Feasibility of magnetic resonance imaging-based radiation therapy for brain tumour treatment

Purpose : The increasing use of MRI alongside CT images has brought about growing interest in trying to determine radiation attenuation information based on MR images only. The primary aim of this thesis is, therefore, to determine what head tissue compartments need to have separate HU values in order to obtain sufficient RT planning accuracy. This can serve as input for an MR-based classification thus enabling pseudo-CT generation in an MR-only RT workflow. Methods: To achieve this target, flattened (stratified) CT images (fCT) were generated and compared to the original CT images. Mean (ME) and mean absolute (MAE) errors were used for the fCT quality assessment, as was dose comparisons. 70 CT-based RT plans were generated and the dose distributions compared to those obtained when using the different fCT versions in place of the original CT images. The dose agreement was assessed using DVH and 1%/1mm gamma analysis. Results: The lowest MAE of 59.63 HU was calculated for an fCT8 version. DVH analysis showed low differences in the range between 3% (water-filled fCT) and 0.05% depending on the tissue stratification of the fCT version. 1%/1mm gamma analysis correctly identified plans where insufficiently fine-grained tissue classification was the main reason for dose discrepancy. The best RT planning accuracy was obtained for the fCT5 with segmented air cavities, fat, water-rich tissue, spongy, and compact bone, and for the fCT8 where also the brain tissue was stratified. Conclusions: The small differences in dose accuracy between CT and fCT images shows the feasibility of using MR-only RT planning for the brain. Nonetheless, other aspects of the MR-only workflow, such as patient positioning, as well as the impact of e.g. the surgical incisions in the skull should be subject to further research

Structures in High-Dimensional Data: Intrinsic Dimension and Cluster Analysis

With today's improved measurement and data storing technologies it has become common to collect data in search for hypotheses instead of for testing hypotheses---to do exploratory data analysis. Finding patterns and structures in data is the main goal. This thesis deals with two kinds of structures that can convey relationships between different parts of data in a high-dimensional space: manifolds and clusters. They are in a way opposites of each other: a manifold structure shows that it is plausible to connect two distant points through the manifold, a clustering shows that it is plausible to separate two nearby points by assigning them to different clusters. But clusters and manifolds can also be the same: each cluster can be a manifold of its own.The first paper in this thesis concerns one specific aspect of a manifold structure, namely its dimension, also called the intrinsic dimension of the data. A novel estimator of intrinsic dimension, taking advantage of ``the curse of dimensionality'', is proposed and evaluated. It is shown that it has in general less bias than estimators from the literature and can therefore better distinguish manifolds with different dimensions.The second and third paper in this thesis concern cluster analysis of data generated by flow cytometry---a high-throughput single-cell measurement technology. In this area, clustering is performed routinely by manual assignment of data in two-dimensional plots, to identify cell populations. It is a tedious and subjective task, especially since data often has four, eight, twelve or even more dimensions, and the analysts need to decide which two dimensions to look at together, and in which order.In the second paper of the thesis a new pipeline for automated cell population identification is proposed, which can process multiple flow cytometry samples in parallel using a hierarchical model that shares information between the clusterings of the samples, thus making corresponding clusters in different samples similar while allowing for variation in cluster location and shape.In the third and final paper of the thesis, statistical tests for unimodality are investigated as a tool for quality control of automated cell population identification algorithms. It is shown that the different tests have different interpretations of unimodality and thus accept different kinds of clusters as sufficiently close to unimodal

Unsupervised learning for vascular heterogeneity assessment of glioblastoma based on magnetic resonance imaging: The Hemodynamic Tissue Signature

