Tahsin Kurç

Lena Maier-Hein, Annika Reinke, Patrick Godau et al. · utoronto

Increasing evidence shows that flaws in machine learning (ML) algorithm validation are an underestimated global problem. Particularly in automatic biomedical image analysis, chosen performance metrics often do not reflect the domain interest, thus failing to adequately measure scientific progress and hindering translation of ML techniques into practice. To overcome this, our large international expert consortium created Metrics Reloaded, a comprehensive framework guiding researchers in the problem-aware selection of metrics. Following the convergence of ML methodology across application domains, Metrics Reloaded fosters the convergence of validation methodology. The framework was developed in a multi-stage Delphi process and is based on the novel concept of a problem fingerprint - a structured representation of the given problem that captures all aspects that are relevant for metric selection, from the domain interest to the properties of the target structure(s), data set and algorithm output. Based on the problem fingerprint, users are guided through the process of choosing and applying appropriate validation metrics while being made aware of potential pitfalls. Metrics Reloaded targets image analysis problems that can be interpreted as a classification task at image, object or pixel level, namely image-level classification, object detection, semantic segmentation, and instance segmentation tasks. To improve the user experience, we implemented the framework in the Metrics Reloaded online tool, which also provides a point of access to explore weaknesses, strengths and specific recommendations for the most common validation metrics. The broad applicability of our framework across domains is demonstrated by an instantiation for various biological and medical image analysis use cases.

Saumya Gupta, Xiaoling Hu, James Kaan et al.

Deep learning methods have achieved impressive performance for multi-class medical image segmentation. However, they are limited in their ability to encode topological interactions among different classes (e.g., containment and exclusion). These constraints naturally arise in biomedical images and can be crucial in improving segmentation quality. In this paper, we introduce a novel topological interaction module to encode the topological interactions into a deep neural network. The implementation is completely convolution-based and thus can be very efficient. This empowers us to incorporate the constraints into end-to-end training and enrich the feature representation of neural networks. The efficacy of the proposed method is validated on different types of interactions. We also demonstrate the generalizability of the method on both proprietary and public challenge datasets, in both 2D and 3D settings, as well as across different modalities such as CT and Ultrasound. Code is available at: https://github.com/TopoXLab/TopoInteraction

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 .

Annika Reinke, Minu D. Tizabi, Michael Baumgartner et al.

Validation metrics are key for the reliable tracking of scientific progress and for bridging the current chasm between artificial intelligence (AI) research and its translation into practice. However, increasing evidence shows that particularly in image analysis, metrics are often chosen inadequately in relation to the underlying research problem. This could be attributed to a lack of accessibility of metric-related knowledge: While taking into account the individual strengths, weaknesses, and limitations of validation metrics is a critical prerequisite to making educated choices, the relevant knowledge is currently scattered and poorly accessible to individual researchers. Based on a multi-stage Delphi process conducted by a multidisciplinary expert consortium as well as extensive community feedback, the present work provides the first reliable and comprehensive common point of access to information on pitfalls related to validation metrics in image analysis. Focusing on biomedical image analysis but with the potential of transfer to other fields, the addressed pitfalls generalize across application domains and are categorized according to a newly created, domain-agnostic taxonomy. To facilitate comprehension, illustrations and specific examples accompany each pitfall. As a structured body of information accessible to researchers of all levels of expertise, this work enhances global comprehension of a key topic in image analysis validation.

Shahira Abousamra, Rajarsi Gupta, Tahsin Kurc et al.

In digital pathology, the spatial context of cells is important for cell classification, cancer diagnosis and prognosis. To model such complex cell context, however, is challenging. Cells form different mixtures, lineages, clusters and holes. To model such structural patterns in a learnable fashion, we introduce several mathematical tools from spatial statistics and topological data analysis. We incorporate such structural descriptors into a deep generative model as both conditional inputs and a differentiable loss. This way, we are able to generate high quality multi-class cell layouts for the first time. We show that the topology-rich cell layouts can be used for data augmentation and improve the performance of downstream tasks such as cell classification.

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.

Mahmudul Hasan, Jakub R. Kaczmarzyk, David Paredes et al.

