Joel H. Saltz

Jakub R. Kaczmarzyk, Alan O'Callaghan, Fiona Inglis et al.

The field of digital pathology has seen a proliferation of deep learning models in recent years. Despite substantial progress, it remains rare for other researchers and pathologists to be able to access models published in the literature and apply them to their own images. This is due to difficulties in both sharing and running models. To address these concerns, we introduce WSInfer: a new, open-source software ecosystem designed to make deep learning for pathology more streamlined and accessible. WSInfer comprises three main elements: 1) a Python package and command line tool to efficiently apply patch-based deep learning inference to whole slide images; 2) a QuPath extension that provides an alternative inference engine through user-friendly and interactive software, and 3) a model zoo, which enables pathology models and metadata to be easily shared in a standardized form. Together, these contributions aim to encourage wider reuse, exploration, and interrogation of deep learning models for research purposes, by putting them into the hands of pathologists and eliminating a need for coding experience when accessed through QuPath. The WSInfer source code is hosted on GitHub and documentation is available at https://wsinfer.readthedocs.io.

Jakub R. Kaczmarzyk, Tahsin M. Kurc, Shahira Abousamra et al.

Histopathology remains the gold standard for diagnosis of various cancers. Recent advances in computer vision, specifically deep learning, have facilitated the analysis of histopathology images for various tasks, including immune cell detection and microsatellite instability classification. The state-of-the-art for each task often employs base architectures that have been pretrained for image classification on ImageNet. The standard approach to develop classifiers in histopathology tends to focus narrowly on optimizing models for a single task, not considering the aspects of modeling innovations that improve generalization across tasks. Here we present ChampKit (Comprehensive Histopathology Assessment of Model Predictions toolKit): an extensible, fully reproducible benchmarking toolkit that consists of a broad collection of patch-level image classification tasks across different cancers. ChampKit enables a way to systematically document the performance impact of proposed improvements in models and methodology. ChampKit source code and data are freely accessible at https://github.com/kaczmarj/champkit .

George Teodoro, Tony Pan, Tahsin M. Kurc et al.

We propose, implement, and experimentally evaluate a runtime middleware to support high-throughput execution on hybrid cluster machines of large-scale analysis applications. A hybrid cluster machine consists of computation nodes which have multiple CPUs and general purpose graphics processing units (GPUs). Our work targets scientific analysis applications in which datasets are processed in application-specific data chunks, and the processing of a data chunk is expressed as a hierarchical pipeline of operations. The proposed middleware system combines a bag-of-tasks style execution with coarse-grain dataflow execution. Data chunks and associated data processing pipelines are scheduled across cluster nodes using a demand driven approach, while within a node operations in a given pipeline instance are scheduled across CPUs and GPUs. The runtime system implements several optimizations, including performance aware task scheduling, architecture aware process placement, data locality conscious task assignment, and data prefetching and asynchronous data copy, to maximize utilization of the aggregate computing power of CPUs and GPUs and minimize data copy overheads. The application and performance benefits of the runtime middleware are demonstrated using an image analysis application, which is employed in a brain cancer study, on a state-of-the-art hybrid cluster in which each node has two 6-core CPUs and three GPUs. Our results show that implementing and scheduling application data processing as a set of fine-grain operations provide more opportunities for runtime optimizations and attain better performance than a coarser-grain, monolithic implementation. The proposed runtime system can achieve high-throughput processing of large datasets - we were able to process an image dataset consisting of 36,848 4Kx4K-pixel image tiles at about 150 tiles/second rate on 100 nodes.

Souradeep Chakraborty, Dana Perez, Paul Friedman et al.

