Immunohistochemistry Biomarkers-Guided Image Search for Histopathology.

Medical practitioners use a number of diagnostic tests to make a reliable diagnosis. Traditionally, Haematoxylin and Eosin (H&E) stained glass slides have been used for cancer diagnosis and tumor detection. However, recently a variety of immunohistochemistry (IHC) stained slides can be requested by pathologists to examine and confirm diagnoses for determining the subtype of a tumor when this is difficult using H&E slides only. Deep learning (DL) has received a lot of interest recently for image search engines to extract features from tissue regions, which may or may not be the target region for diagnosis. This approach generally fails to capture high-level patterns corresponding to the malignant or abnormal content of histopathology images. In this work, we are proposing a targeted image search approach, inspired by the pathologists' workflow, which may use information from multiple IHC biomarker images when available. These IHC images could be aligned, filtered, and merged together to generate a composite biomarker image (CBI) that could eventually be used to generate an attention map to guide the search engine for localized search. In our experiments, we observed that an IHC-guided image search engine can retrieve relevant data more accurately than a conventional (i.e., H&E-only) search engine without IHC guidance. Moreover, such engines are also able to accurately conclude the subtypes through majority votes.

Composite Biomarker Image for Advanced Visualization in Histopathology.

Immunohistochemistry (IHC) biomarkers are essential tools for reliable cancer diagnosis and subtyping. It requires cross-staining comparison among Whole Slide Images (WSIs) of IHCs and hematoxylin and eosin (H&E) slides. Currently, pathologists examine the visually co-localized areas across IHC and H&E glass slides for a final diagnosis, which is a tedious and challenging task. Moreover, visually inspecting different IHC slides back and forth to analyze local co-expressions is inherently subjective and prone to error, even when carried out by experienced pathologists. Relying on digital pathology, we propose "Composite Biomarker Image" (CBI) in this work. CBI is a single image that can be composed using different filtered IHC biomarker images for better visualization. We present a CBI image produced in two steps by the proposed solution for better visualization and hence more efficient clinical workflow. In the first step, IHC biomarker images are aligned with the H&E images using one coordinate system and orientation. In the second step, the positive or negative IHC regions from each biomarker image (based on the pathologists' recommendation) are filtered and combined into one image using a fuzzy inference system. For evaluation, the resulting CBI images, from the proposed system, were evaluated qualitatively by the expert pathologists. The CBI concept helps the pathologists to identify the suspected target tissues more easily, which could be further assessed by examining the actual WSIs at the same suspected regions.

Class-imbalanced Unsupervised and Semi-Supervised Domain Adaptation for Histopathology Images.

In dealing with the lack of sufficient annotated data and in contrast to supervised learning, unsupervised, self-supervised, and semi-supervised domain adaptation methods are promising approaches, enabling us to transfer knowledge from rich labeled source domains to different (but related) unlabeled target domains, reducing distribution discrepancy between the source and target domains. However, most existing domain adaptation methods do not consider the imbalanced nature of the real-world data, affecting their performance in practice. We propose to overcome this limitation by proposing a novel domain adaptation approach that includes two modifications to the existing models. Firstly, we leverage the focal loss function in response to class-imbalanced labeled data in the source domain. Secondly, we introduce a novel co-training approach to involve pseudo-labeled target data points in the training process. Experiments show that the proposed model can be effective in transferring knowledge from source to target domain. As an example, we use the classification of prostate cancer images into low-cancerous and high-cancerous regions.

Learning binary and sparse permutation-invariant representations for fast and memory efficient whole slide image search.