Understanding the impact of tumor biology on the composition of nearby cells often requires characterizing the impact of biologically distinct tumor regions. Biomarkers have been developed to label biologically distinct tumor regions, but challenges arise because of differences in the spatial extent and distribution of differentially labeled regions. In this work, we present a framework for systematically investigating the impact of distinct tumor regions on cells near the tumor borders, accounting their cross spatial distributions. We apply the framework to multiplex immunohistochemistry (mIHC) studies of pancreatic cancer and show its efficacy in demonstrating how biologically different tumor regions impact the immune response in the tumor microenvironment. Furthermore, we show that the proposed framework can be extended to largescale whole slide image analysis.

Rajarsi Gupta, Jakub Kaczmarzyk, Soma Kobayashi et al.

The combination of data analysis methods, increasing computing capacity, and improved sensors enable quantitative granular, multi-scale, cell-based analyses. We describe the rich set of application challenges related to tissue interpretation and survey AI methods currently used to address these challenges. We focus on a particular class of targeted human tissue analysis - histopathology - aimed at quantitative characterization of disease state, patient outcome prediction and treatment steering.

Han Le, Rajarsi Gupta, Le Hou et al.

Quantitative assessment of Tumor-TIL spatial relationships is increasingly important in both basic science and clinical aspects of breast cancer research. We have developed and evaluated convolutional neural network (CNN) analysis pipelines to generate combined maps of cancer regions and tumor infiltrating lymphocytes (TILs) in routine diagnostic breast cancer whole slide tissue images (WSIs). We produce interactive whole slide maps that provide 1) insight about the structural patterns and spatial distribution of lymphocytic infiltrates and 2) facilitate improved quantification of TILs. We evaluated both tumor and TIL analyses using three CNN networks - Resnet-34, VGG16 and Inception v4, and demonstrated that the results compared favorably to those obtained by what believe are the best published methods. We have produced open-source tools and generated a public dataset consisting of tumor/TIL maps for 1,015 TCGA breast cancer images. We also present a customized web-based interface that enables easy visualization and interactive exploration of high-resolution combined Tumor-TIL maps for 1,015TCGA invasive breast cancer cases that can be downloaded for further downstream analyses.

Wentao Huang, Meilong Xu, Xiaoling Hu et al.

Spatial transcriptomics (ST) provides essential spatial context by mapping gene expression within tissue, enabling detailed study of cellular heterogeneity and tissue organization. However, aligning ST data with histology images poses challenges due to inherent spatial distortions and modality-specific variations. Existing methods largely rely on direct alignment, which often fails to capture complex cross-modal relationships. To address these limitations, we propose a novel framework that aligns gene and image features using a ranking-based alignment loss, preserving relative similarity across modalities and enabling robust multi-scale alignment. To further enhance the alignment's stability, we employ self-supervised knowledge distillation with a teacher-student network architecture, effectively mitigating disruptions from high dimensionality, sparsity, and noise in gene expression data. Extensive experiments on seven public datasets that encompass gene expression prediction, slide-level classification, and survival analysis demonstrate the efficacy of our method, showing improved alignment and predictive performance over existing methods.

Srikar Yellapragada, Alexandros Graikos, Prateek Prasanna et al.

To achieve high-quality results, diffusion models must be trained on large datasets. This can be notably prohibitive for models in specialized domains, such as computational pathology. Conditioning on labeled data is known to help in data-efficient model training. Therefore, histopathology reports, which are rich in valuable clinical information, are an ideal choice as guidance for a histopathology generative model. In this paper, we introduce PathLDM, the first text-conditioned Latent Diffusion Model tailored for generating high-quality histopathology images. Leveraging the rich contextual information provided by pathology text reports, our approach fuses image and textual data to enhance the generation process. By utilizing GPT's capabilities to distill and summarize complex text reports, we establish an effective conditioning mechanism. Through strategic conditioning and necessary architectural enhancements, we achieved a SoTA FID score of 7.64 for text-to-image generation on the TCGA-BRCA dataset, significantly outperforming the closest text-conditioned competitor with FID 30.1.

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.

Shahira Abousamra, David Belinsky, John Van Arnam et al.

