Spatially Regularized Reconstruction of Fibre Orientation Distributions in the Presence of Isotropic Diffusion

The connectivity and structural integrity of the white matter of the brain is known to be implicated in a wide range of brain-related diseases and injuries. However, it is only since the advent of diffusion magnetic resonance imaging (dMRI) that researchers have been able to probe the miscrostructure of white matter in vivo. Presently, among a range of methods of dMRI, high angular resolution diffusion imaging (HARDI) is known to excel in its ability to provide reliable information about the local orientations of neural fasciculi (aka fibre tracts). It preserves the high angular resolution property of diffusion spectrum imaging (DSI) but requires less measurements. Meanwhile, as opposed to the more traditional diffusion tensor imaging (DTI), HARDI is capable of distinguishing the orientations of multiple fibres passing through a given spatial voxel. Unfortunately, the ability of HARDI to discriminate neural fibres that cross each other at acute angles is always limited. The limitation becomes the motivation to develop numerous post-processing tools, aiming at the improvement of the angular resolution of HARDI. Among such methods, spherical deconvolution (SD) is the one which attracts the most attentions. Due to its ill-posed nature, however, standard SD relies on a number of a priori assumptions needed to render its results unique and stable. In the present thesis, we introduce a novel approach to the problem of non-blind SD of HARDI signals, which does not only consider the existence of anisotropic diffusion component of HARDI signal but also explicitly take the isotropic diffusion component into account. As a result of that, in addition to reconstruction of fODFs, our algorithm can also yield a useful estimation of its related IDM, which quantifies a relative contribution of the isotropic diffusion component as well as its spatial pattern. Moreover, one of the principal contributions is to demonstrate the effectiveness of exploiting different prior models for regularization of the spatial-domain behaviours of the reconstructed fODFs and IDMs. Specifically, the fibre continuity model has been used to force the local maxima of the fODFs to vary consistently throughout the brain, whereas the bounded variation model has helped us to achieve piecewise smooth reconstruction of the IDMs. The proposed algorithm is formulated as a convex minimization problem, which admits a unique and stable minimizer. Moreover, using ADMM, we have been able to find the optimal solution via a sequence of simpler optimization problems, which are both computationally efficient and amenable to parallel computations. In a series of both in silico and in vivo experiments, we demonstrate how the proposed solution can be used to successfully overcome the effect of partial voluming, while preserving the spatial coherency of cerebral diffusion at moderate to severe noise levels. The performance of the proposed method is compared with that of several available alternatives, with the comparative results clearly supporting the viability and usefulness of our approach. Moreover, the results illustrate the power of applied spatial regularization terms

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

NON-INVASIVE IMAGE ENHANCEMENT OF COLOUR RETINAL FUNDUS IMAGES FOR A COMPUTERISED DIABETIC RETINOPATHY MONITORING AND GRADING SYSTEM

Diabetic Retinopathy (DR) is a sight threatening complication due to diabetes mellitus affecting the retina. The pathologies of DR can be monitored by analysing colour fundus images. However, the low and varied contrast between retinal vessels and the background in colour fundus images remains an impediment to visual analysis in particular in analysing tiny retinal vessels and capillary networks. To circumvent this problem, fundus fluorescein angiography (FF A) that improves the image contrast is used. Unfortunately, it is an invasive procedure (injection of contrast dyes) that leads to other physiological problems and in the worst case may cause death. The objective of this research is to develop a non-invasive digital Image enhancement scheme that can overcome the problem of the varied and low contrast colour fundus images in order that the contrast produced is comparable to the invasive fluorescein method, and without introducing noise or artefacts. The developed image enhancement algorithm (called RETICA) is incorporated into a newly developed computerised DR system (called RETINO) that is capable to monitor and grade DR severity using colour fundus images. RETINO grades DR severity into five stages, namely No DR, Mild Non Proliferative DR (NPDR), Moderate NPDR, Severe NPDR and Proliferative DR (PDR) by enhancing the quality of digital colour fundus image using RETICA in the macular region and analysing the enlargement of the foveal avascular zone (F AZ), a region devoid of retinal vessels in the macular region. The importance of this research is to improve image quality in order to increase the accuracy, sensitivity and specificity of DR diagnosis, and to enable DR grading through either direct observation or computer assisted diagnosis system