[ES] El futuro de la imagen médica está ligado a la inteligencia artificial. El análisis manual de imágenes médicas es hoy en día una tarea ardua, propensa a errores y a menudo inasequible para los humanos, que ha llamado la atención de la comunidad de Aprendizaje Automático (AA). La Imagen por Resonancia Magnética (IRM) nos proporciona una rica variedad de representaciones de la morfología y el comportamiento de lesiones inaccesibles sin una intervención invasiva arriesgada. Sin embargo, explotar la potente pero a menudo latente información contenida en la IRM es una tarea muy complicada, que requiere técnicas de análisis computacional inteligente. Los tumores del sistema nervioso central son una de las enfermedades más críticas estudiadas a través de IRM. Específicamente, el glioblastoma representa un gran desafío, ya que, hasta la fecha, continua siendo un cáncer letal que carece de una terapia satisfactoria. Del conjunto de características que hacen del glioblastoma un tumor tan agresivo, un aspecto particular que ha sido ampliamente estudiado es su heterogeneidad vascular. La fuerte proliferación vascular del glioblastoma, así como su robusta angiogénesis han sido consideradas responsables de la alta letalidad de esta neoplasia. Esta tesis se centra en la investigación y desarrollo del método Hemodynamic Tissue Signature (HTS): un método de AA no supervisado para describir la heterogeneidad vascular de los glioblastomas mediante el análisis de perfusión por IRM. El método HTS se basa en el concepto de hábitat, que se define como una subregión de la lesión con un perfil de IRM que describe un comportamiento fisiológico concreto. El método HTS delinea cuatro hábitats en el glioblastoma: el hábitat HAT, como la región más perfundida del tumor con captación de contraste; el hábitat LAT, como la región del tumor con un perfil angiogénico más bajo; el hábitat IPE, como la región adyacente al tumor con índices de perfusión elevados; y el hábitat VPE, como el edema restante de la lesión con el perfil de perfusión más bajo. La investigación y desarrollo de este método ha originado una serie de contribuciones enmarcadas en esta tesis. Primero, para verificar la fiabilidad de los métodos de AA no supervisados en la extracción de patrones de IRM, se realizó una comparativa para la tarea de segmentación de gliomas de grado alto. Segundo, se propuso un algoritmo de AA no supervisado dentro de la familia de los Spatially Varying Finite Mixture Models. El algoritmo propone una densidad a priori basada en un Markov Random Field combinado con la función probabilística Non-Local Means, para codificar la idea de que píxeles vecinos tienden a pertenecer al mismo objeto. Tercero, se presenta el método HTS para describir la heterogeneidad vascular del glioblastoma. El método se ha aplicado a casos reales en una cohorte local de un solo centro y en una cohorte internacional de más de 180 pacientes de 7 centros europeos. Se llevó a cabo una evaluación exhaustiva del método para medir el potencial pronóstico de los hábitats HTS. Finalmente, la tecnología desarrollada en la tesis se ha integrado en la plataforma online ONCOhabitats (https://www.oncohabitats.upv.es). La plataforma ofrece dos servicios: 1) segmentación de tejidos de glioblastoma, y 2) evaluación de la heterogeneidad vascular del tumor mediante el método HTS. Los resultados de esta tesis han sido publicados en diez contribuciones científicas, incluyendo revistas y conferencias de alto impacto en las áreas de Informática Médica, Estadística y Probabilidad, Radiología y Medicina Nuclear y Aprendizaje Automático. También se emitió una patente industrial registrada en España, Europa y EEUU. Finalmente, las ideas originales concebidas en esta tesis dieron lugar a la creación de ONCOANALYTICS CDX, una empresa enmarcada en el modelo de negocio de los companion diagnostics de compuestos farmacéuticos.[EN] The future of medical imaging is linked to Artificial Intelligence (AI). The manual analysis of medical images is nowadays an arduous, error-prone and often unaffordable task for humans, which has caught the attention of the Machine Learning (ML) community. Magnetic Resonance Imaging (MRI) provides us with a wide variety of rich representations of the morphology and behavior of lesions completely inaccessible without a risky invasive intervention. Nevertheless, harnessing the powerful but often latent information contained in MRI acquisitions is a very complicated task, which requires computational intelligent analysis techniques. Central nervous system tumors are one of the most critical diseases studied through MRI. Specifically, glioblastoma represents a major challenge, as it remains a lethal cancer that, to date, lacks a satisfactory therapy. Of the entire set of characteristics that make glioblastoma so aggressive, a particular aspect that has been widely studied is its vascular heterogeneity. The strong vascular proliferation of glioblastomas, as well as their robust angiogenesis and extensive microvasculature heterogeneity have been claimed responsible for the high lethality of the neoplasm. This thesis focuses on the research and development of the Hemodynamic Tissue Signature (HTS) method: an unsupervised ML approach to describe the vascular heterogeneity of glioblastomas by means of perfusion MRI analysis. The HTS builds on the concept of habitats. A habitat is defined as a sub-region of the lesion with a particular MRI profile describing a specific physiological behavior. The HTS method delineates four habitats within the glioblastoma: the HAT habitat, as the most perfused region of the enhancing tumor; the LAT habitat, as the region of the enhancing tumor with a lower angiogenic profile; the potentially IPE habitat, as the non-enhancing region adjacent to the tumor with elevated perfusion indexes; and the VPE habitat, as the remaining edema of the lesion with the lowest perfusion profile. The research and development of the HTS method has generated a number of contributions to this thesis. First, in order to verify that unsupervised learning methods are reliable to extract MRI patterns to describe the heterogeneity of a lesion, a comparison among several unsupervised