Beyond attention: deriving biologically interpretable insights from weakly-supervised multiple-instance learning models

Recent advances in attention-based multiple instance learning (MIL) have improved our insights into the tissue regions that models rely on to make predictions in digital pathology. However, the interpretability of these approaches is still limited. In particular, they do not report whether high-attention regions are positively or negatively associated with the class labels or how well these regions correspond to previously established clinical and biological knowledge. We address this by introducing a post-training methodology to analyse MIL models. Firstly, we introduce prediction-attention-weighted (PAW) maps by combining tile-level attention and prediction scores produced by a refined encoder, allowing us to quantify the predictive contribution of high-attention regions. Secondly, we introduce a biological feature instantiation technique by integrating PAW maps with nuclei segmentation masks. This further improves interpretability by providing biologically meaningful features related to the cellular organisation of the tissue and facilitates comparisons with known clinical features. We illustrate the utility of our approach by comparing PAW maps obtained for prostate cancer diagnosis (i.e. samples containing malignant tissue, 381/516 tissue samples) and prognosis (i.e. samples from patients with biochemical recurrence following surgery, 98/663 tissue samples) in a cohort of patients from the international cancer genome consortium (ICGC UK Prostate Group). Our approach reveals that regions that are predictive of adverse prognosis do not tend to co-locate with the tumour regions, indicating that non-cancer cells should also be studied when evaluating prognosis.

SSL-CPCD: Self-supervised learning with composite pretext-class discrimination for improved generalisability in endoscopic image analysis

Data-driven methods have shown tremendous progress in medical image analysis. In this context, deep learning-based supervised methods are widely popular. However, they require a large amount of training data and face issues in generalisability to unseen datasets that hinder clinical translation. Endoscopic imaging data incorporates large inter- and intra-patient variability that makes these models more challenging to learn representative features for downstream tasks. Thus, despite the publicly available datasets and datasets that can be generated within hospitals, most supervised models still underperform. While self-supervised learning has addressed this problem to some extent in natural scene data, there is a considerable performance gap in the medical image domain. In this paper, we propose to explore patch-level instance-group discrimination and penalisation of inter-class variation using additive angular margin within the cosine similarity metrics. Our novel approach enables models to learn to cluster similar representative patches, thereby improving their ability to provide better separation between different classes. Our results demonstrate significant improvement on all metrics over the state-of-the-art (SOTA) methods on the test set from the same and diverse datasets. We evaluated our approach for classification, detection, and segmentation. SSL-CPCD achieves 79.77% on Top 1 accuracy for ulcerative colitis classification, 88.62% on mAP for polyp detection, and 82.32% on dice similarity coefficient for segmentation tasks are nearly over 4%, 2%, and 3%, respectively, compared to the baseline architectures. We also demonstrate that our method generalises better than all SOTA methods to unseen datasets, reporting nearly 7% improvement in our generalisability assessment.

Patch-level instance-group discrimination with pretext-invariant learning for colitis scoring

Inflammatory bowel disease (IBD), in particular ulcerative colitis (UC), is graded by endoscopists and this assessment is the basis for risk stratification and therapy monitoring. Presently, endoscopic characterisation is largely operator dependant leading to sometimes undesirable clinical outcomes for patients with IBD. We focus on the Mayo Endoscopic Scoring (MES) system which is widely used but requires the reliable identification of subtle changes in mucosal inflammation. Most existing deep learning classification methods cannot detect these fine-grained changes which make UC grading such a challenging task. In this work, we introduce a novel patch-level instance-group discrimination with pretext-invariant representation learning (PLD-PIRL) for self-supervised learning (SSL). Our experiments demonstrate both improved accuracy and robustness compared to the baseline supervised network and several state-of-the-art SSL methods. Compared to the baseline (ResNet50) supervised classification our proposed PLD-PIRL obtained an improvement of 4.75% on hold-out test data and 6.64% on unseen center test data for top-1 accuracy.