Recent Advances in Signal Processing

The signal processing task is a very critical issue in the majority of new technological inventions and challenges in a variety of applications in both science and engineering fields. Classical signal processing techniques have largely worked with mathematical models that are linear, local, stationary, and Gaussian. They have always favored closed-form tractability over real-world accuracy. These constraints were imposed by the lack of powerful computing tools. During the last few decades, signal processing theories, developments, and applications have matured rapidly and now include tools from many areas of mathematics, computer science, physics, and engineering. This book is targeted primarily toward both students and researchers who want to be exposed to a wide variety of signal processing techniques and algorithms. It includes 27 chapters that can be categorized into five different areas depending on the application at hand. These five categories are ordered to address image processing, speech processing, communication systems, time-series analysis, and educational packages respectively. The book has the advantage of providing a collection of applications that are completely independent and self-contained; thus, the interested reader can choose any chapter and skip to another without losing continuity

Nonlocal Graph-PDEs and Riemannian Gradient Flows for Image Labeling

In this thesis, we focus on the image labeling problem which is the task of performing unique pixel-wise label decisions to simplify the image while reducing its redundant information. We build upon a recently introduced geometric approach for data labeling by assignment flows [ APSS17 ] that comprises a smooth dynamical system for data processing on weighted graphs. Hereby we pursue two lines of research that give new application and theoretically-oriented insights on the underlying segmentation task. We demonstrate using the example of Optical Coherence Tomography (OCT), which is the mostly used non-invasive acquisition method of large volumetric scans of human retinal tis- sues, how incorporation of constraints on the geometry of statistical manifold results in a novel purely data driven geometric approach for order-constrained segmentation of volumetric data in any metric space. In particular, making diagnostic analysis for human eye diseases requires decisive information in form of exact measurement of retinal layer thicknesses that has be done for each patient separately resulting in an demanding and time consuming task. To ease the clinical diagnosis we will introduce a fully automated segmentation algorithm that comes up with a high segmentation accuracy and a high level of built-in-parallelism. As opposed to many established retinal layer segmentation methods, we use only local information as input without incorporation of additional global shape priors. Instead, we achieve physiological order of reti- nal cell layers and membranes including a new formulation of ordered pair of distributions in an smoothed energy term. This systematically avoids bias pertaining to global shape and is hence suited for the detection of anatomical changes of retinal tissue structure. To access the perfor- mance of our approach we compare two different choices of features on a data set of manually annotated 3 D OCT volumes of healthy human retina and evaluate our method against state of the art in automatic retinal layer segmentation as well as to manually annotated ground truth data using different metrics. We generalize the recent work [ SS21 ] on a variational perspective on assignment flows and introduce a novel nonlocal partial difference equation (G-PDE) for labeling metric data on graphs. The G-PDE is derived as nonlocal reparametrization of the assignment flow approach that was introduced in J. Math. Imaging & Vision 58(2), 2017. Due to this parameterization, solving the G-PDE numerically is shown to be equivalent to computing the Riemannian gradient flow with re- spect to a nonconvex potential. We devise an entropy-regularized difference-of-convex-functions (DC) decomposition of this potential and show that the basic geometric Euler scheme for inte- grating the assignment flow is equivalent to solving the G-PDE by an established DC program- ming scheme. Moreover, the viewpoint of geometric integration reveals a basic way to exploit higher-order information of the vector field that drives the assignment flow, in order to devise a novel accelerated DC programming scheme. A detailed convergence analysis of both numerical schemes is provided and illustrated by numerical experiments

