Assessing the Impact of Blood Pressure on Cardiac Function Using Interpretable Biomarkers and Variational Autoencoders

Maintaining good cardiac function for as long as possible is a major concern for healthcare systems worldwide and there is much interest in learning more about the impact of different risk factors on cardiac health. The aim of this study is to analyze the impact of systolic blood pressure (SBP) on cardiac function while preserving the interpretability of the model using known clinical biomarkers in a large cohort of the UK Biobank population. We propose a novel framework that combines deep learning based estimation of interpretable clinical biomarkers from cardiac cine MR data with a variational autoencoder (VAE). The VAE architecture integrates a regression loss in the latent space, which enables the progression of cardiac health with SBP to be learnt. Results on 3,600 subjects from the UK Biobank show that the proposed model allows us to gain important insight into the deterioration of cardiac function with increasing SBP, identify key interpretable factors involved in this process, and lastly exploit the model to understand patterns of positive and adverse adaptation of cardiac function

Machine learning approaches to model cardiac shape in large-scale imaging studies

Recent improvements in non-invasive imaging, together with the introduction of fully-automated segmentation algorithms and big data analytics, has paved the way for large-scale population-based imaging studies. These studies promise to increase our understanding of a large number of medical conditions, including cardiovascular diseases. However, analysis of cardiac shape in such studies is often limited to simple morphometric indices, ignoring large part of the information available in medical images. Discovery of new biomarkers by machine learning has recently gained traction, but often lacks interpretability. The research presented in this thesis aimed at developing novel explainable machine learning and computational methods capable of better summarizing shape variability, to better inform association and predictive clinical models in large-scale imaging studies. A powerful and flexible framework to model the relationship between three-dimensional (3D) cardiac atlases, encoding multiple phenotypic traits, and genetic variables is first presented. The proposed approach enables the detection of regional phenotype-genotype associations that would be otherwise neglected by conventional association analysis. Three learning-based systems based on deep generative models are then proposed. In the first model, I propose a classifier of cardiac shapes which exploits task-specific generative shape features, and it is designed to enable the visualisation of the anatomical effect these features encode in 3D, making the classification task transparent. The second approach models a database of anatomical shapes via a hierarchy of conditional latent variables and it is capable of detecting, quantifying and visualising onto a template shape the most discriminative anatomical features that characterize distinct clinical conditions. Finally, a preliminary analysis of a deep learning system capable of reconstructing 3D high-resolution cardiac segmentations from a sparse set of 2D views segmentations is reported. This thesis demonstrates that machine learning approaches can facilitate high-throughput analysis of normal and pathological anatomy and of its determinants without losing clinical interpretability.Open Acces

Deep Learning Framework for Spleen Volume Estimation from 2D Cross-sectional Views

Abnormal spleen enlargement (splenomegaly) is regarded as a clinical indicator for a range of conditions, including liver disease, cancer and blood diseases. While spleen length measured from ultrasound images is a commonly used surrogate for spleen size, spleen volume remains the gold standard metric for assessing splenomegaly and the severity of related clinical conditions. Computed tomography is the main imaging modality for measuring spleen volume, but it is less accessible in areas where there is a high prevalence of splenomegaly (e.g., the Global South). Our objective was to enable automated spleen volume measurement from 2D cross-sectional segmentations, which can be obtained from ultrasound imaging. In this study, we describe a variational autoencoder-based framework to measure spleen volume from single- or dual-view 2D spleen segmentations. We propose and evaluate three volume estimation methods within this framework. We also demonstrate how 95% confidence intervals of volume estimates can be produced to make our method more clinically useful. Our best model achieved mean relative volume accuracies of 86.62% and 92.58% for single- and dual-view segmentations, respectively, surpassing the performance of the clinical standard approach of linear regression using manual measurements and a comparative deep learning-based 2D-3D reconstruction-based approach. The proposed spleen volume estimation framework can be integrated into standard clinical workflows which currently use 2D ultrasound images to measure spleen length. To the best of our knowledge, this is the first work to achieve direct 3D spleen volume estimation from 2D spleen segmentations.Comment: 22 pages, 7 figure

Deep Learning in Cardiology

The medical field is creating large amount of data that physicians are unable to decipher and use efficiently. Moreover, rule-based expert systems are inefficient in solving complicated medical tasks or for creating insights using big data. Deep learning has emerged as a more accurate and effective technology in a wide range of medical problems such as diagnosis, prediction and intervention. Deep learning is a representation learning method that consists of layers that transform the data non-linearly, thus, revealing hierarchical relationships and structures. In this review we survey deep learning application papers that use structured data, signal and imaging modalities from cardiology. We discuss the advantages and limitations of applying deep learning in cardiology that also apply in medicine in general, while proposing certain directions as the most viable for clinical use.Comment: 27 pages, 2 figures, 10 table

Learning Better Clinical Risk Models.

