Unsupervised Mutual Transformer Learning for Multi-Gigapixel Whole Slide Image Classification

Classification of gigapixel Whole Slide Images (WSIs) is an important prediction task in the emerging area of computational pathology. There has been a surge of research in deep learning models for WSI classification with clinical applications such as cancer detection or prediction of molecular mutations from WSIs. Most methods require expensive and labor-intensive manual annotations by expert pathologists. Weakly supervised Multiple Instance Learning (MIL) methods have recently demonstrated excellent performance; however, they still require large slide-level labeled training datasets that need a careful inspection of each slide by an expert pathologist. In this work, we propose a fully unsupervised WSI classification algorithm based on mutual transformer learning. Instances from gigapixel WSI (i.e., image patches) are transformed into a latent space and then inverse-transformed to the original space. Using the transformation loss, pseudo-labels are generated and cleaned using a transformer label-cleaner. The proposed transformer-based pseudo-label generation and cleaning modules mutually train each other iteratively in an unsupervised manner. A discriminative learning mechanism is introduced to improve normal versus cancerous instance labeling. In addition to unsupervised classification, we demonstrate the effectiveness of the proposed framework for weak supervision for cancer subtype classification as downstream analysis. Extensive experiments on four publicly available datasets show excellent performance compared to the state-of-the-art methods. We intend to make the source code of our algorithm publicly available soon.

Interpretable histopathology-based prediction of disease relevant features in Inflammatory Bowel Disease biopsies using weakly-supervised deep learning

Crohn's Disease (CD) and Ulcerative Colitis (UC) are the two main Inflammatory Bowel Disease (IBD) types. We developed deep learning models to identify histological disease features for both CD and UC using only endoscopic labels. We explored fine-tuning and end-to-end training of two state-of-the-art self-supervised models for predicting three different endoscopic categories (i) CD vs UC (AUC=0.87), (ii) normal vs lesional (AUC=0.81), (iii) low vs high disease severity score (AUC=0.80). We produced visual attention maps to interpret what the models learned and validated them with the support of a pathologist, where we observed a strong association between the models' predictions and histopathological inflammatory features of the disease. Additionally, we identified several cases where the model incorrectly predicted normal samples as lesional but were correct on the microscopic level when reviewed by the pathologist. This tendency of histological presentation to be more severe than endoscopic presentation was previously published in the literature. In parallel, we utilised a model trained on the Colon Nuclei Identification and Counting (CoNIC) dataset to predict and explore 6 cell populations. We observed correlation between areas enriched with the predicted immune cells in biopsies and the pathologist's feedback on the attention maps. Finally, we identified several cell level features indicative of disease severity in CD and UC. These models can enhance our understanding about the pathology behind IBD and can shape our strategies for patient stratification in clinical trials.

Mimicking a Pathologist: Dual Attention Model for Scoring of Gigapixel Histology Images

Some major challenges associated with the automated processing of whole slide images (WSIs) includes their sheer size, different magnification levels and high resolution. Utilizing these images directly in AI frameworks is computationally expensive due to memory constraints, while downsampling WSIs incurs information loss and splitting WSIs into tiles and patches results in loss of important contextual information. We propose a novel dual attention approach, consisting of two main components, to mimic visual examination by a pathologist. The first component is a soft attention model which takes as input a high-level view of the WSI to determine various regions of interest. We employ a custom sampling method to extract diverse and spatially distinct image tiles from selected high attention areas. The second component is a hard attention classification model, which further extracts a sequence of multi-resolution glimpses from each tile for classification. Since hard attention is non-differentiable, we train this component using reinforcement learning and predict the location of glimpses without processing all patches of a given tile, thereby aligning with pathologist's way of diagnosis. We train our components both separately and in an end-to-end fashion using a joint loss function to demonstrate the efficacy of our proposed model. We employ our proposed model on two different IHC use cases: HER2 prediction on breast cancer and prediction of Intact/Loss status of two MMR biomarkers, for colorectal cancer. We show that the proposed model achieves accuracy comparable to state-of-the-art methods while only processing a small fraction of the WSI at highest magnification.

Consistency Regularisation in Varying Contexts and Feature Perturbations for Semi-Supervised Semantic Segmentation of Histology Images

Semantic segmentation of various tissue and nuclei types in histology images is fundamental to many downstream tasks in the area of computational pathology (CPath). In recent years, Deep Learning (DL) methods have been shown to perform well on segmentation tasks but DL methods generally require a large amount of pixel-wise annotated data. Pixel-wise annotation sometimes requires expert's knowledge and time which is laborious and costly to obtain. In this paper, we present a consistency based semi-supervised learning (SSL) approach that can help mitigate this challenge by exploiting a large amount of unlabelled data for model training thus alleviating the need for a large annotated dataset. However, SSL models might also be susceptible to changing context and features perturbations exhibiting poor generalisation due to the limited training data. We propose an SSL method that learns robust features from both labelled and unlabelled images by enforcing consistency against varying contexts and feature perturbations. The proposed method incorporates context-aware consistency by contrasting pairs of overlapping images in a pixel-wise manner from changing contexts resulting in robust and context invariant features. We show that cross-consistency training makes the encoder features invariant to different perturbations and improves the prediction confidence. Finally, entropy minimisation is employed to further boost the confidence of the final prediction maps from unlabelled data. We conduct an extensive set of experiments on two publicly available large datasets (BCSS and MoNuSeg) and show superior performance compared to the state-of-the-art methods.

