A graph-based integration of multimodal brain imaging data for the detection of early mild cognitive impairment (E-MCI)

Alzheimer's disease (AD) is the most common cause of dementia in older adults. By the time an individual has been diagnosed with AD, it may be too late for potential disease modifying therapy to strongly influence outcome. Therefore, it is critical to develop better diagnostic tools that can recognize AD at early symptomatic and especially pre-symptomatic stages. Mild cognitive impairment (MCI), introduced to describe a prodromal stage of AD, is presently classified into early and late stages (E-MCI, L-MCI) based on severity. Using a graph-based semi-supervised learning (SSL) method to integrate multimodal brain imaging data and select valid imaging-based predictors for optimizing prediction accuracy, we developed a model to differentiate E-MCI from healthy controls (HC) for early detection of AD. Multimodal brain imaging scans (MRI and PET) of 174 E-MCI and 98 HC participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort were used in this analysis. Mean targeted region-of-interest (ROI) values extracted from structural MRI (voxel-based morphometry (VBM) and FreeSurfer V5) and PET (FDG and Florbetapir) scans were used as features. Our results show that the graph-based SSL classifiers outperformed support vector machines for this task and the best performance was obtained with 66.8% cross-validated AUC (area under the ROC curve) when FDG and FreeSurfer datasets were integrated. Valid imaging-based phenotypes selected from our approach included ROI values extracted from temporal lobe, hippocampus, and amygdala. Employing a graph-based SSL approach with multimodal brain imaging data appears to have substantial potential for detecting E-MCI for early detection of prodromal AD warranting further investigation

DEEP-AD: The deep learning model for diagnostic classification and prognostic prediction of alzheimer's disease

