Thomas Lampert

Jelica Vasiljević, Friedrich Feuerhake, Cédric Wemmert et al.

Virtual stain transfer is a promising area of research in Computational Pathology, which has a great potential to alleviate important limitations when applying deeplearningbased solutions such as lack of annotations and sensitivity to a domain shift. However, in the literature, the majority of virtual staining approaches are trained for a specific staining or stain combination, and their extension to unseen stainings requires the acquisition of additional data and training. In this paper, we propose HistoStarGAN, a unified framework that performs stain transfer between multiple stainings, stain normalisation and stain invariant segmentation, all in one inference of the model. We demonstrate the generalisation abilities of the proposed solution to perform diverse stain transfer and accurate stain invariant segmentation over numerous unseen stainings, which is the first such demonstration in the field. Moreover, the pre-trained HistoStar-GAN model can serve as a synthetic data generator, which paves the way for the use of fully annotated synthetic image data to improve the training of deep learning-based algorithms. To illustrate the capabilities of our approach, as well as the potential risks in the microscopy domain, inspired by applications in natural images, we generated KidneyArtPathology, a fully annotated artificial image dataset for renal pathology.

Zeeshan Nisar, Jelica Vasiljević, Pierre Gançarski et al.

Domain shift in digital histopathology can occur when different stains or scanners are used, during stain translation, etc. A deep neural network trained on source data may not generalise well to data that has undergone some domain shift. An important step towards being robust to domain shift is the ability to detect and measure it. This article demonstrates that the PixelCNN and domain shift metric can be used to detect and quantify domain shift in digital histopathology, and they demonstrate a strong correlation with generalisation performance. These findings pave the way for a mechanism to infer the average performance of a model (trained on source data) on unseen and unlabelled target data.

Niklas Kormann, Masoud Ramuz, Zeeshan Nisar et al.

Graph Neural Networks (GNNs) have recently been found to excel in histopathology. However, an important histopathological task, where GNNs have not been extensively explored, is the classification of glomeruli health as an important indicator in nephropathology. This task presents unique difficulties, particularly for the graph construction, i.e., the identification of nodes, edges, and informative features. In this work, we propose a pipeline composed of different traditional and machine learning-based computer vision techniques to identify nodes, edges, and their corresponding features to form a heterogeneous graph. We then proceed to propose a novel heterogeneous GNN architecture for glomeruli classification, called HIEGNet, that integrates both glomeruli and their surrounding immune cells. Hence, HIEGNet is able to consider the immune environment of each glomerulus in its classification. Our HIEGNet was trained and tested on a dataset of Whole Slide Images from kidney transplant patients. Experimental results demonstrate that HIEGNet outperforms several baseline models and generalises best between patients among all baseline models. Our implementation is publicly available at https://github.com/nklsKrmnn/HIEGNet.git.

Jelica Vasiljević, Friedrich Feuerhake, Cédric Wemmert et al.

It has been shown that unpaired image-to-image translation methods constrained by cycle-consistency hide the information necessary for accurate input reconstruction as imperceptible noise. We demonstrate that, when applied to histopathology data, this hidden noise appears to be related to stain specific features and show that this is the case with two immunohistochemical stainings during translation to Periodic acid- Schiff (PAS), a histochemical staining method commonly applied in renal pathology. Moreover, by perturbing this hidden information, the translation models produce different, plausible outputs. We demonstrate that this property can be used as an augmentation method which, in a case of supervised glomeruli segmentation, leads to improved performance.

Jelica Vasiljević, Friedrich Feuerhake, Cédric Wemmert et al.