Considering their gigapixel sizes, the representation of whole slide images (WSIs) for classification and retrieval systems is a non-trivial task. Patch processing and multi-Instance Learning (MIL) are common approaches to analyze WSIs. However, in end-to-end training, these methods require high GPU memory consumption due to the simultaneous processing of multiple sets of patches. Furthermore, compact WSI representations through binary and/or sparse representations are urgently needed for real-time image retrieval within large medical archives. To address these challenges, we propose a novel framework for learning compact WSI representations utilizing deep conditional generative modeling and the Fisher Vector Theory. The training of our method is instance-based, achieving better memory and computational efficiency during the training. To achieve efficient large-scale WSI search, we introduce new loss functions, namely gradient sparsity and gradient quantization losses, for learning sparse and binary permutation-invariant WSI representations called Conditioned Sparse Fisher Vector (C-Deep-SFV), and Conditioned Binary Fisher Vector (C-Deep-BFV). The learned WSI representations are validated on the largest public WSI archive, The Cancer Genomic Atlas (TCGA) and also Liver-Kidney-Stomach (LKS) dataset. For WSI search, the proposed method outperforms Yottixel and Gaussian Mixture Model (GMM)-based Fisher Vector both in terms of retrieval accuracy and speed. For WSI classification, we achieve competitive performance against state-of-art on lung cancer data from TCGA and the public benchmark LKS dataset.

Proportionally Fair Hospital Collaborations in Federated Learning of Histopathology Images.

Medical centers and healthcare providers have concerns and hence restrictions around sharing data with external collaborators. Federated learning, as a privacy-preserving method, involves learning a site-independent model without having direct access to patient-sensitive data in a distributed collaborative fashion. The federated approach relies on decentralized data distribution from various hospitals and clinics. The collaboratively learned global model is supposed to have acceptable performance for the individual sites. However, existing methods focus on minimizing the average of the aggregated loss functions, leading to a biased model that performs perfectly for some hospitals while exhibiting undesirable performance for other sites. In this paper, we improve model "fairness" among participating hospitals by proposing a novel federated learning scheme called Proportionally Fair Federated Learning, short Prop-FFL. Prop-FFL is based on a novel optimization objective function to decrease the performance variations among participating hospitals. This function encourages a fair model, providing us with more uniform performance across participating hospitals. We validate the proposed Prop-FFL on two histopathology datasets as well as two general datasets to shed light on its inherent capabilities. The experimental results suggest promising performance in terms of learning speed, accuracy, and fairness.

A self-supervised contrastive learning approach for whole slide image representation in digital pathology.

Image analysis in digital pathology has proven to be one of the most challenging fields in medical imaging for AI-driven classification and search tasks. Due to their gigapixel dimensions, whole slide images (WSIs) are difficult to represent for computational pathology. Self-supervised learning (SSL) has recently demonstrated excellent performance in learning effective representations on pretext objectives, which may improve the generalizations of downstream tasks. Previous self-supervised representation methods rely on patch selection and classification such that the effect of SSL on end-to-end WSI representation is not investigated. In contrast to existing augmentation-based SSL methods, this paper proposes a novel self-supervised learning scheme based on the available primary site information. We also design a fully supervised contrastive learning setup to increase the robustness of the representations for WSI classification and search for both pretext and downstream tasks. We trained and evaluated the model on more than 6000 WSIs from The Cancer Genome Atlas (TCGA) repository provided by the National Cancer Institute. The proposed architecture achieved excellent results on most primary sites and cancer subtypes. We also achieved the best result on validation on a lung cancer classification task.

Automatic Multi-Stain Registration of Whole Slide Images in Histopathology.

Joint analysis of multiple biomarker images and tissue morphology is important for disease diagnosis, treatment planning and drug development. It requires cross-staining comparison among Whole Slide Images (WSIs) of immune-histochemical and hematoxylin and eosin (H&E) microscopic slides. However, automatic, and fast cross-staining alignment of enormous gigapixel WSIs at single-cell precision is challenging. In addition to morphological deformations introduced during slide preparation, there are large variations in cell appearance and tissue morphology across different staining. In this paper, we propose a two-step automatic feature-based cross-staining WSI alignment to assist localization of even tiny metastatic foci in the assessment of lymph node. Image pairs were aligned allowing for translation, rotation, and scaling. The registration was performed automatically by first detecting landmarks in both images, using the scale-invariant image transform (SIFT), followed by the fast sample consensus (FSC) protocol for finding point correspondences and finally aligned the images. The Registration results were evaluated using both visual and quantitative criteria using the Jaccard index. The average Jaccard similarity index of the results produced by the proposed system is 0.942 when compared with the manual registration.