Multiple Instance Learning with Auxiliary Task Weighting for Multiple Myeloma Classification

Whole body magnetic resonance imaging (WB-MRI) is the recommended modality for diagnosis of multiple myeloma (MM). WB-MRI is used to detect sites of disease across the entire skeletal system, but it requires significant expertise and is time-consuming to report due to the great number of images. To aid radiological reading, we propose an auxiliary task-based multiple instance learning approach (ATMIL) for MM classification with the ability to localize sites of disease. This approach is appealing as it only requires patient-level annotations where an attention mechanism is used to identify local regions with active disease. We borrow ideas from multi-task learning and define an auxiliary task with adaptive reweighting to support and improve learning efficiency in the presence of data scarcity. We validate our approach on both synthetic and real multi-center clinical data. We show that the MIL attention module provides a mechanism to localize bone regions while the adaptive reweighting of the auxiliary task considerably improves the performance.

Classification of COVID-19 via Homology of CT-SCAN

In this worldwide spread of SARS-CoV-2 (COVID-19) infection, it is of utmost importance to detect the disease at an early stage especially in the hot spots of this epidemic. There are more than 110 Million infected cases on the globe, sofar. Due to its promptness and effective results computed tomography (CT)-scan image is preferred to the reverse-transcription polymerase chain reaction (RT-PCR). Early detection and isolation of the patient is the only possible way of controlling the spread of the disease. Automated analysis of CT-Scans can provide enormous support in this process. In this article, We propose a novel approach to detect SARS-CoV-2 using CT-scan images. Our method is based on a very intuitive and natural idea of analyzing shapes, an attempt to mimic a professional medic. We mainly trace SARS-CoV-2 features by quantifying their topological properties. We primarily use a tool called persistent homology, from Topological Data Analysis (TDA), to compute these topological properties. We train and test our model on the "SARS-CoV-2 CT-scan dataset" \citep{soares2020sars}, an open-source dataset, containing 2,481 CT-scans of normal and COVID-19 patients. Our model yielded an overall benchmark F1 score of $99.42\% $, accuracy $99.416\%$, precision $99.41\%$, and recall $99.42\%$. The TDA techniques have great potential that can be utilized for efficient and prompt detection of COVID-19. The immense potential of TDA may be exploited in clinics for rapid and safe detection of COVID-19 globally, in particular in the low and middle-income countries where RT-PCR labs and/or kits are in a serious crisis.

HydraMix-Net: A Deep Multi-task Semi-supervised Learning Approach for Cell Detection and Classification

Semi-supervised techniques have removed the barriers of large scale labelled set by exploiting unlabelled data to improve the performance of a model. In this paper, we propose a semi-supervised deep multi-task classification and localization approach HydraMix-Net in the field of medical imagining where labelling is time consuming and costly. Firstly, the pseudo labels are generated using the model's prediction on the augmented set of unlabelled image with averaging. The high entropy predictions are further sharpened to reduced the entropy and are then mixed with the labelled set for training. The model is trained in multi-task learning manner with noise tolerant joint loss for classification localization and achieves better performance when given limited data in contrast to a simple deep model. On DLBCL data it achieves 80\% accuracy in contrast to simple CNN achieving 70\% accuracy when given only 100 labelled examples.

Learning Where to See: A Novel Attention Model for Automated Immunohistochemical Scoring

Estimating over-amplification of human epidermal growth factor receptor 2 (HER2) on invasive breast cancer (BC) is regarded as a significant predictive and prognostic marker. We propose a novel deep reinforcement learning (DRL) based model that treats immunohistochemical (IHC) scoring of HER2 as a sequential learning task. For a given image tile sampled from multi-resolution giga-pixel whole slide image (WSI), the model learns to sequentially identify some of the diagnostically relevant regions of interest (ROIs) by following a parameterized policy. The selected ROIs are processed by recurrent and residual convolution networks to learn the discriminative features for different HER2 scores and predict the next location, without requiring to process all the sub-image patches of a given tile for predicting the HER2 score, mimicking the histopathologist who would not usually analyze every part of the slide at the highest magnification. The proposed model incorporates a task-specific regularization term and inhibition of return mechanism to prevent the model from revisiting the previously attended locations. We evaluated our model on two IHC datasets: a publicly available dataset from the HER2 scoring challenge contest and another dataset consisting of WSIs of gastroenteropancreatic neuroendocrine tumor sections stained with Glo1 marker. We demonstrate that the proposed model outperforms other methods based on state-of-the-art deep convolutional networks. To the best of our knowledge, this is the first study using DRL for IHC scoring and could potentially lead to wider use of DRL in the domain of computational pathology reducing the computational burden of the analysis of large multigigapixel histology images.

Methods for Segmentation and Classification of Digital Microscopy Tissue Images

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.

Leveraging Unlabeled Whole-Slide-Images for Mitosis Detection

Mitosis count is an important biomarker for prognosis of various cancers. At present, pathologists typically perform manual counting on a few selected regions of interest in breast whole-slide-images (WSIs) of patient biopsies. This task is very time-consuming, tedious and subjective. Automated mitosis detection methods have made great advances in recent years. However, these methods require exhaustive labeling of a large number of selected regions of interest. This task is very expensive because expert pathologists are needed for reliable and accurate annotations. In this paper, we present a semi-supervised mitosis detection method which is designed to leverage a large number of unlabeled breast cancer WSIs. As a result, our method capitalizes on the growing number of digitized histology images, without relying on exhaustive annotations, subsequently improving mitosis detection. Our method first learns a mitosis detector from labeled data, uses this detector to mine additional mitosis samples from unlabeled WSIs, and then trains the final model using this larger and diverse set of mitosis samples. The use of unlabeled data improves F1-score by $\sim$5\% compared to our best performing fully-supervised model on the TUPAC validation set. Our submission (single model) to TUPAC challenge ranks highly on the leaderboard with an F1-score of 0.64.