In terms of context, the aim of this dissertation is to aid neuroradiologists in their clinical judgment regarding the early detection of AD by using DL. To that aim, the system design research methodology is suggested in this dissertation for achieving three goals. The first goal is to investigate the DL models that have performed well at identifying patterns associated with AD, as well as the accuracy so far attained, limitations, and gaps. A systematic review of the literature (SLR) revealed a shortage of empirical studies on the early identification of AD through DL. In this regard, thirteen empirical studies were identified and examined. We concluded that three-dimensional (3D) DL models have been generated far less often and that their performance is also inadequate to qualify them for clinical trials. The second goal is to provide the neuroradiologist with the computer-interpretable information they need to analyze neuroimaging biomarkers. Given this context, the next step in this dissertation is to find the optimum DL model to analyze neuroimaging biomarkers. It has been achieved in two steps. In the first step, eight state-of-the-art DL models have been implemented by training from scratch using end-to-end learning (E2EL) for two binary classification tasks (AD vs. CN and AD vs. stable MCI) and compared by utilizing MRI scans from the publicly accessible datasets of neuroimaging biomarkers. Comparative analysis is carried out by utilizing efficiency-effects graphs, comprehensive indicators, and ranking mechanisms. For the training of the AD vs. sMCI task, the EfficientNet-B0 model gets the highest value for the comprehensive indicator and has the fewest parameters. DenseNet264 performed better than the others in terms of evaluation matrices, but since it has the most parameters, it costs more to train. For the AD vs. CN task by DenseNet264, we achieved 100% accuracy for training and 99.56% accuracy for testing. However, the classification accuracy was still only 82.5% for the AD vs. sMCI task. In the second step, fusion of transfer learning (TL) with E2EL is applied to train the EfficientNet-B0 for the AD vs. sMCI task, which achieved 95.29% accuracy for training and 93.10% accuracy for testing. Additionally, we have also implemented EfficientNet-B0 for the multiclass AD vs. CN vs. sMCI classification task with E2EL to be used in ensemble of models and achieved 85.66% training accuracy and 87.38% testing accuracy. To evaluate the model’s robustness, neuroradiologists must validate the implemented model. As a result, the third goal of this dissertation is to create a tool that neuroradiologists may use at their convenience. To achieve this objective, this dissertation proposes a web-based application (DEEP-AD) that has been created by making an ensemble of Efficient-Net B0 and DenseNet 264 (based on the contribution of goal 2). The accuracy of a DEEP-AD prototype has undergone repeated evaluation and improvement. First, we validated 41 subjects of Spanish MRI datasets (acquired from HT Medica, Madrid, Spain), achieving an accuracy of 82.90%, which was later verified by neuroradiologists. The results of these evaluation studies showed the accomplishment of such goals and relevant directions for future research in applied DL for the early detection of AD in clinical settings.En términos de contexto, el objetivo de esta tesis es ayudar a los neurorradiólogos en su juicio clínico sobre la detección precoz de la AD mediante el uso de DL. Para ello, en esta tesis se propone la metodología de investigación de diseño de sistemas para lograr tres objetivos. El segundo objetivo es proporcionar al neurorradiólogo la información interpretable por ordenador que necesita para analizar los biomarcadores de neuroimagen. Dado este contexto, el siguiente paso en esta tesis es encontrar el modelo DL óptimo para analizar biomarcadores de neuroimagen. Esto se ha logrado en dos pasos. En el primer paso, se han implementado ocho modelos DL de última generación mediante entrenamiento desde cero utilizando aprendizaje de extremo a extremo (E2EL) para dos tareas de clasificación binarias (AD vs. CN y AD vs. MCI estable) y se han comparado utilizando escaneos MRI de los conjuntos de datos de biomarcadores de neuroimagen de acceso público. El análisis comparativo se lleva a cabo utilizando gráficos de efecto-eficacia, indicadores exhaustivos y mecanismos de clasificación. Para el entrenamiento de la tarea AD vs. sMCI, el modelo EfficientNet-B0 obtiene el valor más alto para el indicador exhaustivo y tiene el menor número de parámetros. DenseNet264 obtuvo mejores resultados que los demás en términos de matrices de evaluación, pero al ser el que tiene más parámetros, su entrenamiento es más costoso. Para la tarea AD vs. CN de DenseNet264, conseguimos una accuracy del 100% en el entrenamiento y del 99,56% en las pruebas. Sin embargo, la accuracy de la clasificación fue sólo del 82,5% para la tarea AD vs. sMCI. En el segundo paso, se aplica la fusión del aprendizaje por transferencia (TL) con E2EL para entrenar la EfficientNet-B0 para la tarea AD vs. sMCI, que alcanzó una accuracy del 95,29% en el entrenamiento y del 93,10% en las pruebas. Además, también hemos implementado EfficientNet-B0 para la tarea de clasificación multiclase AD vs. CN vs. sMCI con E2EL para su uso en conjuntos de modelos y hemos obtenido una accuracy de entrenamiento del 85,66% y una precisión de prueba del 87,38%. Para evaluar la solidez del modelo, los neurorradiólogos deben validar el modelo implementado. Como resultado, el tercer objetivo de esta disertación es crear una herramienta que los neurorradiólogos puedan utilizar a su conveniencia. Para lograr este objetivo, esta disertación propone una aplicación basada en web (DEEP-AD) que ha sido creada haciendo un ensemble de Efficient-Net B0 y DenseNet 264 (basado en la contribución del objetivo 2). La accuracy del prototipo DEEP-AD ha sido sometida a repetidas evaluaciones y mejoras. En primer lugar, validamos 41 sujetos de conjuntos de datos de MRI españoles (adquiridos de HT Medica, Madrid, España), logrando una accuracy del 82,90%, que posteriormente fue verificada por neurorradiólogos. Los resultados de estos estudios de evaluación mostraron el cumplimiento de dichos objetivos y las direcciones relevantes para futuras investigaciones en DL, aplicada en la detección precoz de la AD en entornos clínicos.Escuela de DoctoradoDoctorado en Tecnologías de la Información y las Telecomunicacione

Pathway and network analysis in proteomics

Proteomics is inherently a systems science that studies not only measured protein and their expressions in a cell, but also the interplay of proteins, protein complexes, signaling pathways, and network modules. There is a rapid accumulation of Proteomics data in recent years. However, Proteomics data are highly variable, with results sensitive to data preparation methods, sample condition, instrument types, and analytical methods. To address the challenge in Proteomics data analysis, we review current tools being developed to incorporate biological function and network topological information. We categorize these tools into four types: tools with basic functional information and little topological features (e.g., GO category analysis), tools with rich functional information and little topological features (e.g., GSEA), tools with basic functional information and rich topological features (e.g., Cytoscape), and tools with rich functional information and rich topological features (e.g., PathwayExpress). We first review the potential application of these tools to Proteomics; then we review tools that can achieve automated learning of pathway modules and features, and tools that help perform integrated network visual analytics

