When the machine does not know measuring uncertainty in deep learning models of medical images

This thesis was submitted for the award of Doctor of Philosophy and was awarded by Brunel University LondonRecently, Deep learning (DL), which involves powerful black box predictors, has outperformed human experts in several medical diagnostic problems. However, these methods focus exclusively on improving the accuracy of point predictions without assessing their outputs’ quality and ignore the asymmetric cost involved in different types of misclassification errors. Neural networks also do not deliver confidence in predictions and suffer from over and under confidence, i.e. are not well calibrated. Knowing how much confidence there is in a prediction is essential for gaining clinicians’ trust in the technology. Calibrated uncertainty quantification is a challenging problem as no ground truth is available. To address this, we make two observations: (i) cost-sensitive deep neural networks with Dropweights models better quantify calibrated predictive uncertainty, and (ii) estimated uncertainty with point predictions in Deep Ensembles Bayesian Neural Networks with DropWeights can lead to a more informed decision and improve prediction quality. This dissertation focuses on quantifying uncertainty using concepts from cost-sensitive neural networks, calibration of confidence, and Dropweights ensemble method. First, we show how to improve predictive uncertainty by deep ensembles of neural networks with Dropweights learning an approximate distribution over its weights in medical image segmentation and its application in active learning. Second, we use the Jackknife resampling technique to correct bias in quantified uncertainty in image classification and propose metrics to measure uncertainty performance. The third part of the thesis is motivated by the discrepancy between the model predictive error and the objective in quantified uncertainty when costs for misclassification errors or unbalanced datasets are asymmetric. We develop cost-sensitive modifications of the neural networks in disease detection and propose metrics to measure the quality of quantified uncertainty. Finally, we leverage an adaptive binning strategy to measure uncertainty calibration error that directly corresponds to estimated uncertainty performance and address problematic evaluation methods. We evaluate the effectiveness of the tools on nuclei images segmentation, multi-class Brain MRI image classification, multi-level cell type-specific protein expression prediction in ImmunoHistoChemistry (IHC) images and cost-sensitive classification for Covid-19 detection from X-Rays and CT image dataset. Our approach is thoroughly validated by measuring the quality of uncertainty. It produces an equally good or better result and paves the way for the future that addresses the practical problems at the intersection of deep learning and Bayesian decision theory. In conclusion, our study highlights the opportunities and challenges of the application of estimated uncertainty in deep learning models of medical images, representing the confidence of the model’s prediction, and the uncertainty quality metrics show a significant improvement when using Deep Ensembles Bayesian Neural Networks with DropWeights

A Survey on Deep Learning in Medical Image Analysis

Deep learning algorithms, in particular convolutional networks, have rapidly become a methodology of choice for analyzing medical images. This paper reviews the major deep learning concepts pertinent to medical image analysis and summarizes over 300 contributions to the field, most of which appeared in the last year. We survey the use of deep learning for image classification, object detection, segmentation, registration, and other tasks and provide concise overviews of studies per application area. Open challenges and directions for future research are discussed.Comment: Revised survey includes expanded discussion section and reworked introductory section on common deep architectures. Added missed papers from before Feb 1st 201

Robust Intent Classification using Bayesian LSTM for Clinical Conversational Agents (CAs)

Conversational Agents (CAs) are software programs that replicate hu-man conversations using machine learning (ML) and natural language processing (NLP). CAs are currently being utilised for diverse clinical applications such as symptom checking, health monitoring, medical triage and diagnosis. Intent clas-sification (IC) is an essential task of understanding user utterance in CAs which makes use of modern deep learning (DL) methods. Because of the inherent model uncertainty associated with those methods, accuracy alone cannot be relied upon in clinical applications where certain errors may compromise patient safety. In this work, we employ Bayesian Long Short-Term Memory Networks (LSTMs) to calculate model uncertainty for IC, with a specific emphasis on symptom checker CAs. This method provides a certainty measure with IC prediction that can be utilised in assuring safe response from CAs. We evaluated our method on in-distribution (ID) and out-of-distribution (OOD) data and found mean uncer-tainty to be much higher for OOD data. These findings suggest that our method is robust to OOD utterances and can detect non-understanding errors in CAs

Interactive medical image segmentation - towards integrating human guidance and deep learning