Assessing generalisability of deep learning-based polyp detection and segmentation methods through a computer vision challenge

Polyps are well-known cancer precursors identified by colonoscopy. However, variability in their size, location, and surface largely affect identification, localisation, and characterisation. Moreover, colonoscopic surveillance and removal of polyps (referred to as polypectomy ) are highly operator-dependent procedures. There exist a high missed detection rate and incomplete removal of colonic polyps due to their variable nature, the difficulties to delineate the abnormality, the high recurrence rates, and the anatomical topography of the colon. There have been several developments in realising automated methods for both detection and segmentation of these polyps using machine learning. However, the major drawback in most of these methods is their ability to generalise to out-of-sample unseen datasets that come from different centres, modalities and acquisition systems. To test this hypothesis rigorously we curated a multi-centre and multi-population dataset acquired from multiple colonoscopy systems and challenged teams comprising machine learning experts to develop robust automated detection and segmentation methods as part of our crowd-sourcing Endoscopic computer vision challenge (EndoCV) 2021. In this paper, we analyse the detection results of the four top (among seven) teams and the segmentation results of the five top teams (among 16). Our analyses demonstrate that the top-ranking teams concentrated on accuracy (i.e., accuracy > 80% on overall Dice score on different validation sets) over real-time performance required for clinical applicability. We further dissect the methods and provide an experiment-based hypothesis that reveals the need for improved generalisability to tackle diversity present in multi-centre datasets.

A Graph Based Neural Network Approach to Immune Profiling of Multiplexed Tissue Samples

Multiplexed immunofluorescence provides an unprecedented opportunity for studying specific cell-to-cell and cell microenvironment interactions. We employ graph neural networks to combine features obtained from tissue morphology with measurements of protein expression to profile the tumour microenvironment associated with different tumour stages. Our framework presents a new approach to analysing and processing these complex multi-dimensional datasets that overcomes some of the key challenges in analysing these data and opens up the opportunity to abstract biologically meaningful interactions.

EndoUDA: A modality independent segmentation approach for endoscopy imaging

Gastrointestinal (GI) cancer precursors require frequent monitoring for risk stratification of patients. Automated segmentation methods can help to assess risk areas more accurately, and assist in therapeutic procedures or even removal. In clinical practice, addition to the conventional white-light imaging (WLI), complimentary modalities such as narrow-band imaging (NBI) and fluorescence imaging are used. While, today most segmentation approaches are supervised and only concentrated on a single modality dataset, this work exploits to use a target-independent unsupervised domain adaptation (UDA) technique that is capable to generalize to an unseen target modality. In this context, we propose a novel UDA-based segmentation method that couples the variational autoencoder and U-Net with a common EfficientNet-B4 backbone, and uses a joint loss for latent-space optimization for target samples. We show that our model can generalize to unseen target NBI (target) modality when trained using only WLI (source) modality. Our experiments on both upper and lower GI endoscopy data show the effectiveness of our approach compared to naive supervised approach and state-of-the-art UDA segmentation methods.

PolypGen: A multi-center polyp detection and segmentation dataset for generalisability assessment

Polyps in the colon are widely known as cancer precursors identified by colonoscopy either related to diagnostic work-up for symptoms, colorectal cancer screening or systematic surveillance of certain diseases. Whilst most polyps are benign, the number, size and the surface structure of the polyp are tightly linked to the risk of colon cancer. There exists a high missed detection rate and incomplete removal of colon polyps due to the variable nature, difficulties to delineate the abnormality, high recurrence rates and the anatomical topography of the colon. In the past, several methods have been built to automate polyp detection and segmentation. However, the key issue of most methods is that they have not been tested rigorously on a large multi-center purpose-built dataset. Thus, these methods may not generalise to different population datasets as they overfit to a specific population and endoscopic surveillance. To this extent, we have curated a dataset from 6 different centers incorporating more than 300 patients. The dataset includes both single frame and sequence data with 3446 annotated polyp labels with precise delineation of polyp boundaries verified by six senior gastroenterologists. To our knowledge, this is the most comprehensive detection and pixel-level segmentation dataset curated by a team of computational scientists and expert gastroenterologists. This dataset has been originated as the part of the Endocv2021 challenge aimed at addressing generalisability in polyp detection and segmentation. In this paper, we provide comprehensive insight into data construction and annotation strategies, annotation quality assurance and technical validation for our extended EndoCV2021 dataset which we refer to as PolypGen.

