Methods for Analysing Endothelial Cell Shape and Behaviour in Relation to the Focal Nature of Atherosclerosis

The aim of this thesis is to develop automated methods for the analysis of the spatial patterns, and the functional behaviour of endothelial cells, viewed under microscopy, with applications to the understanding of atherosclerosis. Initially, a radial search approach to segmentation was attempted in order to trace the cell and nuclei boundaries using a maximum likelihood algorithm; it was found inadequate to detect the weak cell boundaries present in the available data. A parametric cell shape model was then introduced to fit an equivalent ellipse to the cell boundary by matching phase-invariant orientation fields of the image and a candidate cell shape. This approach succeeded on good quality images, but failed on images with weak cell boundaries. Finally, a support vector machines based method, relying on a rich set of visual features, and a small but high quality training dataset, was found to work well on large numbers of cells even in the presence of strong intensity variations and imaging noise. Using the segmentation results, several standard shear-stress dependent parameters of cell morphology were studied, and evidence for similar behaviour in some cell shape parameters was obtained in in-vivo cells and their nuclei. Nuclear and cell orientations around immature and mature aortas were broadly similar, suggesting that the pattern of flow direction near the wall stayed approximately constant with age. The relation was less strong for the cell and nuclear length-to-width ratios. Two novel shape analysis approaches were attempted to find other properties of cell shape which could be used to annotate or characterise patterns, since a wide variability in cell and nuclear shapes was observed which did not appear to fit the standard parameterisations. Although no firm conclusions can yet be drawn, the work lays the foundation for future studies of cell morphology. To draw inferences about patterns in the functional response of cells to flow, which may play a role in the progression of disease, single-cell analysis was performed using calcium sensitive florescence probes. Calcium transient rates were found to change with flow, but more importantly, local patterns of synchronisation in multi-cellular groups were discernable and appear to change with flow. The patterns suggest a new functional mechanism in flow-mediation of cell-cell calcium signalling

Biomechanical Modeling and Inverse Problem Based Elasticity Imaging for Prostate Cancer Diagnosis

Early detection of prostate cancer plays an important role in successful prostate cancer treatment. This requires screening the prostate periodically after the age of 50. If screening tests lead to prostate cancer suspicion, prostate needle biopsy is administered which is still considered as the clinical gold standard for prostate cancer diagnosis. Given that needle biopsy is invasive and is associated with issues including discomfort and infection, it is desirable to develop a prostate cancer diagnosis system that has high sensitivity and specificity for early detection with a potential to improve needle biopsy outcome. Given the complexity and variability of prostate cancer pathologies, many research groups have been pursuing multi-parametric imaging approach as no single modality imaging technique has proven to be adequate. While imaging additional tissue properties increases the chance of reliable prostate cancer detection and diagnosis, selecting an additional property needs to be done carefully by considering clinical acceptability and cost. Clinical acceptability entails ease with respect to both operating by the radiologist and patient comfort. In this work, effective tissue biomechanics based diagnostic techniques are proposed for prostate cancer assessment with the aim of early detection and minimizing the numbers of prostate biopsies. The techniques take advantage of the low cost, widely available and well established TRUS imaging method. The proposed techniques include novel elastography methods which were formulated based on an inverse finite element frame work. Conventional finite element analysis is known to have high computational complexity, hence computation time demanding. This renders the proposed elastography methods not suitable for real-time applications. To address this issue, an accelerated finite element method was proposed which proved to be suitable for prostate elasticity reconstruction. In this method, accurate finite element analysis of a large number of prostates undergoing TRUS probe loadings was performed. Geometry input and displacement and stress fields output obtained from the analysis were used to train a neural network mapping function to be used for elastopgraphy imaging of prostate cancer patients. The last part of the research presented in this thesis tackles an issue with the current 3D TRUS prostate needle biopsy. Current 3D TRUS prostate needle biopsy systems require registering preoperative 3D TRUS to intra-operative 2D TRUS images. Such image registration is time-consuming while its real-time implementation is yet to be developed. To bypass this registration step, concept of a robotic system was proposed which can reliably determine the preoperative TRUS probe position relative to the prostate to place at the same position relative to the prostate intra-operatively. For this purpose, a contact pressure feedback system is proposed to ensure similar prostate deformation during 3D and 2D image acquisition in order to bypass the registration step

Simulation-Based Joint Estimation of Body Deformation and Elasticity Parameters for Medical Image Analysis