learning methods was conducted for the task of high grade glioma segmentation. Second, a Bayesian unsupervised learning algorithm from the family of Spatially Varying Finite Mixture Models is proposed. The algorithm integrates a Markov Random Field prior density weighted by the probabilistic Non-Local Means function, to codify the idea that neighboring pixels tend to belong to the same semantic object. Third, the HTS method to describe the vascular heterogeneity of glioblastomas is presented. The HTS method has been applied to real cases, both in a local single-center cohort of patients, and in an international retrospective cohort of more than 180 patients from 7 European centers. A comprehensive evaluation of the method was conducted to measure the prognostic potential of the HTS habitats. Finally, the technology developed in this thesis has been integrated into an online open-access platform for its academic use. The ONCOhabitats platform is hosted at https://www.oncohabitats.upv.es, and provides two main services: 1) glioblastoma tissue segmentation, and 2) vascular heterogeneity assessment of glioblastomas by means of the HTS method. The results of this thesis have been published in ten scientific contributions, including top-ranked journals and conferences in the areas of Medical Informatics, Statistics and Probability, Radiology & Nuclear Medicine and Machine Learning. An industrial patent registered in Spain, Europe and EEUU was also issued. Finally, the original ideas conceived in this thesis led to the foundation of ONCOANALYTICS CDX, a company framed into the business model of companion diagnostics for pharmaceutical compounds.[CA] El futur de la imatge mèdica està lligat a la intel·ligència artificial. L'anàlisi manual d'imatges mèdiques és hui dia una tasca àrdua, propensa a errors i sovint inassequible per als humans, que ha cridat l'atenció de la comunitat d'Aprenentatge Automàtic (AA). La Imatge per Ressonància Magnètica (IRM) ens proporciona una àmplia varietat de representacions de la morfologia i el comportament de lesions inaccessibles sense una intervenció invasiva arriscada. Tanmateix, explotar la potent però sovint latent informació continguda a les adquisicions de IRM esdevé una tasca molt complicada, que requereix tècniques d'anàlisi computacional intel·ligent. Els tumors del sistema nerviós central són una de les malalties més crítiques estudiades a través de IRM. Específicament, el glioblastoma representa un gran repte, ja que, fins hui, continua siguent un càncer letal que manca d'una teràpia satisfactòria. Del conjunt de característiques que fan del glioblastoma un tumor tan agressiu, un aspecte particular que ha sigut àmpliament estudiat és la seua heterogeneïtat vascular. La forta proliferació vascular dels glioblastomes, així com la seua robusta angiogènesi han sigut considerades responsables de l'alta letalitat d'aquesta neoplàsia. Aquesta tesi es centra en la recerca i desenvolupament del mètode Hemodynamic Tissue Signature (HTS): un mètode d'AA no supervisat per descriure l'heterogeneïtat vascular dels glioblastomas mitjançant l'anàlisi de perfusió per IRM. El mètode HTS es basa en el concepte d'hàbitat, que es defineix com una subregió de la lesió amb un perfil particular d'IRM, que descriu un comportament fisiològic concret. El mètode HTS delinea quatre hàbitats dins del glioblastoma: l'hàbitat HAT, com la regió més perfosa del tumor amb captació de contrast; l'hàbitat LAT, com la regió del tumor amb un perfil angiogènic més baix; l'hàbitat IPE, com la regió adjacent al tumor amb índexs de perfusió elevats, i l'hàbitat VPE, com l'edema restant de la lesió amb el perfil de perfusió més baix. La recerca i desenvolupament del mètode HTS ha originat una sèrie de contribucions emmarcades a aquesta tesi. Primer, per verificar la fiabilitat dels mètodes d'AA no supervisats en l'extracció de patrons d'IRM, es va realitzar una comparativa en la tasca de segmentació de gliomes de grau alt. Segon, s'ha proposat un algorisme d'AA no supervisat dintre de la família dels Spatially Varying Finite Mixture Models. L'algorisme proposa un densitat a priori basada en un Markov Random Field combinat amb la funció probabilística Non-Local Means, per a codificar la idea que els píxels veïns tendeixen a pertànyer al mateix objecte semàntic. Tercer, es presenta el mètode HTS per descriure l'heterogeneïtat vascular dels glioblastomas. El mètode HTS s'ha aplicat a casos reals en una cohort local d'un sol centre i en una cohort internacional de més de 180 pacients de 7 centres europeus. Es va dur a terme una avaluació exhaustiva del mètode per mesurar el potencial pronòstic dels hàbitats HTS. Finalment, la tecnologia desenvolupada en aquesta tesi s'ha integrat en una plataforma online ONCOhabitats (https://www.oncohabitats.upv.es). La plataforma ofereix dos serveis: 1) segmentació dels teixits del glioblastoma, i 2) avaluació de l'heterogeneïtat vascular dels glioblastomes mitjançant el mètode HTS. Els resultats d'aquesta tesi han sigut publicats en deu contribucions científiques, incloent revistes i conferències de primer nivell a les àrees d'Informàtica Mèdica, Estadística i Probabilitat, Radiologia i Medicina Nuclear i Aprenentatge Automàtic. També es va emetre una patent industrial registrada a Espanya, Europa i els EEUU. Finalment, les idees originals concebudes en aquesta tesi van donar lloc a la creació d'ONCOANALYTICS CDX, una empresa emmarcada en el model de negoci dels companion diagnostics de compostos farmacèutics.En este sentido quiero agradecer a las diferentes instituciones y estructuras de financiación de investigación que han contribuido al desarrollo de esta tesis. En especial quiero agradecer a la Universitat Politècnica de València, donde he desarrollado toda mi carrera acadèmica y científica, así como al Ministerio de Ciencia e Innovación, al Ministerio de Economía y Competitividad, a la Comisión Europea, al EIT Health Programme y a la fundación Caixa ImpulseJuan Albarracín, J. (2020). Unsupervised learning for vascular heterogeneity assessment of glioblastoma based on magnetic resonance imaging: The Hemodynamic Tissue Signature [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/149560TESI