Multi-class motion-based semantic segmentation for ureteroscopy and laser lithotripsy

Kidney stones represent a considerable burden for public health-care systems. Ureteroscopy with laser lithotripsy has evolved as the most commonly used technique for the treatment of kidney stones. Automated segmentation of kidney stones and laser fiber is an important initial step to performing any automated quantitative analysis of the stones, particularly stone-size estimation, that helps the surgeon decide if the stone requires more fragmentation. Factors such as turbid fluid inside the cavity, specularities, motion blur due to kidney movements and camera motion, bleeding, and stone debris impact the quality of vision within the kidney and lead to extended operative times. To the best of our knowledge, this is the first attempt made towards multi-class segmentation in ureteroscopy and laser lithotripsy data. We propose an end-to-end CNN-based framework for the segmentation of stones and laser fiber. The proposed approach utilizes two sub-networks: HybResUNet, a version of residual U-Net, that uses residual connections in the encoder path of U-Net and a DVFNet that generates DVF predictions which are then used to prune the prediction maps. We also present ablation studies that combine dilated convolutions, recurrent and residual connections, ASPP and attention gate. We propose a compound loss function that improves our segmentation performance. We have also provided an ablation study to determine the optimal data augmentation strategy. Our qualitative and quantitative results illustrate that our proposed method outperforms SOTA methods such as UNet and DeepLabv3+ showing an improvement of 5.2% and 15.93%, respectively, for the combined mean of DSC and JI in our invivo test dataset. We also show that our proposed model generalizes better on a new clinical dataset showing a mean improvement of 25.4%, 20%, and 11% over UNet, HybResUNet, and DeepLabv3+, respectively, for the same metric.

FANet: A Feedback Attention Network for Improved Biomedical Image Segmentation

With the increase in available large clinical and experimental datasets, there has been substantial amount of work being done on addressing the challenges in the area of biomedical image analysis. Image segmentation, which is crucial for any quantitative analysis, has especially attracted attention. Recent hardware advancement has led to the success of deep learning approaches. However, although deep learning models are being trained on large datasets, existing methods do not use the information from different learning epochs effectively. In this work, we leverage the information of each training epoch to prune the prediction maps of the subsequent epochs. We propose a novel architecture called feedback attention network (FANet) that unifies the previous epoch mask with the feature map of the current training epoch. The previous epoch mask is then used to provide a hard attention to the learnt feature maps at different convolutional layers. The network also allows to rectify the predictions in an iterative fashion during the test time. We show that our proposed feedback attention model provides a substantial improvement on most segmentation metrics tested on seven publicly available biomedical imaging datasets demonstrating the effectiveness of the proposed FANet.

Unsupervised Adversarial Domain Adaptation For Barrett's Segmentation

Barrett's oesophagus (BE) is one of the early indicators of esophageal cancer. Patients with BE are monitored and undergo ablation therapies to minimise the risk, thereby making it eminent to identify the BE area precisely. Automated segmentation can help clinical endoscopists to assess and treat BE area more accurately. Endoscopy imaging of BE can include multiple modalities in addition to the conventional white light (WL) modality. Supervised models require large amount of manual annotations incorporating all data variability in the training data. However, it becomes cumbersome, tedious and labour intensive work to generate manual annotations, and additionally modality specific expertise is required. In this work, we aim to alleviate this problem by applying an unsupervised domain adaptation technique (UDA). Here, UDA is trained on white light endoscopy images as source domain and are well-adapted to generalise to produce segmentation on different imaging modalities as target domain, namely narrow band imaging and post acetic-acid WL imaging. Our dataset consists of a total of 871 images consisting of both source and target domains. Our results show that the UDA-based approach outperforms traditional supervised U-Net segmentation by nearly 10% on both Dice similarity coefficient and intersection-over-union.