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

Deep learning of brain asymmetry digital biomarkers to support early diagnosis of cognitive decline and dementia

Early identification of degenerative processes in the human brain is essential for proper care and treatment. This may involve different instrumental diagnostic methods, including the most popular computer tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) scans. These technologies provide detailed information about the shape, size, and function of the human brain. Structural and functional cerebral changes can be detected by computational algorithms and used to diagnose dementia and its stages (amnestic early mild cognitive impairment - EMCI, Alzheimer’s Disease - AD). They can help monitor the progress of the disease. Transformation shifts in the degree of asymmetry between the left and right hemispheres illustrate the initialization or development of a pathological process in the brain. In this vein, this study proposes a new digital biomarker for the diagnosis of early dementia based on the detection of image asymmetries and crosssectional comparison of NC (normal cognitively), EMCI and AD subjects. Features of brain asymmetries extracted from MRI of the ADNI and OASIS databases are used to analyze structural brain changes and machine learning classification of the pathology. The experimental part of the study includes results of supervised machine learning algorithms and transfer learning architectures of convolutional neural networks for distinguishing between cognitively normal subjects and patients with early or progressive dementia. The proposed pipeline offers a low-cost imaging biomarker for the classification of dementia. It can be potentially helpful to other brain degenerative disorders accompanied by changes in brain asymmetries

Using Unsupervised Learning Methods to Analyse Magnetic Resonance Imaging (MRI) Scans for the Detection of Alzheimer’s Disease

Background: Alzheimer’s disease (AD) is the most common cause of dementia, characterised by behavioural and cognitive impairment. The manual diagnosis of AD by doctors is time-consuming and can be ineffective, so machine learning methods are increasingly being proposed to diagnose AD in many recent studies. Most research developing machine learning algorithms to diagnose AD use supervised learning to classify magnetic resonance imaging (MRI) scans. However, supervised learning requires a considerable volume of labelled data and MRI scans are difficult to label. The aim of this thesis was therefore to use unsupervised learning methods to differentiate between MRI scans from people who were cognitively normal (CN), people with mild cognitive impairment (MCI), and people with AD. Objectives: This study applied a statistical method and unsupervised learning methods to discriminate scans from (1) people with CN and with AD; (2) people with stable mild cognitive impairment (sMCI) and with progressive mild cognitive impairment (pMCI); (3) people with CN and with pMCI, using a limited number of labelled structural MRI scans. Methods: Two-sample t-tests were used to detect the regions of interest (ROIs) between each of the two groups (CN vs. AD; sMCI vs. pMCI; CN vs. pMCI), and then an unsupervised learning neural network was employed to extract features from the regions. Finally, a clustering algorithm was implemented to discriminate between each of the two groups based on the extracted features. The approach was tested on baseline brain structural MRI scans from 715 individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), of which 231 were CN, 198 had AD, 152 had sMCI, and 134 were pMCI. The results were evaluated by calculating the overall accuracy, the sensitivity, specificity, and positive and negative predictive values. Results: The abnormal regions around the lower parts of the limbic system were indicated as AD-relevant regions based on the two-sample t-test (p<0.001), and the proposed method yielded an overall accuracy of 0.842 for discriminating between CN and AD, an overall accuracy of 0.672 for discriminating between sMCI and pMCI, and an overall accuracy of 0.776 for discriminating between CN and pMCI. Conclusion: The study combined statistical and unsupervised learning methods to identify scans of people with different stages of AD. This method can detect AD-relevant regions and could be used to accurately diagnose stages of AD; it has the advantage that it does not require large amounts of labelled MRI scans. The performances of the three discriminations were all comparable to those of previous state-of-the-art studies. The research in this thesis could be implemented in the future to help in the automatic diagnosis of AD and provide a basis for diagnosing sMCI and pMCI

Explainable deep learning classifiers for disease detection based on structural brain MRI data

