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Register a new userWhole slide image registration for the study of tumor heterogeneity
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Added by
Leslie Solorzano
Publication date
2019
fields
Informatics Engineering
and research's language is
English
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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.
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Weak supervision learning on classification labels has demonstrated high performance in various tasks. When a few pixel-level fine annotations are also affordable, it is natural to leverage both of the pixel-level (e.g., segmentation) and image level (e.g., classification) annotation to further improve the performance. In computational pathology, however, such weak or mixed supervision learning is still a challenging task, since the high resolution of whole slide images makes it unattainable to perform end-to-end training of classification models. An alternative approach is to analyze such data by patch-base model training, i.e., using self-supervised learning to generate pixel-level pseudo labels for patches. However, such methods usually have model drifting issues, i.e., hard to converge, because the noise accumulates during the self-training process. To handle those problems, we propose a mixed supervision learning framework for super high-resolution images to effectively utilize their various labels (e.g., sufficient image-level coarse annotations and a few pixel-level fine labels). During the patch training stage, this framework can make use of coarse image-level labels to refine self-supervised learning and generate high-quality pixel-level pseudo labels. A comprehensive strategy is proposed to suppress pixel-level false positives and false negatives. Three real-world datasets with very large number of images (i.e., more than 10,000 whole slide images) and various types of labels are used to evaluate the effectiveness of mixed supervision learning. We reduced the false positive rate by around one third compared to state of the art while retaining 100% sensitivity, in the task of image-level classification.
Tumor proliferation is an important biomarker indicative of the prognosis of breast cancer patients. Assessment of tumor proliferation in a clinical setting is highly subjective and labor-intensive task. Previous efforts to automate tumor proliferation assessment by image analysis only focused on mitosis detection in predefined tumor regions. However, in a real-world scenario, automatic mitosis detection should be performed in whole-slide images (WSIs) and an automatic method should be able to produce a tumor proliferation score given a WSI as input. To address this, we organized the TUmor Proliferation Assessment Challenge 2016 (TUPAC16) on prediction of tumor proliferation scores from WSIs. The challenge dataset consisted of 500 training and 321 testing breast cancer histopathology WSIs. In order to ensure fair and independent evaluation, only the ground truth for the training dataset was provided to the challenge participants. The first task of the challenge was to predict mitotic scores, i.e., to reproduce the manual method of assessing tumor proliferation by a pathologist. The second task was to predict the gene expression based PAM50 proliferation scores from the WSI. The best performing automatic method for the first task achieved a quadratic-weighted Cohens kappa score of $kappa$ = 0.567, 95% CI [0.464, 0.671] between the predicted scores and the ground truth. For the second task, the predictions of the top method had a Spearmans correlation coefficient of r = 0.617, 95% CI [0.581 0.651] with the ground truth. This was the first study that investigated tumor proliferation assessment from WSIs. The achieved results are promising given the difficulty of the tasks and weakly-labelled nature of the ground truth. However, further research is needed to improve the practical utility of image analysis methods for this task.
There has been a long pursuit for precise and reproducible glomerular quantification on renal pathology to leverage both research and practice. When digitizing the biopsy tissue samples using whole slide imaging (WSI), a set of serial sections from the same tissue can be acquired as a stack of images, similar to frames in a video. In radiology, the stack of images (e.g., computed tomography) are naturally used to provide 3D context for organs, tissues, and tumors. In pathology, it is appealing to do a similar 3D assessment. However, the 3D identification and association of large-scale glomeruli on renal pathology is challenging due to large tissue deformation, missing tissues, and artifacts from WSI. In this paper, we propose a novel Multi-object Association for Pathology in 3D (Map3D) method for automatically identifying and associating large-scale cross-sections of 3D objects from routine serial sectioning and WSI. The innovations of the Map3D method are three-fold: (1) the large-scale glomerular association is formed as a new multi-object tracking (MOT) perspective; (2) the quality-aware whole series registration is proposed to not only provide affinity estimation but also offer automatic kidney-wise quality assurance (QA) for registration; (3) a dual-path association method is proposed to tackle the large deformation, missing tissues, and artifacts during tracking. To the best of our knowledge, the Map3D method is the first approach that enables automatic and large-scale glomerular association across 3D serial sectioning using WSI. Our proposed method Map3D achieved MOTA= 44.6, which is 12.1% higher than the non deep learning benchmarks.
Convolutional Neural Networks (CNN) are state-of-the-art models for many image classification tasks. However, to recognize cancer subtypes automatically, training a CNN on gigapixel resolution Whole Slide Tissue Images (WSI) is currently computationally impossible. The differentiation of cancer subtypes is based on cellular-level visual features observed on image patch scale. Therefore, we argue that in this situation, training a patch-level classifier on image patches will perform better than or similar to an image-level classifier. The challenge becomes how to intelligently combine patch-level classification results and model the fact that not all patches will be discriminative. We propose to train a decision fusion model to aggregate patch-level predictions given by patch-level CNNs, which to the best of our knowledge has not been shown before. Furthermore, we formulate a novel Expectation-Maximization (EM) based method that automatically locates discriminative patches robustly by utilizing the spatial relationships of patches. We apply our method to the classification of glioma and non-small-cell lung carcinoma cases into subtypes. The classification accuracy of our method is similar to the inter-observer agreement between pathologists. Although it is impossible to train CNNs on WSIs, we experimentally demonstrate using a comparable non-cancer dataset of smaller images that a patch-based CNN can outperform an image-based CNN.
In this paper, we propose a novel method for highly efficient follicular segmentation of thyroid cytopathological WSIs. Firstly, we propose a hybrid segmentation architecture, which integrates a classifier into Deeplab V3 by adding a branch. A large amount of the WSI segmentation time is saved by skipping the irrelevant areas using the classification branch. Secondly, we merge the low scale fine features into the original atrous spatial pyramid pooling (ASPP) in Deeplab V3 to accurately represent the details in cytopathological images. Thirdly, our hybrid model is trained by a criterion-oriented adaptive loss function, which leads the model converging much faster. Experimental results on a collection of thyroid patches demonstrate that the proposed model reaches 80.9% on the segmentation accuracy. Besides, 93% time is reduced for the WSI segmentation by using our proposed method, and the WSI-level accuracy achieves 53.4%.
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