Medical image segmentation is an essential step in many clinical workflows involving diagnostics and patient treatment planning. Deep learning has advanced the field of medical image segmentation, particularly with respect to automating contouring. However, some anatomical structures, such as tumours, are challenging for fully automated methods. When automatic methods fail, manual contouring is required. In such cases, semi-automatic tools can support clinicians in contouring tasks. The objective of this thesis was to leverage clinicians’ expert knowledge when performing segmentation tasks, allowing for interactions along the segmentation workflow and improving deep learning predictions. In this thesis, a deep learning approach is proposed that produces a 3D segmentation of a structure of interest based on a user-provided input. If trained on a diverse set of structures, state-of-the-art performance was achieved for structures included in the training set. More importantly, the model was also able to generalize and make predictions for unseen structures that were not represented in the training set. Various avenues to guide user interaction and leverage multiple user inputs more effectively were also investigated. These further improved the segmentation performance and demonstrated the ability to accurately segment a broad range of anatomical structures. An evaluation by clinicians demonstrated that time spent contouring was reduced when using the contextual deep learning tool as compared to conventional contouring tools. This evaluation also revealed that the majority of contouring time is observation time, which is only indirectly affected by the segmentation approach. This suggests, that user interface design and guiding the user’s attention to critical areas can have a large impact on time taken on the contouring task. Overall, this thesis proposes an interactive deep learning segmentation method, demonstrates its clinical impact, and highlights the potential synergies between clinicians and artificial intelligence

DeepHistoClass: A novel strategy for confident classification of immunohistochemistry images using Deep Learning

© 2021 Elsevier Ltd. All rights reserved. This is the accepted manuscript version of the article. The final version is available online from Elsevier at: https://doi.org/10.1016/j.mcpro.2021.100140A multitude of efforts worldwide aim to create a single cell reference map of the human body, for fundamental understanding of human health, molecular medicine and targeted treatment. Antibody-based proteomics using immunohistochemistry (IHC) has proven to be an excellent technology for integration with large-scale single cell transcriptomics datasets. The golden standard for evaluation of IHC staining patterns is manual annotation, which is expensive and may lead to subjective errors. Artificial intelligence holds much promise for efficient and accurate pattern recognition, but confidence in prediction needs to be addressed. Here, the aim was to present a reliable and comprehensive framework for automated annotation of IHC images. We developed a multi-label classification of 7,848 complex IHC images of human testis corresponding to 2,794 unique proteins, generated as part of the Human Protein Atlas (HPA) project. Manual annotation data for eight different cell types was generated as a basis for training and testing a proposed Hybrid Bayesian Neural Network. By combining the deep learning model with a novel uncertainty metric; DeepHistoClass (DHC) confidence score; the average diagnostic performance improved from 86.9% to 96.3%. This metric not only reveals which images are reliably classified by the model, but can also be utilized for identification of manual annotation errors. The proposed streamlined workflow can be developed further for other tissue types in health and disease, and has important implications for digital pathology initiatives or large-scale protein mapping efforts such as the HPA project.Knut and Alice Wallenberg Foundation

Computer aided diagnosis system for breast cancer using deep learning.