Risk models are used to estimate a patient’s risk of suffering particular outcomes throughout clinical practice. These models are important for matching patients to the appropriate level of treatment, for effective allocation of resources, and for fairly evaluating the performance of healthcare providers. The application and development of methods from the field of machine learning has the potential to improve patient outcomes and reduce healthcare spending with more accurate estimates of patient risk. This dissertation addresses several limitations of currently used clinical risk models, through the identification of novel risk factors and through the training of more effective models. As wearable monitors become more effective and less costly, the previously untapped predictive information in a patient’s physiology over time has the potential to greatly improve clinical practice. However translating these technological advances into real-world clinical impacts will require computational methods to identify high-risk structure in the data. This dissertation presents several approaches to learning risk factors from physiological recordings, through the discovery of latent states using topic models, and through the identification of predictive features using convolutional neural networks. We evaluate these approaches on patients from a large clinical trial and find that these methods not only outperform prior approaches to leveraging heart rate for cardiac risk stratification, but that they improve overall prediction of cardiac death when considered alongside standard clinical risk factors. We also demonstrate the utility of this work for learning a richer description of sleep recordings. Additionally, we consider the development of risk models in the presence of missing data, which is ubiquitous in real-world medical settings. We present a novel method for jointly learning risk and imputation models in the presence of missing data, and find significant improvements relative to standard approaches when evaluated on a large national registry of trauma patients.PhDComputer Science and EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/113326/1/alexve_1.pd

Recent Advances in Variational Autoencoders With Representation Learning for Biomedical Informatics: A Survey

Variational autoencoders (VAEs) are deep latent space generative models that have been immensely successful in multiple exciting applications in biomedical informatics such as molecular design, protein design, medical image classification and segmentation, integrated multi-omics data analyses, and large-scale biological sequence analyses, among others. The fundamental idea in VAEs is to learn the distribution of data in such a way that new meaningful data with more intra-class variations can be generated from the encoded distribution. The ability of VAEs to synthesize new data with more representation variance at state-of-art levels provides hope that the chronic scarcity of labeled data in the biomedical field can be resolved. Furthermore, VAEs have made nonlinear latent variable models tractable for modeling complex distributions. This has allowed for efficient extraction of relevant biomedical information from learned features for biological data sets, referred to as unsupervised feature representation learning. In this article, we review the various recent advancements in the development and application of VAEs for biomedical informatics. We discuss challenges and future opportunities for biomedical research with respect to VAEs.https://doi.org/10.1109/ACCESS.2020.304830

Computational approaches to Explainable Artificial Intelligence: Advances in theory, applications and trends

Deep Learning (DL), a groundbreaking branch of Machine Learning (ML), has emerged as a driving force in both theoretical and applied Artificial Intelligence (AI). DL algorithms, rooted in complex and non-linear artificial neural systems, excel at extracting high-level features from data. DL has demonstrated human-level performance in real-world tasks, including clinical diagnostics, and has unlocked solutions to previously intractable problems in virtual agent design, robotics, genomics, neuroimaging, computer vision, and industrial automation. In this paper, the most relevant advances from the last few years in Artificial Intelligence (AI) and several applications to neuroscience, neuroimaging, computer vision, and robotics are presented, reviewed and discussed. In this way, we summarize the state-of-the-art in AI methods, models and applications within a collection of works presented at the 9 International Conference on the Interplay between Natural and Artificial Computation (IWINAC). The works presented in this paper are excellent examples of new scientific discoveries made in laboratories that have successfully transitioned to real-life applications