Selection, Visualization, and Interpretation of Deep Features in Lung Adenocarcinoma and Squamous Cell Carcinoma.

Although deep learning networks applied to digital images have shown impressive results for many pathology-related tasks, their black-box approach and limitation in terms of interpretability are significant obstacles for their widespread clinical utility. This study investigates the visualization of deep features (DFs) to characterize two lung cancer subtypes, adenocarcinoma and squamous cell carcinoma. It demonstrates that a subset of DFs, called prominent DFs, can accurately distinguish these two cancer subtypes. Visualization of such individual DFs allows for a better understanding of histopathologic patterns at both the whole-slide and patch levels, and discrimination of these cancer types. These DFs were visualized at the whole slide image level through DF-specific heatmaps and at tissue patch level through the generation of activation maps. In addition, these prominent DFs can distinguish carcinomas of organs other than the lung. This framework may serve as a platform for evaluating the interpretability of any deep network for diagnostic decision making.

Fine-Tuning and training of densenet for histopathology image representation using TCGA diagnostic slides.

Feature vectors provided by pre-trained deep artificial neural networks have become a dominant source for image representation in recent literature. Their contribution to the performance of image analysis can be improved through fine-tuning. As an ultimate solution, one might even train a deep network from scratch with the domain-relevant images, a highly desirable option which is generally impeded in pathology by lack of labeled images and the computational expense. In this study, we propose a new network, namely KimiaNet, that employs the topology of the DenseNet with four dense blocks, fine-tuned and trained with histopathology images in different configurations. We used more than 240,000 image patches with 1000×1000 pixels acquired at 20× magnification through our proposed "high-cellularity mosaic" approach to enable the usage of weak labels of 7126 whole slide images of formalin-fixed paraffin-embedded human pathology samples publicly available through The Cancer Genome Atlas (TCGA) repository. We tested KimiaNet using three public datasets, namely TCGA, endometrial cancer images, and colorectal cancer images by evaluating the performance of search and classification when corresponding features of different networks are used for image representation. As well, we designed and trained multiple convolutional batch-normalized ReLU (CBR) networks. The results show that KimiaNet provides superior results compared to the original DenseNet and smaller CBR networks when used as feature extractor to represent histopathology images.

Searching Images for Consensus: Can AI Remove Observer Variability in Pathology?

One of the major obstacles in reaching diagnostic consensus is observer variability. With the recent success of artificial intelligence, particularly the deep networks, the question emerges as to whether the fundamental challenge of diagnostic imaging can now be resolved. This article briefly reviews the problem and how eventually both supervised and unsupervised AI technologies could help to overcome it.

A Digital Pathology Solution to Resolve the Tissue Floater Conundrum.

CONTEXT.­: Pathologists may encounter extraneous pieces of tissue (tissue floaters) on glass slides because of specimen cross-contamination. Troubleshooting this problem, including performing molecular tests for tissue identification if available, is time consuming and often does not satisfactorily resolve the problem. OBJECTIVE.­: To demonstrate the feasibility of using an image search tool to resolve the tissue floater conundrum. DESIGN.­: A glass slide was produced containing 2 separate hematoxylin and eosin (H&E)-stained tissue floaters. This fabricated slide was digitized along with the 2 slides containing the original tumors used to create these floaters. These slides were then embedded into a dataset of 2325 whole slide images comprising a wide variety of H&E stained diagnostic entities. Digital slides were broken up into patches and the patch features converted into barcodes for indexing and easy retrieval. A deep learning-based image search tool was employed to extract features from patches via barcodes, hence enabling image matching to each tissue floater. RESULTS.­: There was a very high likelihood of finding a correct tumor match for the queried tissue floater when searching the digital database. Search results repeatedly yielded a correct match within the top 3 retrieved images. The retrieval accuracy improved when greater proportions of the floater were selected. The time to run a search was completed within several milliseconds. CONCLUSIONS.­: Using an image search tool offers pathologists an additional method to rapidly resolve the tissue floater conundrum, especially for those laboratories that have transitioned to going fully digital for primary diagnosis.