The recent rise of big data technology surrounding the electronic systems and developed toolkits gave birth to new promises for Artificial Intelligence (AI). With the continuous use of data-centric systems and machines in our lives, such as social media, surveys, emails, reports, etc., there is no doubt that data has gained the center of attention by scientists and motivated them to provide more decision-making and operational support systems across multiple domains. With the recent breakthroughs in artificial intelligence, the use of machine learning and deep learning models have achieved remarkable advances in computer vision, ecommerce, cybersecurity, and healthcare. Particularly, numerous applications provided efficient solutions to assist radiologists and doctors for medical imaging analysis, which has remained the essence of the visual representation that is used to construct the final observation and diagnosis. Medical research in cancerology and oncology has been recently blended with the knowledge gained from computer engineering and data science experts. In this context, an automatic assistance or commonly known as Computer-aided Diagnosis (CAD) system has become a popular area of research and development in the last decades. As a result, the CAD systems have been developed using multidisciplinary knowledge and expertise and they have been used to analyze the patient information to assist clinicians and practitioners in their decision-making process. Treating and preventing cancer remains a crucial task that radiologists and oncologists face every day to detect and investigate abnormal tumors. Therefore, a CAD system could be developed to provide decision support for many applications in the cancer patient care processes, such as lesion detection, characterization, cancer staging, tumors assessment, recurrence, and prognosis prediction. Breast cancer has been considered one of the common types of cancers in females across the world. It was also considered the leading cause of mortality among women, and it has been increased drastically every year. Early detection and diagnosis of abnormalities in screened breasts has been acknowledged as the optimal solution to examine the risk of developing breast cancer and thus reduce the increasing mortality rate. Accordingly, this dissertation proposes a new state-of-the-art CAD system for breast cancer diagnosis that is based on deep learning technology and cutting-edge computer vision techniques. Mammography screening has been recognized as the most effective tool to early detect breast lesions for reducing the mortality rate. It helps reveal abnormalities in the breast such as Mass lesion, Architectural Distortion, Microcalcification. With the number of daily patients that were screened is continuously increasing, having a second reading tool or assistance system could leverage the process of breast cancer diagnosis. Mammograms could be obtained using different modalities such as X-ray scanner and Full-Field Digital mammography (FFDM) system. The quality of the mammograms, the characteristics of the breast (i.e., density, size) or/and the tumors (i.e., location, size, shape) could affect the final diagnosis. Therefore, radiologists could miss the lesions and consequently they could generate false detection and diagnosis. Therefore, this work was motivated to improve the reading of mammograms in order to increase the accuracy of the challenging tasks. The efforts presented in this work consists of new design and implementation of neural network models for a fully integrated CAD system dedicated to breast cancer diagnosis. The approach is designed to automatically detect and identify breast lesions from the entire mammograms at a first step using fusion models’ methodology. Then, the second step only focuses on the Mass lesions and thus the proposed system should segment the detected bounding boxes of the Mass lesions to mask their background. A new neural network architecture for mass segmentation was suggested that was integrated with a new data enhancement and augmentation technique. Finally, a third stage was conducted using a stacked ensemble of neural networks for classifying and diagnosing the pathology (i.e., malignant, or benign), the Breast Imaging Reporting and Data System (BI-RADS) assessment score (i.e., from 2 to 6), or/and the shape (i.e., round, oval, lobulated, irregular) of the segmented breast lesions. Another contribution was achieved by applying the first stage of the CAD system for a retrospective analysis and comparison of the model on Prior mammograms of a private dataset. The work was conducted by joining the learning of the detection and classification model with the image-to-image mapping between Prior and Current screening views. Each step presented in the CAD system was evaluated and tested on public and private datasets and consequently the results have been fairly compared with benchmark mammography datasets. The integrated framework for the CAD system was also tested for deployment and showcase. The performance of the CAD system for the detection and identification of breast masses reached an overall accuracy of 97%. The segmentation of breast masses was evaluated together with the previous stage and the approach achieved an overall performance of 92%. Finally, the classification and diagnosis step that defines the outcome of the CAD system reached an overall pathology classification accuracy of 96%, a BIRADS categorization accuracy of 93%, and a shape classification accuracy of 90%. Results given in this dissertation indicate that our suggested integrated framework might surpass the current deep learning approaches by using all the proposed automated steps. Limitations of the proposed work could occur on the long training time of the different methods which is due to the high computation of the developed neural networks that have a huge number of the trainable parameters. Future works can include new orientations of the methodologies by combining different mammography datasets and improving the long training of deep learning models. Moreover, motivations could upgrade the CAD system by using annotated datasets to integrate more breast cancer lesions such as Calcification and Architectural distortion. The proposed framework was first developed to help detect and identify suspicious breast lesions in X-ray mammograms. Next, the work focused only on Mass lesions and segment the detected ROIs to remove the tumor’s background and highlight the contours, the texture, and the shape of the lesions. Finally, the diagnostic decision was predicted to classify the pathology of the lesions and investigate other characteristics such as the tumors’ grading assessment and type of the shape. The dissertation presented a CAD system to assist doctors and experts to identify the risk of breast cancer presence. Overall, the proposed CAD method incorporates the advances of image processing, deep learning, and image-to-image translation for a biomedical application

Data synthesis and adversarial networks: A review and meta-analysis in cancer imaging

Despite technological and medical advances, the detection, interpretation, and treatment of cancer based on imaging data continue to pose significant challenges. These include inter-observer variability, class imbalance, dataset shifts, inter- and intra-tumour heterogeneity, malignancy determination, and treatment effect uncertainty. Given the recent advancements in image synthesis, Generative Adversarial Networks (GANs), and adversarial training, we assess the potential of these technologies to address a number of key challenges of cancer imaging. We categorise these challenges into (a) data scarcity and imbalance, (b) data access and privacy, (c) data annotation and segmentation, (d) cancer detection and diagnosis, and (e) tumour profiling, treatment planning and monitoring. Based on our analysis of 164 publications that apply adversarial training techniques in the context of cancer imaging, we highlight multiple underexplored solutions with research potential. We further contribute the Synthesis Study Trustworthiness Test (SynTRUST), a meta-analysis framework for assessing the validation rigour of medical image synthesis studies. SynTRUST is based on 26 concrete measures of thoroughness, reproducibility, usefulness, scalability, and tenability. Based on SynTRUST, we analyse 16 of the most promising cancer imaging challenge solutions and observe a high validation rigour in general, but also several desirable improvements. With this work, we strive to bridge the gap between the needs of the clinical cancer imaging community and the current and prospective research on data synthesis and adversarial networks in the artificial intelligence community