3D shape matching and registration : a probabilistic perspective

Dense correspondence is a key area in computer vision and medical image analysis. It has applications in registration and shape analysis. In this thesis, we develop a technique to recover dense correspondences between the surfaces of neuroanatomical objects over heterogeneous populations of individuals. We recover dense correspondences based on 3D shape matching. In this thesis, the 3D shape matching problem is formulated under the framework of Markov Random Fields (MRFs). We represent the surfaces of neuroanatomical objects as genus zero voxel-based meshes. The surface meshes are projected into a Markov random field space. The projection carries both geometric and topological information in terms of Gaussian curvature and mesh neighbourhood from the original space to the random field space. Gaussian curvature is projected to the nodes of the MRF, and the mesh neighbourhood structure is projected to the edges. 3D shape matching between two surface meshes is then performed by solving an energy function minimisation problem formulated with MRFs. The outcome of the 3D shape matching is dense point-to-point correspondences. However, the minimisation of the energy function is NP hard. In this thesis, we use belief propagation to perform the probabilistic inference for 3D shape matching. A sparse update loopy belief propagation algorithm adapted to the 3D shape matching is proposed to obtain an approximate global solution for the 3D shape matching problem. The sparse update loopy belief propagation algorithm demonstrates significant efficiency gain compared to standard belief propagation. The computational complexity and convergence property analysis for the sparse update loopy belief propagation algorithm are also conducted in the thesis. We also investigate randomised algorithms to minimise the energy function. In order to enhance the shape matching rate and increase the inlier support set, we propose a novel clamping technique. The clamping technique is realized by combining the loopy belief propagation message updating rule with the feedback from 3D rigid body registration. By using this clamping technique, the correct shape matching rate is increased significantly. Finally, we investigate 3D shape registration techniques based on the 3D shape matching result. Based on the point-to-point dense correspondences obtained from the 3D shape matching, a three-point based transformation estimation technique is combined with the RANdom SAmple Consensus (RANSAC) algorithm to obtain the inlier support set. The global registration approach is purely dependent on point-wise correspondences between two meshed surfaces. It has the advantage that the need for orientation initialisation is eliminated and that all shapes of spherical topology. The comparison of our MRF based 3D registration approach with a state-of-the-art registration algorithm, the first order ellipsoid template, is conducted in the experiments. These show dense correspondence for pairs of hippocampi from two different data sets, each of around 20 60+ year old healthy individuals

Pattern Analysis and Prediction of Mild Cognitive Impairment Using the Conn Toolbox

Alzheimer\u27s is an irreversible neurodegenerative disorder described by dynamic psychological and memory defalcation. It has been accounted for that the pervasiveness of Alzheimer\u27s is to increase by 4 times in a few years, where one in every 75 people will have this disorder. Hence, there is a critical requirement for the analysis of Alzheimer\u27s at its beginning stage to diminish the difficulty of the overall medical complications. The initial state of Alzheimer’s is called Mild cognitive impairment (MCI), and hence it is a decent target for premature diagnosis and treatment of Alzheimer\u27s. This project focuses on coordinating numerous imaging modalities to identify people in danger for MCI. The current advancement of brain network connectivity analysis has led to the identification of neurological issues at an entire connectivity level, thereby providing a new road to the classification of brain-related diseases. Utilizing neuroimage pattern classification and various machine learning techniques, we endeavor to incorporate information from CONN toolbox and resting-state functional magnetic resonance imaging (rs-fMRI) for refining MCI prediction accuracy