In digital pathology, both detection and classification of cells are important for automatic diagnostic and prognostic tasks. Classifying cells into subtypes, such as tumor cells, lymphocytes or stromal cells is particularly challenging. Existing methods focus on morphological appearance of individual cells, whereas in practice pathologists often infer cell classes through their spatial context. In this paper, we propose a novel method for both detection and classification that explicitly incorporates spatial contextual information. We use the spatial statistical function to describe local density in both a multi-class and a multi-scale manner. Through representation learning and deep clustering techniques, we learn advanced cell representation with both appearance and spatial context. On various benchmarks, our method achieves better performance than state-of-the-arts, especially on the classification task. We also create a new dataset for multi-class cell detection and classification in breast cancer and we make both our code and data publicly available.

Annika Reinke, Minu D. Tizabi, Carole H. Sudre et al.

While the importance of automatic image analysis is continuously increasing, recent meta-research revealed major flaws with respect to algorithm validation. Performance metrics are particularly key for meaningful, objective, and transparent performance assessment and validation of the used automatic algorithms, but relatively little attention has been given to the practical pitfalls when using specific metrics for a given image analysis task. These are typically related to (1) the disregard of inherent metric properties, such as the behaviour in the presence of class imbalance or small target structures, (2) the disregard of inherent data set properties, such as the non-independence of the test cases, and (3) the disregard of the actual biomedical domain interest that the metrics should reflect. This living dynamically document has the purpose to illustrate important limitations of performance metrics commonly applied in the field of image analysis. In this context, it focuses on biomedical image analysis problems that can be phrased as image-level classification, semantic segmentation, instance segmentation, or object detection task. The current version is based on a Delphi process on metrics conducted by an international consortium of image analysis experts from more than 60 institutions worldwide.

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

Shahira Abousamra, Le Hou, Rajarsi Gupta et al.

Deep learning classifiers for characterization of whole slide tissue morphology require large volumes of annotated data to learn variations across different tissue and cancer types. As is well known, manual generation of digital pathology training data is time consuming and expensive. In this paper, we propose a semi-automated method for annotating a group of similar instances at once, instead of collecting only per-instance manual annotations. This allows for a much larger training set, that reflects visual variability across multiple cancer types and thus training of a single network which can be automatically applied to each cancer type without human adjustment. We apply our method to the important task of classifying Tumor Infiltrating Lymphocytes (TILs) in H&E images. Prior approaches were trained for individual cancer types, with smaller training sets and human-in-the-loop threshold adjustment. We utilize these thresholded results as large scale "semi-automatic" annotations. Combined with existing manual annotations, our trained deep networks are able to automatically produce better TIL prediction results in 12 cancer types, compared to the human-in-the-loop approach.

Maozheng Zhao, Le Hou, Han Le et al.

For the task of semantic segmentation, high-resolution (pixel-level) ground truth is very expensive to collect, especially for high resolution images such as gigapixel pathology images. On the other hand, collecting low resolution labels (labels for a block of pixels) for these high resolution images is much more cost efficient. Conventional methods trained on these low-resolution labels are only capable of giving low-resolution predictions. The existing state-of-the-art label super resolution (LSR) method is capable of predicting high resolution labels, using only low-resolution supervision, given the joint distribution between low resolution and high resolution labels. However, it does not consider the inter-instance variance which is crucial in the ideal mathematical formulation. In this work, we propose a novel loss function modeling the inter-instance variance. We test our method on a real world application: infiltrating breast cancer region segmentation in histopathology slides. Experimental results show the effectiveness of our method.

Quoc Dang Vu, Simon Graham, Minh Nguyen Nhat To et al.

High-resolution microscopy images of tissue specimens provide detailed information about the morphology of normal and diseased tissue. Image analysis of tissue morphology can help cancer researchers develop a better understanding of cancer biology. Segmentation of nuclei and classification of tissue images are two common tasks in tissue image analysis. Development of accurate and efficient algorithms for these tasks is a challenging problem because of the complexity of tissue morphology and tumor heterogeneity. In this paper we present two computer algorithms; one designed for segmentation of nuclei and the other for classification of whole slide tissue images. The segmentation algorithm implements a multiscale deep residual aggregation network to accurately segment nuclear material and then separate clumped nuclei into individual nuclei. The classification algorithm initially carries out patch-level classification via a deep learning method, then patch-level statistical and morphological features are used as input to a random forest regression model for whole slide image classification. The segmentation and classification algorithms were evaluated in the MICCAI 2017 Digital Pathology challenge. The segmentation algorithm achieved an accuracy score of 0.78. The classification algorithm achieved an accuracy score of 0.81.

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.