Scalable software and models for large-scale extracellular recordings

The brain represents information about the world through the electrical activity of populations of neurons. By placing an electrode near a neuron that is firing (spiking), it is possible to detect the resulting extracellular action potential (EAP) that is transmitted down an axon to other neurons. In this way, it is possible to monitor the communication of a group of neurons to uncover how they encode and transmit information. As the number of recorded neurons continues to increase, however, so do the data processing and analysis challenges. It is crucial that scalable software and analysis tools are developed and made available to the neuroscience community to keep up with the large amounts of data that are already being gathered. This thesis is composed of three pieces of work which I develop in order to better process and analyze large-scale extracellular recordings. My work spans all stages of extracellular analysis from the processing of raw electrical recordings to the development of statistical models to reveal underlying structure in neural population activity. In the first work, I focus on developing software to improve the comparison and adoption of different computational approaches for spike sorting. When analyzing neural recordings, most researchers are interested in the spiking activity of individual neurons, which must be extracted from the raw electrical traces through a process called spike sorting. Much development has been directed towards improving the performance and automation of spike sorting. This continuous development, while essential, has contributed to an over-saturation of new, incompatible tools that hinders rigorous benchmarking and complicates reproducible analysis. To address these limitations, I develop SpikeInterface, an open-source, Python framework designed to unify preexisting spike sorting technologies into a single toolkit and to facilitate straightforward benchmarking of different approaches. With this framework, I demonstrate that modern, automated spike sorters have low agreement when analyzing the same dataset, i.e. they find different numbers of neurons with different activity profiles; This result holds true for a variety of simulated and real datasets. Also, I demonstrate that utilizing a consensus-based approach to spike sorting, where the outputs of multiple spike sorters are combined, can dramatically reduce the number of falsely detected neurons. In the second work, I focus on developing an unsupervised machine learning approach for determining the source location of individually detected spikes that are recorded by high-density, microelectrode arrays. By localizing the source of individual spikes, my method is able to determine the approximate position of the recorded neuriii ons in relation to the microelectrode array. To allow my model to work with large-scale datasets, I utilize deep neural networks, a family of machine learning algorithms that can be trained to approximate complicated functions in a scalable fashion. I evaluate my method on both simulated and real extracellular datasets, demonstrating that it is more accurate than other commonly used methods. Also, I show that location estimates for individual spikes can be utilized to improve the efficiency and accuracy of spike sorting. After training, my method allows for localization of one million spikes in approximately 37 seconds on a TITAN X GPU, enabling real-time analysis of massive extracellular datasets. In my third and final presented work, I focus on developing an unsupervised machine learning model that can uncover patterns of activity from neural populations associated with a behaviour being performed. Specifically, I introduce Targeted Neural Dynamical Modelling (TNDM), a statistical model that jointly models the neural activity and any external behavioural variables. TNDM decomposes neural dynamics (i.e. temporal activity patterns) into behaviourally relevant and behaviourally irrelevant dynamics; the behaviourally relevant dynamics constitute all activity patterns required to generate the behaviour of interest while behaviourally irrelevant dynamics may be completely unrelated (e.g. other behavioural or brain states), or even related to behaviour execution (e.g. dynamics that are associated with behaviour generally but are not task specific). Again, I implement TNDM using a deep neural network to improve its scalability and expressivity. On synthetic data and on real recordings from the premotor (PMd) and primary motor cortex (M1) of a monkey performing a center-out reaching task, I show that TNDM is able to extract low-dimensional neural dynamics that are highly predictive of behaviour without sacrificing its fit to the neural data

Reasoning with Uncertainty in Deep Learning for Safer Medical Image Computing

Deep learning is now ubiquitous in the research field of medical image computing. As such technologies progress towards clinical translation, the question of safety becomes critical. Once deployed, machine learning systems unavoidably face situations where the correct decision or prediction is ambiguous. However, the current methods disproportionately rely on deterministic algorithms, lacking a mechanism to represent and manipulate uncertainty. In safety-critical applications such as medical imaging, reasoning under uncertainty is crucial for developing a reliable decision making system. Probabilistic machine learning provides a natural framework to quantify the degree of uncertainty over different variables of interest, be it the prediction, the model parameters and structures, or the underlying data (images and labels). Probability distributions are used to represent all the uncertain unobserved quantities in a model and how they relate to the data, and probability theory is used as a language to compute and manipulate these distributions. In this thesis, we explore probabilistic modelling as a framework to integrate uncertainty information into deep learning models, and demonstrate its utility in various high-dimensional medical imaging applications. In the process, we make several fundamental enhancements to current methods. We categorise our contributions into three groups according to the types of uncertainties being modelled: (i) predictive; (ii) structural and (iii) human uncertainty. Firstly, we discuss the importance of quantifying predictive uncertainty and understanding its sources for developing a risk-averse and transparent medical image enhancement application. We demonstrate how a measure of predictive uncertainty can be used as a proxy for the predictive accuracy in the absence of ground-truths. Furthermore, assuming the structure of the model is flexible enough for the task, we introduce a way to decompose the predictive uncertainty into its orthogonal sources i.e. aleatoric and parameter uncertainty. We show the potential utility of such decoupling in providing a quantitative “explanations” into the model performance. Secondly, we introduce our recent attempts at learning model structures directly from data. One work proposes a method based on variational inference to learn a posterior distribution over connectivity structures within a neural network architecture for multi-task learning, and share some preliminary results in the MR-only radiotherapy planning application. Another work explores how the training algorithm of decision trees could be extended to grow the architecture of a neural network to adapt to the given availability of data and the complexity of the task. Lastly, we develop methods to model the “measurement noise” (e.g., biases and skill levels) of human annotators, and integrate this information into the learning process of the neural network classifier. In particular, we show that explicitly modelling the uncertainty involved in the annotation process not only leads to an improvement in robustness to label noise, but also yields useful insights into the patterns of errors that characterise individual experts