BrainPrint: A discriminative characterization of brain morphology

We introduce BrainPrint, a compact and discriminative representation of brain morphology. BrainPrint captures shape information of an ensemble of cortical and subcortical structures by solving the eigenvalue problem of the 2D and 3D Laplace–Beltrami operator on triangular (boundary) and tetrahedral (volumetric) meshes. This discriminative characterization enables new ways to study the similarity between brains; the focus can either be on a specific brain structure of interest or on the overall brain similarity. We highlight four applications for BrainPrint in this article: (i) subject identification, (ii) age and sex prediction, (iii) brain asymmetry analysis, and (iv) potential genetic influences on brain morphology. The properties of BrainPrint require the derivation of new algorithms to account for the heterogeneous mix of brain structures with varying discriminative power. We conduct experiments on three datasets, including over 3000 MRI scans from the ADNI database, 436 MRI scans from the OASIS dataset, and 236 MRI scans from the VETSA twin study. All processing steps for obtaining the compact representation are fully automated, making this processing framework particularly attractive for handling large datasets.National Cancer Institute (U.S.) (1K25-CA181632-01)Athinoula A. Martinos Center for Biomedical Imaging (P41-RR014075)Athinoula A. Martinos Center for Biomedical Imaging (P41-EB015896)National Alliance for Medical Image Computing (U.S.) (U54-EB005149)Neuroimaging Analysis Center (U.S.) (P41-EB015902)National Center for Research Resources (U.S.) (U24 RR021382)National Institute of Biomedical Imaging and Bioengineering (U.S.) (5P41EB015896-15)National Institute of Biomedical Imaging and Bioengineering (U.S.) (R01EB006758)National Institute on Aging (AG022381)National Institute on Aging (5R01AG008122-22)National Institute on Aging (AG018344)National Institute on Aging (AG018386)National Center for Complementary and Alternative Medicine (U.S.) (RC1 AT005728-01)National Institute of Neurological Diseases and Stroke (U.S.) (R01 NS052585-01)National Institute of Neurological Diseases and Stroke (U.S.) (1R21NS072652-01)National Institute of Neurological Diseases and Stroke (U.S.) (1R01NS070963)National Institute of Neurological Diseases and Stroke (U.S.) (R01NS083534)National Institutes of Health (U.S.) ((5U01-MH093765

BrainPrint: A discriminative characterization of brain morphology

We introduce BrainPrint, a compact and discriminative representation of brain morphology. BrainPrint captures shape information of an ensemble of cortical and subcortical structures by solving the eigenvalue problem of the 2D and 3D Laplace–Beltrami operator on triangular (boundary) and tetrahedral (volumetric) meshes. This discriminative characterization enables new ways to study the similarity between brains; the focus can either be on a specific brain structure of interest or on the overall brain similarity. We highlight four applications for BrainPrint in this article: (i) subject identification, (ii) age and sex prediction, (iii) brain asymmetry analysis, and (iv) potential genetic influences on brain morphology. The properties of BrainPrint require the derivation of new algorithms to account for the heterogeneous mix of brain structures with varying discriminative power. We conduct experiments on three datasets, including over 3000 MRI scans from the ADNI database, 436 MRI scans from the OASIS dataset, and 236 MRI scans from the VETSA twin study. All processing steps for obtaining the compact representation are fully automated, making this processing framework particularly attractive for handling large datasets.National Cancer Institute (U.S.) (1K25-CA181632-01)Athinoula A. Martinos Center for Biomedical Imaging (P41-RR014075)Athinoula A. Martinos Center for Biomedical Imaging (P41-EB015896)National Alliance for Medical Image Computing (U.S.) (U54-EB005149)Neuroimaging Analysis Center (U.S.) (P41-EB015902)National Center for Research Resources (U.S.) (U24 RR021382)National Institute of Biomedical Imaging and Bioengineering (U.S.) (5P41EB015896-15)National Institute of Biomedical Imaging and Bioengineering (U.S.) (R01EB006758)National Institute on Aging (AG022381)National Institute on Aging (5R01AG008122-22)National Institute on Aging (AG018344)National Institute on Aging (AG018386)National Center for Complementary and Alternative Medicine (U.S.) (RC1 AT005728-01)National Institute of Neurological Diseases and Stroke (U.S.) (R01 NS052585-01)National Institute of Neurological Diseases and Stroke (U.S.) (1R21NS072652-01)National Institute of Neurological Diseases and Stroke (U.S.) (1R01NS070963)National Institute of Neurological Diseases and Stroke (U.S.) (R01NS083534)National Institutes of Health (U.S.) ((5U01-MH093765