We present a method for classifying the expertise of a pathologist based on how they allocated their attention during a cancer reading. We engage this decoding task by developing a novel method for predicting the attention of pathologists as they read whole-slide Images (WSIs) of prostate and make cancer grade classifications. Our ground truth measure of a pathologists' attention is the x, y and z (magnification) movement of their viewport as they navigated through WSIs during readings, and to date we have the attention behavior of 43 pathologists reading 123 WSIs. These data revealed that specialists have higher agreement in both their attention and cancer grades compared to general pathologists and residents, suggesting that sufficient information may exist in their attention behavior to classify their expertise level. To attempt this, we trained a transformer-based model to predict the visual attention heatmaps of resident, general, and specialist (GU) pathologists during Gleason grading. Based solely on a pathologist's attention during a reading, our model was able to predict their level of expertise with 75.3%, 56.1%, and 77.2% accuracy, respectively, better than chance and baseline models. Our model therefore enables a pathologist's expertise level to be easily and objectively evaluated, important for pathology training and competency assessment. Tools developed from our model could also be used to help pathology trainees learn how to read WSIs like an expert.

Jakub R. Kaczmarzyk, Rishul Sharma, Peter K. Koo et al.

Foundation models for computational pathology have shown great promise for specimen-level tasks and are increasingly accessible to researchers. However, specimen-level models built on these foundation models remain largely unavailable, hindering their broader utility and impact. To address this gap, we developed SpinPath, a toolkit designed to democratize specimen-level deep learning by providing a zoo of pretrained specimen-level models, a Python-based inference engine, and a JavaScript-based inference platform. We demonstrate the utility of SpinPath in metastasis detection tasks across nine foundation models. SpinPath may foster reproducibility, simplify experimentation, and accelerate the adoption of specimen-level deep learning in computational pathology research.

Ujjwal Baid, Sarthak Pati, Tahsin M. Kurc et al.

We evaluate the performance of federated learning (FL) in developing deep learning models for analysis of digitized tissue sections. A classification application was considered as the example use case, on quantifiying the distribution of tumor infiltrating lymphocytes within whole slide images (WSIs). A deep learning classification model was trained using 50*50 square micron patches extracted from the WSIs. We simulated a FL environment in which a dataset, generated from WSIs of cancer from numerous anatomical sites available by The Cancer Genome Atlas repository, is partitioned in 8 different nodes. Our results show that the model trained with the federated training approach achieves similar performance, both quantitatively and qualitatively, to that of a model trained with all the training data pooled at a centralized location. Our study shows that FL has tremendous potential for enabling development of more robust and accurate models for histopathology image analysis without having to collect large and diverse training data at a single location.

Souradeep Chakraborty, Ke Ma, Rajarsi Gupta et al.

We study the attention of pathologists as they examine whole-slide images (WSIs) of prostate cancer tissue using a digital microscope. To the best of our knowledge, our study is the first to report in detail how pathologists navigate WSIs of prostate cancer as they accumulate information for their diagnoses. We collected slide navigation data (i.e., viewport location, magnification level, and time) from 13 pathologists in 2 groups (5 genitourinary (GU) specialists and 8 general pathologists) and generated visual attention heatmaps and scanpaths. Each pathologist examined five WSIs from the TCGA PRAD dataset, which were selected by a GU pathology specialist. We examined and analyzed the distributions of visual attention for each group of pathologists after each WSI was examined. To quantify the relationship between a pathologist's attention and evidence for cancer in the WSI, we obtained tumor annotations from a genitourinary specialist. We used these annotations to compute the overlap between the distribution of visual attention and annotated tumor region to identify strong correlations. Motivated by this analysis, we trained a deep learning model to predict visual attention on unseen WSIs. We find that the attention heatmaps predicted by our model correlate quite well with the ground truth attention heatmap and tumor annotations on a test set of 17 WSIs by using various spatial and temporal evaluation metrics.

Sarthak Pati, Siddhesh P. Thakur, İbrahim Ethem Hamamcı et al.

Deep Learning (DL) has the potential to optimize machine learning in both the scientific and clinical communities. However, greater expertise is required to develop DL algorithms, and the variability of implementations hinders their reproducibility, translation, and deployment. Here we present the community-driven Generally Nuanced Deep Learning Framework (GaNDLF), with the goal of lowering these barriers. GaNDLF makes the mechanism of DL development, training, and inference more stable, reproducible, interpretable, and scalable, without requiring an extensive technical background. GaNDLF aims to provide an end-to-end solution for all DL-related tasks in computational precision medicine. We demonstrate the ability of GaNDLF to analyze both radiology and histology images, with built-in support for k-fold cross-validation, data augmentation, multiple modalities and output classes. Our quantitative performance evaluation on numerous use cases, anatomies, and computational tasks supports GaNDLF as a robust application framework for deployment in clinical workflows.

