Whole slide image registration for the study of tumor heterogeneity

Consecutive thin sections of tissue samples make it possible to study local variation in e.g. protein expression and tumor heterogeneity by staining for a new protein in each section. In order to compare and correlate patterns of different proteins, the images have to be registered with high accuracy. The problem we want to solve is registration of gigapixel whole slide images (WSI). This presents 3 challenges: (i) Images are very large; (ii) Thin sections result in artifacts that make global affine registration prone to very large local errors; (iii) Local affine registration is required to preserve correct tissue morphology (local size, shape and texture). In our approach we compare WSI registration based on automatic and manual feature selection on either the full image or natural sub-regions (as opposed to square tiles). Working with natural sub-regions, in an interactive tool makes it possible to exclude regions containing scientifically irrelevant information. We also present a new way to visualize local registration quality by a Registration Confidence Map (RCM). With this method, intra-tumor heterogeneity and charateristics of the tumor microenvironment can be observed and quantified.Comment: MICCAI2018 - Computational Pathology and Ophthalmic Medical Image Analysis - COMPA

Context-based Normalization of Histological Stains using Deep Convolutional Features

While human observers are able to cope with variations in color and appearance of histological stains, digital pathology algorithms commonly require a well-normalized setting to achieve peak performance, especially when a limited amount of labeled data is available. This work provides a fully automated, end-to-end learning-based setup for normalizing histological stains, which considers the texture context of the tissue. We introduce Feature Aware Normalization, which extends the framework of batch normalization in combination with gating elements from Long Short-Term Memory units for normalization among different spatial regions of interest. By incorporating a pretrained deep neural network as a feature extractor steering a pixelwise processing pipeline, we achieve excellent normalization results and ensure a consistent representation of color and texture. The evaluation comprises a comparison of color histogram deviations, structural similarity and measures the color volume obtained by the different methods.Comment: In: 3rd Workshop on Deep Learning in Medical Image Analysis (DLMIA 2017

Scale Stain: Multi-Resolution Feature Enhancement in Pathology Visualization

Digital whole-slide images of pathological tissue samples have recently become feasible for use within routine diagnostic practice. These gigapixel sized images enable pathologists to perform reviews using computer workstations instead of microscopes. Existing workstations visualize scanned images by providing a zoomable image space that reproduces the capabilities of the microscope. This paper presents a novel visualization approach that enables filtering of the scale-space according to color preference. The visualization method reveals diagnostically important patterns that are otherwise not visible. The paper demonstrates how this approach has been implemented into a fully functional prototype that lets the user navigate the visualization parameter space in real time. The prototype was evaluated for two common clinical tasks with eight pathologists in a within-subjects study. The data reveal that task efficiency increased by 15% using the prototype, with maintained accuracy. By analyzing behavioral strategies, it was possible to conclude that efficiency gain was caused by a reduction of the panning needed to perform systematic search of the images. The prototype system was well received by the pathologists who did not detect any risks that would hinder use in clinical routine

A Method of Drusen Measurement Based on the Geometry of Fundus Reflectance

BACKGROUND: The hallmarks of age-related macular degeneration, the leading cause of blindness in the developed world, are the subretinal deposits known as drusen. Drusen identification and measurement play a key role in clinical studies of this disease. Current manual methods of drusen measurement are laborious and subjective. Our purpose was to expedite clinical research with an accurate, reliable digital method. METHODS: An interactive semi-automated procedure was developed to level the macular background reflectance for the purpose of morphometric analysis of drusen. 12 color fundus photographs of patients with age-related macular degeneration and drusen were analyzed. After digitizing the photographs, the underlying background pattern in the green channel was leveled by an algorithm based on the elliptically concentric geometry of the reflectance in the normal macula: the gray scale values of all structures within defined elliptical boundaries were raised sequentially until a uniform background was obtained. Segmentation of drusen and area measurements in the central and middle subfields (1000 μm and 3000 μm diameters) were performed by uniform thresholds. Two observers using this interactive semi-automated software measured each image digitally. The mean digital measurements were compared to independent stereo fundus gradings by two expert graders (stereo Grader 1 estimated the drusen percentage in each of the 24 regions as falling into one of four standard broad ranges; stereo Grader 2 estimated drusen percentages in 1% to 5% intervals). RESULTS: The mean digital area measurements had a median standard deviation of 1.9%. The mean digital area measurements agreed with stereo Grader 1 in 22/24 cases. The 95% limits of agreement between the mean digital area measurements and the more precise stereo gradings of Grader 2 were -6.4 % to +6.8 % in the central subfield and -6.0 % to +4.5 % in the middle subfield. The mean absolute differences between the digital and stereo gradings 2 were 2.8 +/- 3.4% in the central subfield and 2.2 +/- 2.7% in the middle subfield. CONCLUSIONS: Semi-automated, supervised drusen measurements may be done reproducibly and accurately with adaptations of commercial software. This technique for macular image analysis has potential for use in clinical research