Recognizing Magnification Levels in Microscopic Snapshots.

Recent advances in digital imaging has transformed computer vision and machine learning to new tools for analyzing pathology images. This trend could automate some of the tasks in the diagnostic pathology and elevate the pathologist workload. The final step of any cancer diagnosis procedure is performed by the expert pathologist. These experts use microscopes with high level of optical magnification to observe minute characteristics of the tissue acquired through biopsy and fixed on glass slides. Switching between different magnifications, and finding the magnification level at which they identify the presence or absence of malignant tissues is important. As the majority of pathologists still use light microscopy, compared to digital scanners, in many instance a mounted camera on the microscope is used to capture snapshots from significant field- of-views. Repositories of such snapshots usually do not contain the magnification information. In this paper, we extract deep features of the images available on TCGA dataset with known magnification to train a classifier for magnification recognition. We compared the results with LBP, a well-known handcrafted feature extraction method. The proposed approach achieved a mean accuracy of 96% when a multi-layer perceptron was trained as a classifier.

Pan-cancer diagnostic consensus through searching archival histopathology images using artificial intelligence.

The emergence of digital pathology has opened new horizons for histopathology. Artificial intelligence (AI) algorithms are able to operate on digitized slides to assist pathologists with different tasks. Whereas AI-involving classification and segmentation methods have obvious benefits for image analysis, image search represents a fundamental shift in computational pathology. Matching the pathology of new patients with already diagnosed and curated cases offers pathologists a new approach to improve diagnostic accuracy through visual inspection of similar cases and computational majority vote for consensus building. In this study, we report the results from searching the largest public repository (The Cancer Genome Atlas, TCGA) of whole-slide images from almost 11,000 patients. We successfully indexed and searched almost 30,000 high-resolution digitized slides constituting 16 terabytes of data comprised of 20 million 1000 × 1000 pixels image patches. The TCGA image database covers 25 anatomic sites and contains 32 cancer subtypes. High-performance storage and GPU power were employed for experimentation. The results were assessed with conservative "majority voting" to build consensus for subtype diagnosis through vertical search and demonstrated high accuracy values for both frozen section slides (e.g., bladder urothelial carcinoma 93%, kidney renal clear cell carcinoma 97%, and ovarian serous cystadenocarcinoma 99%) and permanent histopathology slides (e.g., prostate adenocarcinoma 98%, skin cutaneous melanoma 99%, and thymoma 100%). The key finding of this validation study was that computational consensus appears to be possible for rendering diagnoses if a sufficiently large number of searchable cases are available for each cancer subtype.

Representing Medical Images With Encoded Local Projections.

This paper introduces the "encoded local projections" (ELP) as a new dense-sampling image descriptor for search and classification problems. The gradient changes of multiple projections in local windows of gray-level images are encoded to build a histogram that captures spatial projection patterns. Using projections is a conventional technique in both medical imaging and computer vision. Furthermore, powerful dense-sampling methods, such as local binary patterns and the histogram of oriented gradients, are widely used for image classification and recognition. Inspired by many achievements of such existing descriptors, we explore the design of a new class of histogram-based descriptors with particular applications in medical imaging. We experiment with three public datasets (IRMA, Kimia Path24, and CT Emphysema) to comparatively evaluate the performance of ELP histograms. In light of the tremendous success of deep architectures, we also compare the results with deep features generated by pretrained networks. The results are quite encouraging as the ELP descriptor can surpass both conventional and deep descriptors in performance in several experimental settings.