Automated deep phenotyping of the cardiovascular system using magnetic resonance imaging

Across a lifetime, the cardiovascular system must adapt to a great range of demands from the body. The individual changes in the cardiovascular system that occur in response to loading conditions are influenced by genetic susceptibility, and the pattern and extent of these changes have prognostic value. Brachial blood pressure (BP) and left ventricular ejection fraction (LVEF) are important biomarkers that capture this response, and their measurements are made at high resolution. Relatively, clinical analysis is crude, and may result in lost information and the introduction of noise. Digital information storage enables efficient extraction of information from a dataset, and this strategy may provide more precise and deeper measures to breakdown current phenotypes into their component parts. The aim of this thesis was to develop automated analysis of cardiovascular magnetic resonance (CMR) imaging for more detailed phenotyping, and apply these techniques for new biological insights into the cardiovascular response to different loading conditions. I therefore tested the feasibility and clinical utility of computational approaches for image and waveform analysis, recruiting and acquiring additional patient cohorts where necessary, and then applied these approaches prospectively to participants before and after six-months of exercise training for a first-time marathon. First, a multi-centre, multi-vendor, multi-field strength, multi-disease CMR resource of 110 patients undergoing repeat imaging in a short time-frame was assembled. The resource was used to assess whether automated analysis of LV structure and function is feasible on real-world data, and if it can improve upon human precision. This showed that clinicians can be confident in detecting a 9% change in EF or a 20g change in LV mass. This will be difficult to improve by clinicians because the greatest source of human error was attributable to the observer rather than modifiable factors. Having understood these errors, a convolutional neural network was trained on separate multi-centre data for automated analysis and was successfully generalizable to the real-world CMR data. Precision was similar to human analysis, and performance was 186 times faster. This real-world benchmarking resource has been made freely available (thevolumesresource.com). Precise automated segmentations were then used as a platform to delve further into the LV phenotype. Global LVEFs measured from CMR imaging in 116 patients with severe aortic stenosis were broken down into ~10 million regional measurements of structure and function, represented by computational three-dimensional LV models for each individual. A cardiac atlas approach was used to compile, label, segment and represent these data. Models were compared with healthy matched controls, and co-registered with follow-up one year after aortic valve replacement (AVR). This showed that there is a tendency to asymmetric septal hypertrophy in all patients with severe aortic stenosis (AS), rather than a characteristic specific to predisposed patients. This response to AS was more unfavourable in males than females (associated with higher NT-proBNP, and lower blood pressure), but was more modifiable with AVR. This was not detected using conventional analysis. Because cardiac function is coupled with the vasculature, a novel integrated assessment of the cardiovascular system was developed. Wave intensity theory was used to combine central blood pressure and CMR aortic blood flow-velocity waveforms to represent the interaction of the heart with the vessels in terms of traveling energy waves. This was performed and then validated in 206 individuals (the largest cohort to date), demonstrating inefficient ventriculo-arterial coupling in female sex and healthy ageing. CMR imaging was performed in 236 individuals before training for a first-time marathon and 138 individuals were followed-up after marathon completion. After training, systolic/diastolic blood pressure reduced by 4/3mmHg, descending aortic stiffness decreased by 16%, and ventriculo-arterial coupling improved by 14%. LV mass increased slightly, with a tendency to more symmetrical hypertrophy. The reduction in aortic stiffness was equivalent to a 4-year reduction in estimated biological aortic age, and the benefit was greater in older, male, and slower individuals. In conclusion, this thesis demonstrates that automating analysis of clinical cardiovascular phenotypes is precise with significant time-saving. Complex data that is usually discarded can be used efficiently to identify new biology. Deeper phenotypes developed in this work inform risk reduction behaviour in healthy individuals, and demonstrably deliver a more sensitive marker of LV remodelling, potentially enhancing risk prediction in severe aortic stenosis

Fast catheter segmentation and tracking based on x-ray fluoroscopic and echocardiographic modalities for catheter-based cardiac minimally invasive interventions