Real-time Ultrasound Signals Processing: Denoising and Super-resolution

Ultrasound acquisition is widespread in the biomedical field, due to its properties of low cost, portability, and non-invasiveness for the patient. The processing and analysis of US signals, such as images, 2D videos, and volumetric images, allows the physician to monitor the evolution of the patient's disease, and support diagnosis, and treatments (e.g., surgery). US images are affected by speckle noise, generated by the overlap of US waves. Furthermore, low-resolution images are acquired when a high acquisition frequency is applied to accurately characterise the behaviour of anatomical features that quickly change over time. Denoising and super-resolution of US signals are relevant to improve the visual evaluation of the physician and the performance and accuracy of processing methods, such as segmentation and classification. The main requirements for the processing and analysis of US signals are real-time execution, preservation of anatomical features, and reduction of artefacts. In this context, we present a novel framework for the real-time denoising of US 2D images based on deep learning and high-performance computing, which reduces noise while preserving anatomical features in real-time execution. We extend our framework to the denoise of arbitrary US signals, such as 2D videos and 3D images, and we apply denoising algorithms that account for spatio-temporal signal properties into an image-to-image deep learning model. As a building block of this framework, we propose a novel denoising method belonging to the class of low-rank approximations, which learns and predicts the optimal thresholds of the Singular Value Decomposition. While previous denoise work compromises the computational cost and effectiveness of the method, the proposed framework achieves the results of the best denoising algorithms in terms of noise removal, anatomical feature preservation, and geometric and texture properties conservation, in a real-time execution that respects industrial constraints. The framework reduces the artefacts (e.g., blurring) and preserves the spatio-temporal consistency among frames/slices; also, it is general to the denoising algorithm, anatomical district, and noise intensity. Then, we introduce a novel framework for the real-time reconstruction of the non-acquired scan lines through an interpolating method; a deep learning model improves the results of the interpolation to match the target image (i.e., the high-resolution image). We improve the accuracy of the prediction of the reconstructed lines through the design of the network architecture and the loss function. %The design of the deep learning architecture and the loss function allow the network to improve the accuracy of the prediction of the reconstructed lines. In the context of signal approximation, we introduce our kernel-based sampling method for the reconstruction of 2D and 3D signals defined on regular and irregular grids, with an application to US 2D and 3D images. Our method improves previous work in terms of sampling quality, approximation accuracy, and geometry reconstruction with a slightly higher computational cost. For both denoising and super-resolution, we evaluate the compliance with the real-time requirement of US applications in the medical domain and provide a quantitative evaluation of denoising and super-resolution methods on US and synthetic images. Finally, we discuss the role of denoising and super-resolution as pre-processing steps for segmentation and predictive analysis of breast pathologies