The application of supervised deep learning methods in digital pathology is limited due to their sensitivity to domain shift. Digital Pathology is an area prone to high variability due to many sources, including the common practice of evaluating several consecutive tissue sections stained with different staining protocols. Obtaining labels for each stain is very expensive and time consuming as it requires a high level of domain knowledge. In this article, we propose an unsupervised augmentation approach based on adversarial image-to-image translation, which facilitates the training of stain invariant supervised convolutional neural networks. By training the network on one commonly used staining modality and applying it to images that include corresponding, but differently stained, tissue structures, the presented method demonstrates significant improvements over other approaches. These benefits are illustrated in the problem of glomeruli segmentation in seven different staining modalities (PAS, Jones H&E, CD68, Sirius Red, CD34, H&E and CD3) and analysis of the learned representations demonstrate their stain invariance.

Odyssee Merveille, Thomas Lampert, Jessica Schmitz et al.

Objective: This article presents an automatic image processing framework to extract quantitative high-level information describing the micro-environment of glomeruli in consecutive whole slide images (WSIs) processed with different staining modalities of patients with chronic kidney rejection after kidney transplantation. Methods: This four-step framework consists of: 1) approximate rigid registration, 2) cell and anatomical structure segmentation 3) fusion of information from different stainings using a newly developed registration algorithm 4) feature extraction. Results: Each step of the framework is validated independently both quantitatively and qualitatively by pathologists. An illustration of the different types of features that can be extracted is presented. Conclusion: The proposed generic framework allows for the analysis of the micro-environment surrounding large structures that can be segmented (either manually or automatically). It is independent of the segmentation approach and is therefore applicable to a variety of biomedical research questions. Significance: Chronic tissue remodelling processes after kidney transplantation can result in interstitial fibrosis and tubular atrophy (IFTA) and glomerulosclerosis. This pipeline provides tools to quantitatively analyse, in the same spatial context, information from different consecutive WSIs and help researchers understand the complex underlying mechanisms leading to IFTA and glomerulosclerosis.

Thomas Lampert, Odyssée Merveille, Jessica Schmitz et al.

An important part of Digital Pathology is the analysis of multiple digitised whole slide images from differently stained tissue sections. It is common practice to mount consecutive sections containing corresponding microscopic structures on glass slides, and to stain them differently to highlight specific tissue components. These multiple staining modalities result in very different images but include a significant amount of consistent image information. Deep learning approaches have recently been proposed to analyse these images in order to automatically identify objects of interest for pathologists. These supervised approaches require a vast amount of annotations, which are difficult and expensive to acquire---a problem that is multiplied with multiple stainings. This article presents several training strategies that make progress towards stain invariant networks. By training the network on one commonly used staining modality and applying it to images that include corresponding but differently stained tissue structures, the presented unsupervised strategies demonstrate significant improvements over standard training strategies.

Thomas A. Lampert, André Stumpf, Pierre Gançarski

Although agreement between annotators has been studied in the past from a statistical viewpoint, little work has attempted to quantify the extent to which this phenomenon affects the evaluation of computer vision (CV) object detection algorithms. Many researchers utilise ground truth (GT) in experiments and more often than not this GT is derived from one annotator's opinion. How does the difference in opinion affect an algorithm's evaluation? Four examples of typical CV problems are chosen, and a methodology is applied to each to quantify the inter-annotator variance and to offer insight into the mechanisms behind agreement and the use of GT. It is found that when detecting linear objects annotator agreement is very low. The agreement in object position, linear or otherwise, can be partially explained through basic image properties. Automatic object detectors are compared to annotator agreement and it is found that a clear relationship exists. Several methods for calculating GTs from a number of annotations are applied and the resulting differences in the performance of the object detectors are quantified. It is found that the rank of a detector is highly dependent upon the method used to form the GT. It is also found that although the STAPLE and LSML GT estimation methods appear to represent the mean of the performance measured using the individual annotations, when there are few annotations, or there is a large variance in them, these estimates tend to degrade. Furthermore, one of the most commonly adopted annotation combination methods--consensus voting--accentuates more obvious features, which results in an overestimation of the algorithm's performance. Finally, it is concluded that in some datasets it may not be possible to state with any confidence that one algorithm outperforms another when evaluating upon one GT and a method for calculating confidence bounds is discussed.