X-ray fluoroscopy and echocardiography imaging (ultrasound, US) are two imaging modalities that are widely used in cardiac catheterization. For these modalities, a fast, accurate and stable algorithm for the detection and tracking of catheters is required to allow clinicians to observe the catheter location in real-time. Currently X-ray fluoroscopy is routinely used as the standard modality in catheter ablation interventions. However, it lacks the ability to visualize soft tissue and uses harmful radiation. US does not have these limitations but often contains acoustic artifacts and has a small field of view. These make the detection and tracking of the catheter in US very challenging. The first contribution in this thesis is a framework which combines Kalman filter and discrete optimization for multiple catheter segmentation and tracking in X-ray images. Kalman filter is used to identify the whole catheter from a single point detected on the catheter in the first frame of a sequence of x-ray images. An energy-based formulation is developed that can be used to track the catheters in the following frames. We also propose a discrete optimization for minimizing the energy function in each frame of the X-ray image sequence. Our approach is robust to tangential motion of the catheter and combines the tubular and salient feature measurements into a single robust and efficient framework. The second contribution is an algorithm for catheter extraction in 3D ultrasound images based on (a) the registration between the X-ray and ultrasound images and (b) the segmentation of the catheter in X-ray images. The search space for the catheter extraction in the ultrasound images is constrained to lie on or close to a curved surface in the ultrasound volume. The curved surface corresponds to the back-projection of the extracted catheter from the X-ray image to the ultrasound volume. Blob-like features are detected in the US images and organized in a graphical model. The extracted catheter is modelled as the optimal path in this graphical model. Both contributions allow the use of ultrasound imaging for the improved visualization of soft tissue. However, X-ray imaging is still required for each ultrasound frame and the amount of X-ray exposure has not been reduced. The final contribution in this thesis is a system that can track the catheter in ultrasound volumes automatically without the need for X-ray imaging during the tracking. Instead X-ray imaging is only required for the system initialization and for recovery from tracking failures. This allows a significant reduction in the amount of X-ray exposure for patient and clinicians.Open Acces

QUANTITATIVE NUCLEAR MEDICINE IMAGING USING ADVANCED IMAGE RECONSTRUCTION AND RADIOMICS

Our aim is to help put nuclear medicine at the forefront of quantitation on the path to the realization of personalized medicine. We propose and evaluate (Part I) advanced image reconstruction and (Part II) robust radiomics (large-scale data-oriented study of radiological images). The goal is to attain significantly improved diagnostic, prognostic and treatment-response assessment capabilities. Part I presents a new paradigm in point-spread function (PSF)-modeling, a partial volume correction method in PET imaging where resolution-degrading phenomena are modeled within the reconstruction framework. PSF-modeling improves resolution and enhances contrast, but significantly alters noise properties and induces edge-overshoots. Past efforts involve a dichotomy of PSF vs. no-PSF modeling; by contrast, we focus on a wide-spectrum of PSF models, including under- and over-estimation of the true PSF, for the potential of enhanced quantitation in standardized uptake values (SUVs). We show for the standard range of iterations employed in clinic (not excessive), edge enhancement due to overestimation actually lower SUV bias in small regions, while inter-voxel correlations suppress image roughness and enhance uniformity. An overestimated PSF yields improved contrast and limited edge-overshoot effects at lower iterations, enabling enhanced SUV quantitation. Overall, our framework provides an effective venue for quantitative task-based optimization. Part II proposes robust and reproducible radiomics methods. Radiomics workflows are complex, generating hundreds of features, which can lead to high variability and overfitting, and ultimately hampering performance. We developed and released a Standardized Environment for Radiomics Analysis (SERA) solution to enable robust radiomics analyses. We conduct studies on two unique imaging datasets – renal cell carcinoma SPECT and prostate cancer PET – identifying robust and reproducible radiomic features. In addition, we evaluate a novel hypothesis that radiomic features extracted from clinically normal (non-ischemic) myocardial perfusion SPECT (MPS) can predict coronary artery calcification (CAC; as extracted from CT). This has important implications, since CAC assessment is not commonly-performed nor reimbursed in wide community settings. SERA-derived radiomic features were utilized in a multi-step feature selection framework, followed by the application of machine learning to radiomic features. Our results show the potential to predict CAC from normal MPS, suggesting added usage and value for routine standard MPS

Machine Learning for Biomedical Application

Biomedicine is a multidisciplinary branch of medical science that consists of many scientific disciplines, e.g., biology, biotechnology, bioinformatics, and genetics; moreover, it covers various medical specialties. In recent years, this field of science has developed rapidly. This means that a large amount of data has been generated, due to (among other reasons) the processing, analysis, and recognition of a wide range of biomedical signals and images obtained through increasingly advanced medical imaging devices. The analysis of these data requires the use of advanced IT methods, which include those related to the use of artificial intelligence, and in particular machine learning. It is a summary of the Special Issue “Machine Learning for Biomedical Application”, briefly outlining selected applications of machine learning in the processing, analysis, and recognition of biomedical data, mostly regarding biosignals and medical images