Le Hou, Rajarsi Gupta, John S. Van Arnam et al.

The distribution and appearance of nuclei are essential markers for the diagnosis and study of cancer. Despite the importance of nuclear morphology, there is a lack of large scale, accurate, publicly accessible nucleus segmentation data. To address this, we developed an analysis pipeline that segments nuclei in whole slide tissue images from multiple cancer types with a quality control process. We have generated nucleus segmentation results in 5,060 Whole Slide Tissue images from 10 cancer types in The Cancer Genome Atlas. One key component of our work is that we carried out a multi-level quality control process (WSI-level and image patch-level), to evaluate the quality of our segmentation results. The image patch-level quality control used manual segmentation ground truth data from 1,356 sampled image patches. The datasets we publish in this work consist of roughly 5 billion quality controlled nuclei from more than 5,060 TCGA WSIs from 10 different TCGA cancer types and 1,356 manually segmented TCGA image patches from the same 10 cancer types plus additional 4 cancer types. Data is available at https://doi.org/10.7937/tcia.2019.4a4dkp9u

Le Hou, Ayush Agarwal, Dimitris Samaras et al.

Hematoxylin and Eosin stained histopathology image analysis is essential for the diagnosis and study of complicated diseases such as cancer. Existing state-of-the-art approaches demand extensive amount of supervised training data from trained pathologists. In this work we synthesize in an unsupervised manner, large histopathology image datasets, suitable for supervised training tasks. We propose a unified pipeline that: a) generates a set of initial synthetic histopathology images with paired information about the nuclei such as segmentation masks; b) refines the initial synthetic images through a Generative Adversarial Network (GAN) to reference styles; c) trains a task-specific CNN and boosts the performance of the task-specific CNN with on-the-fly generated adversarial examples. Our main contribution is that the synthetic images are not only realistic, but also representative (in reference styles) and relatively challenging for training task-specific CNNs. We test our method for nucleus segmentation using images from four cancer types. When no supervised data exists for a cancer type, our method without supervision cost significantly outperforms supervised methods which perform across-cancer generalization. Even when supervised data exists for all cancer types, our approach without supervision cost performs better than supervised methods.

Le Hou, Vu Nguyen, Dimitris Samaras et al.

Histopathology images are crucial to the study of complex diseases such as cancer. The histologic characteristics of nuclei play a key role in disease diagnosis, prognosis and analysis. In this work, we propose a sparse Convolutional Autoencoder (CAE) for fully unsupervised, simultaneous nucleus detection and feature extraction in histopathology tissue images. Our CAE detects and encodes nuclei in image patches in tissue images into sparse feature maps that encode both the location and appearance of nuclei. Our CAE is the first unsupervised detection network for computer vision applications. The pretrained nucleus detection and feature extraction modules in our CAE can be fine-tuned for supervised learning in an end-to-end fashion. We evaluate our method on four datasets and reduce the errors of state-of-the-art methods up to 42%. We are able to achieve comparable performance with only 5% of the fully-supervised annotation cost.

Veda Murthy, Le Hou, Dimitris Samaras et al.

Classifying the various shapes and attributes of a glioma cell nucleus is crucial for diagnosis and understanding the disease. We investigate automated classification of glioma nuclear shapes and visual attributes using Convolutional Neural Networks (CNNs) on pathology images of automatically segmented nuclei. We propose three methods that improve the performance of a previously-developed semi-supervised CNN. First, we propose a method that allows the CNN to focus on the most important part of an image- the image's center containing the nucleus. Second, we inject (concatenate) pre-extracted VGG features into an intermediate layer of our Semi-Supervised CNN so that during training, the CNN can learn a set of complementary features. Third, we separate the losses of the two groups of target classes (nuclear shapes and attributes) into a single-label loss and a multi-label loss so that the prior knowledge of inter-label exclusiveness can be incorporated. On a dataset of 2078 images, the proposed methods combined reduce the error rate of attribute and shape classification by 21.54% and 15.07% respectively compared to the existing state-of-the-art method on the same dataset.