Advanced machine learning methods for oncological image analysis

Cancer is a major public health problem, accounting for an estimated 10 million deaths worldwide in 2020 alone. Rapid advances in the field of image acquisition and hardware development over the past three decades have resulted in the development of modern medical imaging modalities that can capture high-resolution anatomical, physiological, functional, and metabolic quantitative information from cancerous organs. Therefore, the applications of medical imaging have become increasingly crucial in the clinical routines of oncology, providing screening, diagnosis, treatment monitoring, and non/minimally- invasive evaluation of disease prognosis. The essential need for medical images, however, has resulted in the acquisition of a tremendous number of imaging scans. Considering the growing role of medical imaging data on one side and the challenges of manually examining such an abundance of data on the other side, the development of computerized tools to automatically or semi-automatically examine the image data has attracted considerable interest. Hence, a variety of machine learning tools have been developed for oncological image analysis, aiming to assist clinicians with repetitive tasks in their workflow. This thesis aims to contribute to the field of oncological image analysis by proposing new ways of quantifying tumor characteristics from medical image data. Specifically, this thesis consists of six studies, the first two of which focus on introducing novel methods for tumor segmentation. The last four studies aim to develop quantitative imaging biomarkers for cancer diagnosis and prognosis. The main objective of Study I is to develop a deep learning pipeline capable of capturing the appearance of lung pathologies, including lung tumors, and integrating this pipeline into the segmentation networks to leverage the segmentation accuracy. The proposed pipeline was tested on several comprehensive datasets, and the numerical quantifications show the superiority of the proposed prior-aware DL framework compared to the state of the art. Study II aims to address a crucial challenge faced by supervised segmentation models: dependency on the large-scale labeled dataset. In this study, an unsupervised segmentation approach is proposed based on the concept of image inpainting to segment lung and head- neck tumors in images from single and multiple modalities. The proposed autoinpainting pipeline shows great potential in synthesizing high-quality tumor-free images and outperforms a family of well-established unsupervised models in terms of segmentation accuracy. Studies III and IV aim to automatically discriminate the benign from the malignant pulmonary nodules by analyzing the low-dose computed tomography (LDCT) scans. In Study III, a dual-pathway deep classification framework is proposed to simultaneously take into account the local intra-nodule heterogeneities and the global contextual information. Study IV seeks to compare the discriminative power of a series of carefully selected conventional radiomics methods, end-to-end Deep Learning (DL) models, and deep features-based radiomics analysis on the same dataset. The numerical analyses show the potential of fusing the learned deep features into radiomic features for boosting the classification power. Study V focuses on the early assessment of lung tumor response to the applied treatments by proposing a novel feature set that can be interpreted physiologically. This feature set was employed to quantify the changes in the tumor characteristics from longitudinal PET-CT scans in order to predict the overall survival status of the patients two years after the last session of treatments. The discriminative power of the introduced imaging biomarkers was compared against the conventional radiomics, and the quantitative evaluations verified the superiority of the proposed feature set. Whereas Study V focuses on a binary survival prediction task, Study VI addresses the prediction of survival rate in patients diagnosed with lung and head-neck cancer by investigating the potential of spherical convolutional neural networks and comparing their performance against other types of features, including radiomics. While comparable results were achieved in intra- dataset analyses, the proposed spherical-based features show more predictive power in inter-dataset analyses. In summary, the six studies incorporate different imaging modalities and a wide range of image processing and machine-learning techniques in the methods developed for the quantitative assessment of tumor characteristics and contribute to the essential procedures of cancer diagnosis and prognosis

Exploring variability in medical imaging

Although recent successes of deep learning and novel machine learning techniques improved the perfor- mance of classification and (anomaly) detection in computer vision problems, the application of these methods in medical imaging pipeline remains a very challenging task. One of the main reasons for this is the amount of variability that is encountered and encapsulated in human anatomy and subsequently reflected in medical images. This fundamental factor impacts most stages in modern medical imaging processing pipelines. Variability of human anatomy makes it virtually impossible to build large datasets for each disease with labels and annotation for fully supervised machine learning. An efficient way to cope with this is to try and learn only from normal samples. Such data is much easier to collect. A case study of such an automatic anomaly detection system based on normative learning is presented in this work. We present a framework for detecting fetal cardiac anomalies during ultrasound screening using generative models, which are trained only utilising normal/healthy subjects. However, despite the significant improvement in automatic abnormality detection systems, clinical routine continues to rely exclusively on the contribution of overburdened medical experts to diagnosis and localise abnormalities. Integrating human expert knowledge into the medical imaging processing pipeline entails uncertainty which is mainly correlated with inter-observer variability. From the per- spective of building an automated medical imaging system, it is still an open issue, to what extent this kind of variability and the resulting uncertainty are introduced during the training of a model and how it affects the final performance of the task. Consequently, it is very important to explore the effect of inter-observer variability both, on the reliable estimation of model’s uncertainty, as well as on the model’s performance in a specific machine learning task. A thorough investigation of this issue is presented in this work by leveraging automated estimates for machine learning model uncertainty, inter-observer variability and segmentation task performance in lung CT scan images. Finally, a presentation of an overview of the existing anomaly detection methods in medical imaging was attempted. This state-of-the-art survey includes both conventional pattern recognition methods and deep learning based methods. It is one of the first literature surveys attempted in the specific research area.Open Acces