In dieser Doktorarbeit wird die Frage untersucht, wie erfolgreich deep learning bei der Diagnostik von neurodegenerativen Erkrankungen unterstützen kann. In 5 experimentellen Studien wird die Anwendung von Convolutional Neural Networks (CNNs) auf Daten der Magnetresonanztomographie (MRT) untersucht. Ein Schwerpunkt wird dabei auf die Erklärbarkeit der eigentlich intransparenten Modelle gelegt. Mit Hilfe von Methoden der erklärbaren künstlichen Intelligenz (KI) werden Heatmaps erstellt, die die Relevanz einzelner Bildbereiche für das Modell darstellen. Die 5 Studien dieser Dissertation zeigen das Potenzial von CNNs zur Krankheitserkennung auf neurologischen MRT, insbesondere bei der Kombination mit Methoden der erklärbaren KI. Mehrere Herausforderungen wurden in den Studien aufgezeigt und Lösungsansätze in den Experimenten evaluiert. Über alle Studien hinweg haben CNNs gute Klassifikationsgenauigkeiten erzielt und konnten durch den Vergleich von Heatmaps zur klinischen Literatur validiert werden. Weiterhin wurde eine neue CNN Architektur entwickelt, spezialisiert auf die räumlichen Eigenschaften von Gehirn MRT Bildern.Deep learning and especially convolutional neural networks (CNNs) have a high potential of being implemented into clinical decision support software for tasks such as diagnosis and prediction of disease courses. This thesis has studied the application of CNNs on structural MRI data for diagnosing neurological diseases. Specifically, multiple sclerosis and Alzheimer’s disease were used as classification targets due to their high prevalence, data availability and apparent biomarkers in structural MRI data. The classification task is challenging since pathology can be highly individual and difficult for human experts to detect and due to small sample sizes, which are caused by the high acquisition cost and sensitivity of medical imaging data. A roadblock in adopting CNNs to clinical practice is their lack of interpretability. Therefore, after optimizing the machine learning models for predictive performance (e.g. balanced accuracy), we have employed explainability methods to study the reliability and validity of the trained models. The deep learning models achieved good predictive performance of over 87% balanced accuracy on all tasks and the explainability heatmaps showed coherence with known clinical biomarkers for both disorders. Explainability methods were compared quantitatively using brain atlases and shortcomings regarding their robustness were revealed. Further investigations showed clear benefits of transfer-learning and image registration on the model performance. Lastly, a new CNN layer type was introduced, which incorporates a prior on the spatial homogeneity of neuro-MRI data. CNNs excel when used on natural images which possess spatial heterogeneity, and even though MRI data and natural images share computational similarities, the composition and orientation of neuro-MRI is very distinct. The introduced patch-individual filter (PIF) layer breaks the assumption of spatial invariance of CNNs and reduces convergence time on different data sets without reducing predictive performance. The presented work highlights many challenges that CNNs for disease diagnosis face on MRI data and defines as well as tests strategies to overcome those

Pacific Symposium on Biocomputing 2023

The Pacific Symposium on Biocomputing (PSB) 2023 is an international, multidisciplinary conference for the presentation and discussion of current research in the theory and application of computational methods in problems of biological significance. Presentations are rigorously peer reviewed and are published in an archival proceedings volume. PSB 2023 will be held on January 3-7, 2023 in Kohala Coast, Hawaii. Tutorials and workshops will be offered prior to the start of the conference.PSB 2023 will bring together top researchers from the US, the Asian Pacific nations, and around the world to exchange research results and address open issues in all aspects of computational biology. It is a forum for the presentation of work in databases, algorithms, interfaces, visualization, modeling, and other computational methods, as applied to biological problems, with emphasis on applications in data-rich areas of molecular biology.The PSB has been designed to be responsive to the need for critical mass in sub-disciplines within biocomputing. For that reason, it is the only meeting whose sessions are defined dynamically each year in response to specific proposals. PSB sessions are organized by leaders of research in biocomputing's 'hot topics.' In this way, the meeting provides an early forum for serious examination of emerging methods and approaches in this rapidly changing field

Single-slice Alzheimer's disease classification and disease regional analysis with supervised switching autoencoders