Le Hou, Dimitris Samaras, Tahsin M. Kurc et al.

In Neural Networks (NN), Adaptive Activation Functions (AAF) have parameters that control the shapes of activation functions. These parameters are trained along with other parameters in the NN. AAFs have improved performance of Neural Networks (NN) in multiple classification tasks. In this paper, we propose and apply AAFs on feedforward NNs for regression tasks. We argue that applying AAFs in the regression (second-to-last) layer of a NN can significantly decrease the bias of the regression NN. However, using existing AAFs may lead to overfitting. To address this problem, we propose a Smooth Adaptive Activation Function (SAAF) with piecewise polynomial form which can approximate any continuous function to arbitrary degree of error. NNs with SAAFs can avoid overfitting by simply regularizing the parameters. In particular, an NN with SAAFs is Lipschitz continuous given a bounded magnitude of the NN parameters. We prove an upper-bound for model complexity in terms of fat-shattering dimension for any Lipschitz continuous regression model. Thus, regularizing the parameters in NNs with SAAFs avoids overfitting. We empirically evaluated NNs with SAAFs and achieved state-of-the-art results on multiple regression datasets.

Le Hou, Dimitris Samaras, Tahsin M. Kurc et al.

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.

Thiago S. F. X. Teixeira, George Teodoro, Eduardo Valle et al.

Similarity search is critical for many database applications, including the increasingly popular online services for Content-Based Multimedia Retrieval (CBMR). These services, which include image search engines, must handle an overwhelming volume of data, while keeping low response times. Thus, scalability is imperative for similarity search in Web-scale applications, but most existing methods are sequential and target shared-memory machines. Here we address these issues with a distributed, efficient, and scalable index based on Locality-Sensitive Hashing (LSH). LSH is one of the most efficient and popular techniques for similarity search, but its poor referential locality properties has made its implementation a challenging problem. Our solution is based on a widely asynchronous dataflow parallelization with a number of optimizations that include a hierarchical parallelization to decouple indexing and data storage, locality-aware data partition strategies to reduce message passing, and multi-probing to limit memory usage. The proposed parallelization attained an efficiency of 90% in a distributed system with about 800 CPU cores. In particular, the original locality-aware data partition reduced the number of messages exchanged in 30%. Our parallel LSH was evaluated using the largest public dataset for similarity search (to the best of our knowledge) with $10^9$ 128-d SIFT descriptors extracted from Web images. This is two orders of magnitude larger than datasets that previous LSH parallelizations could handle.

George Teodoro, Eduardo Valle, Nathan Mariano et al.

Similarity search in high-dimentional spaces is a pivotal operation found a variety of database applications. Recently, there has been an increase interest in similarity search for online content-based multimedia services. Those services, however, introduce new challenges with respect to the very large volumes of data that have to be indexed/searched, and the need to minimize response times observed by the end-users. Additionally, those users dynamically interact with the systems creating fluctuating query request rates, requiring the search algorithm to adapt in order to better utilize the underline hardware to reduce response times. In order to address these challenges, we introduce hypercurves, a flexible framework for answering approximate k-nearest neighbor (kNN) queries for very large multimedia databases, aiming at online content-based multimedia services. Hypercurves executes on hybrid CPU--GPU environments, and is able to employ those devices cooperatively to support massive query request rates. In order to keep the response times optimal as the request rates vary, it employs a novel dynamic scheduler to partition the work between CPU and GPU. Hypercurves was throughly evaluated using a large database of multimedia descriptors. Its cooperative CPU--GPU execution achieved performance improvements of up to 30x when compared to the single CPU-core version. The dynamic work partition mechanism reduces the observed query response times in about 50% when compared to the best static CPU--GPU task partition configuration. In addition, Hypercurves achieves superlinear scalability in distributed (multi-node) executions, while keeping a high guarantee of equivalence with its sequential version --- thanks to the proof of probabilistic equivalence, which supported its aggressive parallelization design.