Elasticity parameter estimation is essential for generating accurate and controlled simulation results for computer animation and medical image analysis. However, finding the optimal parameters for a particular simulation often requires iterations of simulation, assessment, and adjustment and can become a tedious process. Elasticity values are especially important in medical image analysis, since cancerous tissues tend to be stiffer. Elastography is a popular type of method for finding stiffness values by reconstructing a dense displacement field from medical images taken during the application of forces or vibrations. These methods, however, are limited by the imaging modality and the force exertion or vibration actuation mechanisms, which can be complicated for deep-seated organs. In this thesis, I present a novel method for reconstructing elasticity parameters without requiring a dense displacement field or a force exertion device. The method makes use of natural deformations within the patient and relies on surface information from segmented images taken on different days. The elasticity value of the target organ and boundary forces acting on surrounding organs are optimized with an iterative optimizer, within which the deformation is always generated by a physically-based simulator. Experimental results on real patient data are presented to show the positive correlation between recovered elasticity values and clinical prostate cancer stages. Furthermore, to resolve the performance issue arising from the high dimensionality of boundary forces, I propose to use a reduced finite element model to improve the convergence of the optimizer. To find the set of bases to represent the dimensions for forces, a statistical training based on real patient data is performed. I demonstrate the trade-off between accuracy and performance by using different numbers of bases in the optimization using synthetic data. A speedup of more than an order of magnitude is observed without sacrificing too much accuracy in recovered elasticity.Doctor of Philosoph

Registration of magnetic resonance and ultrasound images for guiding prostate cancer interventions

Prostate cancer is a major international health problem with a large and rising incidence in many parts of the world. Transrectal ultrasound (TRUS) imaging is used routinely to guide surgical procedures, such as needle biopsy and a number of minimally-invasive therapies, but its limited ability to visualise prostate cancer is widely recognised. Magnetic resonance (MR) imaging techniques, on the other hand, have recently been developed that can provide clinically useful diagnostic information. Registration (or alignment) of MR and TRUS images during TRUS-guided surgical interventions potentially provides a cost-effective approach to augment TRUS images with clinically useful, MR-derived information (for example, tumour location, shape and size). This thesis describes a deformable image registration framework that enables automatic and/or semi-automatic alignment of MR and 3D TRUS images of the prostate gland. The method combines two technical developments in the field: First, a method for constructing patient-specific statistical shape models of prostate motion/deformation, based on learning from finite element simulations of gland motion using geometric data from a preoperative MR image, is proposed. Second, a novel “model-to-image” registration framework is developed to register this statistical shape model automatically to an intraoperative TRUS image. This registration approach is implemented using a novel model-to-image vector alignment (MIVA) algorithm, which maximises the likelihood of a particular instance of a statistical shape model given a voxel-intensity-based feature vector that represents an estimate of the surface normal vectors at the boundary of the organ in question. Using real patient data, the MR-TRUS registration accuracy of the new algorithm is validated using intra-prostatic anatomical landmarks. A rigorous and extensive validation analysis is also provided for assessing the image registration experiments. The final target registration error after performing 100 MR–TRUS registrations for each patient have a median of 2.40 mm, meaning that over 93% registrations may successfully hit the target representing a clinically significant lesion. The implemented registration algorithms took less than 30 seconds and 2 minutes for manually defined point- and normal vector features, respectively. The thesis concludes with a summary of potential applications and future research directions

Deformable Medical Image Registration: A Survey

Deformable image registration is a fundamental task in medical image processing. Among its most important applications, one may cite: i) multi-modality fusion, where information acquired by different imaging devices or protocols is fused to facilitate diagnosis and treatment planning; ii) longitudinal studies, where temporal structural or anatomical changes are investigated; and iii) population modeling and statistical atlases used to study normal anatomical variability. In this technical report, we attempt to give an overview of deformable registration methods, putting emphasis on the most recent advances in the domain. Additional emphasis has been given to techniques applied to medical images. In order to study image registration methods in depth, their main components are identified and studied independently. The most recent techniques are presented in a systematic fashion. The contribution of this technical report is to provide an extensive account of registration techniques in a systematic manner.Le recalage déformable d'images est une des tâches les plus fondamentales dans l'imagerie médicale. Parmi ses applications les plus importantes, on compte: i) la fusion d' information provenant des différents types de modalités a n de faciliter le diagnostic et la planification du traitement; ii) les études longitudinales, oú des changements structurels ou anatomiques sont étudiées en fonction du temps; et iii) la modélisation de la variabilité anatomique normale d'une population et les atlas statistiques. Dans ce rapport de recherche, nous essayons de donner un aperçu des différentes méthodes du recalage déformables, en mettant l'accent sur les avancées les plus récentes du domaine. Nous avons particulièrement insisté sur les techniques appliquées aux images médicales. A n d'étudier les méthodes du recalage d'images, leurs composants principales sont d'abord identifiés puis étudiées de manière indépendante, les techniques les plus récentes étant classifiées en suivant un schéma logique déterminé. La contribution de ce rapport de recherche est de fournir un compte rendu détaillé des techniques de recalage d'une manière systématique

Studying the Optimal Scheduling for Controlling Prostate Cancer under Intermittent Androgen Suppression

This retrospective study shows that the majority of patients’ correlations between PSA and Testosterone during the on-treatment period is at least 0.90. Model-based duration calculations to control PSA levels during off-treatment are provided. There are two pairs of models. In one pair, the Generalized Linear Model and Mixed Model are both used to analyze the variability of PSA at the individual patient level by using the variable “Patient ID” as a repeated measure. In the second pair, Patient ID is not used as a repeated measure but additional baseline variables are included to analyze the variability of PSA

Developing advanced mathematical models for detecting abnormalities in 2D/3D medical structures.