Q2Q2Background Alzheimer's disease (AD) is a difficult to diagnose pathology of the brain that progressively impairs cognitive functions. Computer-assisted diagnosis of AD based on image analysis is an emerging tool to support AD diagnosis. In this article, we explore the application of Supervised Switching Autoencoders (SSAs) to perform AD classification using only one structural Magnetic Resonance Imaging (sMRI) slice. SSAs are revised supervised autoencoder architectures, combining unsupervised representation and supervised classification as one unified model. In this work, we study the capabilities of SSAs to capture complex visual neurodegeneration patterns, and fuse disease semantics simultaneously. We also examine how regions associated to disease state can be discovered by SSAs following a local patch-based approach. Results Our experiments employing a single 2D T1-w sMRI slice per subject show that SSAs perform similarly to previous proposals that rely on full volumetric information and feature-engineered representations. SSAs classification accuracy on slices extracted along the Axial, Coronal, and Sagittal anatomical planes from a balanced cohort of 40 independent test subjects was 87.5%, 90.0%, and 90.0%, respectively. A top sensitivity of 95.0% on both Coronal and Sagittal planes was also obtained. Conclusions SSAs provided well-ranked accuracy performance among previous classification proposals, including feature-engineered and feature learning based methods, using only one scan slice per subject, instead of the whole 3D volume, as it is conventionally done. In addition, regions identified as relevant by SSAs’ were, in most part, coherent or partially coherent in regard to relevant regions reported on previous works. These regions were also associated with findings from medical knowledge, which gives value to our methodology as a potential analytical aid for disease understanding.Revista Internacional - Indexad

Single-slice Alzheimer's disease classification and disease regional analysis with Supervised Switching Autoencoders

International audienceBackground Alzheimer's disease (AD) is a difficult to diagnose pathology of the brain that progressively impairs cognitive functions. Computer-assisted diagnosis of AD based on image analysis is an emerging tool to support AD diagnosis. In this article, we explore the application of Supervised Switching Autoencoders (SSAs) to perform AD classification using only one structural Magnetic Resonance Imaging (sMRI) slice. SSAs are revised supervised autoencoder architectures, combining unsupervised representation and supervised classification as one unified model. In this work, we study the capabilities of SSAs to capture complex visual neurodegeneration patterns, and fuse disease semantics simultaneously. We also examine how regions associated to disease state can be discovered by SSAs following a local patch-based approach. Methods Patch-based SSAs models are trained on individual patches extracted from a single 2D slice, independently for Axial, Coronal, and Sagittal anatomical planes of the brain at selected informative locations, exploring different patch sizes and network parameterizations. Then, models perform binary class prediction - healthy (CDR = 0) or AD-demented (CDR > 0) - on test data at patch level. The final subject classification is performed employing a majority rule from the ensemble of patch predictions. In addition, relevant regions are identified, by computing accuracy densities from patch-level predictions, and analyzed, supported by Atlas-based regional definitions. Results Our experiments employing a single 2D T1-w sMRI slice per subject show that SSAs perform similarly to previous proposals that rely on full volumetric information and feature-engineered representations. SSAs classification accuracy on slices extracted along the Axial, Coronal, and Sagittal anatomical planes from a balanced cohort of 40 independent test subjects was 87.5%, 90.0%, and 90.0%, respectively. A top sensitivity of 95.0% on both Coronal and Sagittal planes was also obtained. Conclusions SSAs provided well-ranked accuracy performance among previous classification proposals, including feature-engineered and feature learning based methods, using only one scan slice per subject, instead of the whole 3D volume, as it is conventionally done. In addition, regions identified as relevant by SSAs' were, in most part, coherent or partially coherent in regard to relevant regions reported on previous works. These regions were also associated with findings from medical knowledge, which gives value to our methodology as a potential analytical aid for disease understanding

MS FT-2-2 7 Orthogonal polynomials and quadrature: Theory, computation, and applications

Quadrature rules find many applications in science and engineering. Their analysis is a classical area of applied mathematics and continues to attract considerable attention. This seminar brings together speakers with expertise in a large variety of quadrature rules. It is the aim of the seminar to provide an overview of recent developments in the analysis of quadrature rules. The computation of error estimates and novel applications also are described

Generalized averaged Gaussian quadrature and applications

A simple numerical method for constructing the optimal generalized averaged Gaussian quadrature formulas will be presented. These formulas exist in many cases in which real positive GaussKronrod formulas do not exist, and can be used as an adequate alternative in order to estimate the error of a Gaussian rule. We also investigate the conditions under which the optimal averaged Gaussian quadrature formulas and their truncated variants are internal