Representation learning for generalisation in medical image analysis

To help diagnose, treat, manage, prevent and predict diseases, medical image analysis plays an increasingly crucial role in modern health care. In particular, using machine learning (ML) and deep learning (DL) techniques to process medical imaging data such as MRI, CT and X-Rays scans has been a research hot topic. Accurate and generalisable medical image segmentation using ML and DL is one of the most challenging medical image analysis tasks. The challenges are mainly caused by two key reasons: a) the variations of data statistics across different clinical centres or hospitals, and b) the lack of extensive annotations of medical data. To tackle the above challenges, one of the best ways is to learn disentangled representations. Learning disentangled representations aims to separate out, or disentangle, the underlying explanatory generative factors into disjoint subsets. Importantly, disentangled representations can be efficiently learnt from raw training data with limited annotations. Although, it is evident that learning disentangled representations is well suited for the challenges, there are several open problems in this area. First, there is no work to systematically study how much disentanglement is achieved with different learning and design biases and how different biases affect the task performance for medical data. Second, the benefit of leveraging disentanglement to design models that generalise well on new data has not been well studied especially in medical domain. Finally, the independence prior for disentanglement is a too strong assumption that does not approximate well the true generative factors. According to these problems, this thesis focuses on understanding the role of disentanglement in medical image analysis, measuring how different biases affect disentanglement and the task performance, and then finally using disentangled representations to improve generalisation performance and exploring better representations beyond disentanglement. In the medical domain, content-style disentanglement is one of the most effective frameworks to learn disentangled presentations. It disentangles and encodes image “content” into a spatial tensor, and image appearance or “style” into a vector that contains information on imaging characteristics. Based on an extensive review of disentanglement, I conclude that it is unclear how different design and learning biases affect the performance of content-style disentanglement methods. Hence, two metrics are proposed to measure the degree of content-style disentanglement by evaluating the informativeness and correlation of representations. By modifying the design and learning biases in three popular content-style disentanglement models, the degree of disentanglement and task performance of different model variants have been evaluated. A key conclusion is that there exists a sweet spot between task performance and the degree of disentanglement; achieving this sweet spot is the key to design disentanglement models. Generalising deep models to new data from new centres (termed here domains) remains a challenge. This is largely attributed to shifts in data statistics (domain shifts) between source and unseen domains. With the findings of aforementioned disentanglement metrics study, I design two content-style disentanglement approaches for generalisation. First, I propose two data augmentation methods that improve generalisation. The Resolution Augmentation method generates more diverse data by rescaling images to different resolutions. Subsequently, the Factor-based Augmentation method generates more diverse data by projecting the original samples onto disentangled latent spaces, and combining the learned content and style factors from different domains. To learn more generalisable representations, I integrate gradient-based meta-learning in disentanglement. Gradient-based meta-learning splits the training data into meta-train and meta-test sets to simulate and handle the domain shifts during training, which has shown superior generalisation performance. Considering limited annotations of data, I propose a novel semi-supervised meta-learning framework with disentanglement. I explicitly model the representations related to domain shifts. Disentangling the representations and combining them to reconstruct the input image, allows unlabeled data to be used to better approximate the true domain shifts within a meta-learning setting. Humans can quickly learn to accurately recognise anatomy of interest from medical images with limited guidance. Such recognition ability can easily generalise to new images from different clinical centres and new tasks in other contexts. This rapid and generalisable learning ability is mostly due to the compositional structure of image patterns in the human brain, which is less incorporated in the medical domain. In this thesis, I explore how compositionality can be applied to learning more interpretable and generalisable representations. Overall, I propose that the ground-truth generative factors that generate the medical images satisfy the compositional equivariance property. Hence, a good representation that approximates well the ground-truth factor has to be compositionally equivariant. By modelling the compositional representations with the learnable von-Mises-Fisher kernels, I explore how different design and learning biases can be used to enforce the representations to be more compositionally equivariant under different learning settings. Overall, this thesis creates new avenues for further research in the area of generalisable representation learning in medical image analysis, which we believe are key to more generalised machine learning and deep learning solutions in healthcare. In particular, the proposed metrics can be used to guide future work on designing better content-style frameworks. The disentanglement-based meta-learning approach sheds light on leveraging meta-learning for better model generalisation in a low-data regime. Finally, compositional representation learning we believe will play an increasingly important role in designing more generalisable and interpretable models in the future