Detecting abnormalities in two-dimensional (2D) and three-dimensional (3D) medical structures is among the most interesting and challenging research areas in the medical imaging field. Obtaining the desired accurate automated quantification of abnormalities in medical structures is still very challenging. This is due to a large and constantly growing number of different objects of interest and associated abnormalities, large variations of their appearances and shapes in images, different medical imaging modalities, and associated changes of signal homogeneity and noise for each object. The main objective of this dissertation is to address these problems and to provide proper mathematical models and techniques that are capable of analyzing low and high resolution medical data and providing an accurate, automated analysis of the abnormalities in medical structures in terms of their area/volume, shape, and associated abnormal functionality. This dissertation presents different preliminary mathematical models and techniques that are applied in three case studies: (i) detecting abnormal tissue in the left ventricle (LV) wall of the heart from delayed contrast-enhanced cardiac magnetic resonance images (MRI), (ii) detecting local cardiac diseases based on estimating the functional strain metric from cardiac cine MRI, and (iii) identifying the abnormalities in the corpus callosum (CC) brain structure—the largest fiber bundle that connects the two hemispheres in the brain—for subjects that suffer from developmental brain disorders. For detecting the abnormal tissue in the heart, a graph-cut mathematical optimization model with a cost function that accounts for the object’s visual appearance and shape is used to segment the the inner cavity. The model is further integrated with a geometric model (i.e., a fast marching level set model) to segment the outer border of the myocardial wall (the LV). Then the abnormal tissue in the myocardium wall (also called dead tissue, pathological tissue, or infarct area) is identified based on a joint Markov-Gibbs random field (MGRF) model of the image and its region (segmentation) map that accounts for the pixel intensities and the spatial interactions between the pixels. Experiments with real in-vivo data and comparative results with ground truth (identified by a radiologist) and other approaches showed that the proposed framework can accurately detect the pathological tissue and can provide useful metrics for radiologists and clinicians. To estimate the strain from cardiac cine MRI, a novel method based on tracking the LV wall geometry is proposed. To achieve this goal, a partial differential equation (PDE) method is applied to track the LV wall points by solving the Laplace equation between the LV contours of each two successive image frames over the cardiac cycle. The main advantage of the proposed tracking method over traditional texture-based methods is its ability to track the movement and rotation of the LV wall based on tracking the geometric features of the inner, mid-, and outer walls of the LV. This overcomes noise sources that come from scanner and heart motion. To identify the abnormalities in the CC from brain MRI, the CCs are aligned using a rigid registration model and are segmented using a shape-appearance model. Then, they are mapped to a simple unified space for analysis. This work introduces a novel cylindrical mapping model, which is conformal (i.e., one to one transformation and bijective), that enables accurate 3D shape analysis of the CC in the cylindrical domain. The framework can detect abnormalities in all divisions of the CC (i.e., splenium, rostrum, genu and body). In addition, it offers a whole 3D analysis of the CC abnormalities instead of only area-based analysis as done by previous groups. The initial classification results based on the centerline length and CC thickness suggest that the proposed CC shape analysis is a promising supplement to the current techniques for diagnosing dyslexia. The proposed techniques in this dissertation have been successfully tested on complex synthetic and MR images and can be used to advantage in many of today’s clinical applications of computer-assisted medical diagnostics and intervention

Validation Strategies Supporting Clinical Integration of Prostate Segmentation Algorithms for Magnetic Resonance Imaging

Segmentation of the prostate in medical images is useful for prostate cancer diagnosis and therapy guidance. However, manual segmentation of the prostate is laborious and time-consuming, with inter-observer variability. The focus of this thesis was on accuracy, reproducibility and procedure time measurement for prostate segmentation on T2-weighted endorectal magnetic resonance imaging, and assessment of the potential of a computer-assisted segmentation technique to be translated to clinical practice for prostate cancer management. We collected an image data set from prostate cancer patients with manually-delineated prostate borders by one observer on all the images and by two other observers on a subset of images. We used a complementary set of error metrics to measure the different types of observed segmentation errors. We compared expert manual segmentation as well as semi-automatic and automatic segmentation approaches before and after manual editing by expert physicians. We recorded the time needed for user interaction to initialize the semi-automatic algorithm, algorithm execution, and manual editing as necessary. Comparing to manual segmentation, the measured errors for the algorithms compared favourably with observed differences between manual segmentations. The measured average editing times for the computer-assisted segmentation were lower than fully manual segmentation time, and the algorithms reduced the inter-observer variability as compared to manual segmentation. The accuracy of the computer-assisted approaches was near to or within the range of observed variability in manual segmentation. The recorded procedure time for prostate segmentation was reduced using computer-assisted segmentation followed by manual editing, compared to the time required for fully manual segmentation