Visuelle Analyse großer Partikeldaten

Partikelsimulationen sind eine bewährte und weit verbreitete numerische Methode in der Forschung und Technik. Beispielsweise werden Partikelsimulationen zur Erforschung der Kraftstoffzerstäubung in Flugzeugturbinen eingesetzt. Auch die Entstehung des Universums wird durch die Simulation von dunkler Materiepartikeln untersucht. Die hierbei produzierten Datenmengen sind immens. So enthalten aktuelle Simulationen Billionen von Partikeln, die sich über die Zeit bewegen und miteinander interagieren. Die Visualisierung bietet ein großes Potenzial zur Exploration, Validation und Analyse wissenschaftlicher Datensätze sowie der zugrundeliegenden Modelle. Allerdings liegt der Fokus meist auf strukturierten Daten mit einer regulären Topologie. Im Gegensatz hierzu bewegen sich Partikel frei durch Raum und Zeit. Diese Betrachtungsweise ist aus der Physik als das lagrange Bezugssystem bekannt. Zwar können Partikel aus dem lagrangen in ein reguläres eulersches Bezugssystem, wie beispielsweise in ein uniformes Gitter, konvertiert werden. Dies ist bei einer großen Menge an Partikeln jedoch mit einem erheblichen Aufwand verbunden. Darüber hinaus führt diese Konversion meist zu einem Verlust der Präzision bei gleichzeitig erhöhtem Speicherverbrauch. Im Rahmen dieser Dissertation werde ich neue Visualisierungstechniken erforschen, welche speziell auf der lagrangen Sichtweise basieren. Diese ermöglichen eine effiziente und effektive visuelle Analyse großer Partikeldaten

Doctor of Philosophy in Computing

dissertationAn important area of medical imaging research is studying anatomical diffeomorphic shape changes and detecting their relationship to disease processes. For example, neurodegenerative disorders change the shape of the brain, thus identifying differences between the healthy control subjects and patients affected by these diseases can help with understanding the disease processes. Previous research proposed a variety of mathematical approaches for statistical analysis of geometrical brain structure in three-dimensional (3D) medical imaging, including atlas building, brain variability quantification, regression, etc. The critical component in these statistical models is that the geometrical structure is represented by transformations rather than the actual image data. Despite the fact that such statistical models effectively provide a way for analyzing shape variation, none of them have a truly probabilistic interpretation. This dissertation contributes a novel Bayesian framework of statistical shape analysis for generic manifold data and its application to shape variability and brain magnetic resonance imaging (MRI). After we carefully define the distributions on manifolds, we then build Bayesian models for analyzing the intrinsic variability of manifold data, involving the mean point, principal modes, and parameter estimation. Because there is no closed-form solution for Bayesian inference of these models on manifolds, we develop a Markov Chain Monte Carlo method to sample the hidden variables from the distribution. The main advantages of these Bayesian approaches are that they provide parameter estimation and automatic dimensionality reduction for analyzing generic manifold-valued data, such as diffeomorphisms. Modeling the mean point of a group of images in a Bayesian manner allows for learning the regularity parameter from data directly rather than having to set it manually, which eliminates the effort of cross validation for parameter selection. In population studies, our Bayesian model of principal modes analysis (1) automatically extracts a low-dimensional, second-order statistics of manifold data variability and (2) gives a better geometric data fit than nonprobabilistic models. To make this Bayesian framework computationally more efficient for high-dimensional diffeomorphisms, this dissertation presents an algorithm, FLASH (finite-dimensional Lie algebras for shooting), that hugely speeds up the diffeomorphic image registration. Instead of formulating diffeomorphisms in a continuous variational problem, Flash defines a completely new discrete reparameterization of diffeomorphisms in a low-dimensional bandlimited velocity space, which results in the Bayesian inference via sampling on the space of diffeomorphisms being more feasible in time. Our entire Bayesian framework in this dissertation is used for statistical analysis of shape data and brain MRIs. It has the potential to improve hypothesis testing, classification, and mixture models

