated 288,000 hours to automate the vital, but time-consuming, process of nuclei detection.

Cell nuclei detection and fine-grained classification have been fundamental yet challenging problems in histopathology image analysis. Due to the nuclei tiny size, significant inter-/intra-class variances, as well as the inferior image quality, previous automated methods would easily suffer from limited accuracy and robustness. In the meanwhile, existing approaches usually deal with these two tasks independently, which would neglect the close relatedness of them. In this paper, we present a novel method of sibling fully convolutional network with prior objectness interaction (called SFCN-OPI) to tackle the two tasks simultaneously and interactively using a unified end-to-end framework. Specifically, the sibling FCN branches share features in earlier layers while holding respective higher layers for specific tasks. More importantly, the detection branch outputs the objectness prior which dynamically interacts with the fine-grained classification sibling branch during the training and testing processes. With this mechanism, the fine-grained classification successfully focuses on regions with high confidence of nuclei existence and outputs the conditional probability, which in turn benefits the detection through back propagation. Extensive experiments on colon cancer histology images have validated the effectiveness of our proposed SFCN-OPI and our method has outperformed the state-of-the-art methods by a large margin.