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

Geodesic Active Fields:A Geometric Framework for Image Registration

Image registration is the concept of mapping homologous points in a pair of images. In other words, one is looking for an underlying deformation field that matches one image to a target image. The spectrum of applications of image registration is extremely large: It ranges from bio-medical imaging and computer vision, to remote sensing or geographic information systems, and even involves consumer electronics. Mathematically, image registration is an inverse problem that is ill-posed, which means that the exact solution might not exist or not be unique. In order to render the problem tractable, it is usual to write the problem as an energy minimization, and to introduce additional regularity constraints on the unknown data. In the case of image registration, one often minimizes an image mismatch energy, and adds an additive penalty on the deformation field regularity as smoothness prior. Here, we focus on the registration of the human cerebral cortex. Precise cortical registration is required, for example, in statistical group studies in functional MR imaging, or in the analysis of brain connectivity. In particular, we work with spherical inflations of the extracted hemispherical surface and associated features, such as cortical mean curvature. Spatial mapping between cortical surfaces can then be achieved by registering the respective spherical feature maps. Despite the simplified spherical geometry, inter-subject registration remains a challenging task, mainly due to the complexity and inter-subject variability of the involved brain structures. In this thesis, we therefore present a registration scheme, which takes the peculiarities of the spherical feature maps into particular consideration. First, we realize that we need an appropriate hierarchical representation, so as to coarsely align based on the important structures with greater inter-subject stability, before taking smaller and more variable details into account. Based on arguments from brain morphogenesis, we propose an anisotropic scale-space of mean-curvature maps, built around the Beltrami framework. Second, inspired by concepts from vision-related elements of psycho-physical Gestalt theory, we hypothesize that anisotropic Beltrami regularization better suits the requirements of image registration regularization, compared to traditional Gaussian filtering. Different objects in an image should be allowed to move separately, and regularization should be limited to within the individual Gestalts. We render the regularization feature-preserving by limiting diffusion across edges in the deformation field, which is in clear contrast to the indifferent linear smoothing. We do so by embedding the deformation field as a manifold in higher-dimensional space, and minimize the associated Beltrami energy which represents the hyperarea of this embedded manifold as measure of deformation field regularity. Further, instead of simply adding this regularity penalty to the image mismatch in lieu of the standard penalty, we propose to incorporate the local image mismatch as weighting function into the Beltrami energy. The image registration problem is thus reformulated as a weighted minimal surface problem. This approach has several appealing aspects, including (1) invariance to re-parametrization and ability to work with images defined on non-flat, Riemannian domains (e.g., curved surfaces, scalespaces), and (2) intrinsic modulation of the local regularization strength as a function of the local image mismatch and/or noise level. On a side note, we show that the proposed scheme can easily keep up with recent trends in image registration towards using diffeomorphic and inverse consistent deformation models. The proposed registration scheme, called Geodesic Active Fields (GAF), is non-linear and non-convex. Therefore we propose an efficient optimization scheme, based on splitting. Data-mismatch and deformation field regularity are optimized over two different deformation fields, which are constrained to be equal. The constraint is addressed using an augmented Lagrangian scheme, and the resulting optimization problem is solved efficiently using alternate minimization of simpler sub-problems. In particular, we show that the proposed method can easily compete with state-of-the-art registration methods, such as Demons. Finally, we provide an implementation of the fast GAF method on the sphere, so as to register the triangulated cortical feature maps. We build an automatic parcellation algorithm for the human cerebral cortex, which combines the delineations available on a set of atlas brains in a Bayesian approach, so as to automatically delineate the corresponding regions on a subject brain given its feature map. In a leave-one-out cross-validation study on 39 brain surfaces with 35 manually delineated gyral regions, we show that the pairwise subject-atlas registration with the proposed spherical registration scheme significantly improves the individual alignment of cortical labels between subject and atlas brains, and, consequently, that the estimated automatic parcellations after label fusion are of better quality