AUTOMATED TREE-LEVEL FOREST QUANTIFICATION USING AIRBORNE LIDAR

Traditional forest management relies on a small field sample and interpretation of aerial photography that not only are costly to execute but also yield inaccurate estimates of the entire forest in question. Airborne light detection and ranging (LiDAR) is a remote sensing technology that records point clouds representing the 3D structure of a forest canopy and the terrain underneath. We present a method for segmenting individual trees from the LiDAR point clouds without making prior assumptions about tree crown shapes and sizes. We then present a method that vertically stratifies the point cloud to an overstory and multiple understory tree canopy layers. Using the stratification method, we modeled the occlusion of higher canopy layers with respect to point density. We also present a distributed computing approach that enables processing the massive data of an arbitrarily large forest. Lastly, we investigated using deep learning for coniferous/deciduous classification of point cloud segments representing individual tree crowns. We applied the developed methods to the University of Kentucky Robinson Forest, a natural, majorly deciduous, closed-canopy forest. 90% of overstory and 47% of understory trees were detected with false positive rates of 14% and 2% respectively. Vertical stratification improved the detection rate of understory trees to 67% at the cost of increasing their false positive rate to 12%. According to our occlusion model, a point density of about 170 pt/m² is needed to segment understory trees located in the third layer as accurately as overstory trees. Using our distributed processing method, we segmented about two million trees within a 7400-ha forest in 2.5 hours using 192 processing cores, showing a speedup of ~170. Our deep learning experiments showed high classification accuracies (~82% coniferous and ~90% deciduous) without the need to manually assemble the features. In conclusion, the methods developed are steps forward to remote, accurate quantification of large natural forests at the individual tree level

Quantitative lung CT analysis for the study and diagnosis of Chronic Obstructive Pulmonary Disease

The importance of medical imaging in the research of Chronic Obstructive Pulmonary Dis- ease (COPD) has risen over the last decades. COPD affects the pulmonary system through two competing mechanisms; emphysema and small airways disease. The relative contribu- tion of each component varies widely across patients whilst they can also evolve regionally in the lung. Patients can also be susceptible to exacerbations, which can dramatically ac- celerate lung function decline. Diagnosis of COPD is based on lung function tests, which measure airflow limitation. There is a growing consensus that this is inadequate in view of the complexities of COPD. Computed Tomography (CT) facilitates direct quantification of the pathological changes that lead to airflow limitation and can add to our understanding of the disease progression of COPD. There is a need to better capture lung pathophysiology whilst understanding regional aspects of disease progression. This has motivated the work presented in this thesis. Two novel methods are proposed to quantify the severity of COPD from CT by analysing the global distribution of features sampled locally in the lung. They can be exploited in the classification of lung CT images or to uncover potential trajectories of disease progression. A novel lobe segmentation algorithm is presented that is based on a probabilistic segmen- tation of the fissures whilst also constructing a groupwise fissure prior. In combination with the local sampling methods, a pipeline of analysis was developed that permits a re- gional analysis of lung disease. This was applied to study exacerbation susceptible COPD. Lastly, the applicability of performing disease progression modelling to study COPD has been shown. Two main subgroups of COPD were found, which are consistent with current clinical knowledge of COPD subtypes. This research may facilitate precise phenotypic characterisation of COPD from CT, which will increase our understanding of its natural history and associated heterogeneities. This will be instrumental in the precision medicine of COPD