Sparse Multivariate Autoregressive Modeling for Mild Cognitive Impairment Classification

Brain connectivity network derived from functional magnetic resonance imaging (fMRI) is becoming increasingly prevalent in the researches related to cognitive and perceptual processes. The capability to detect causal or effective connectivity is highly desirable for understanding the cooperative nature of brain network, particularly when the ultimate goal is to obtain good performance of control-patient classification with biological meaningful interpretations. Understanding directed functional interactions between brain regions via brain connectivity network is a challenging task. Since many genetic and biomedical networks are intrinsically sparse, incorporating sparsity property into connectivity modeling can make the derived models more biologically plausible. Accordingly, we propose an effective connectivity modeling of resting-state fMRI data based on the multivariate autoregressive (MAR) modeling technique, which is widely used to characterize temporal information of dynamic systems. This MAR modeling technique allows for the identification of effective connectivity using the Granger causality concept and reducing the spurious causality connectivity in assessment of directed functional interaction from fMRI data. A forward orthogonal least squares (OLS) regression algorithm is further used to construct a sparse MAR model. By applying the proposed modeling to mild cognitive impairment (MCI) classification, we identify several most discriminative regions, including middle cingulate gyrus, posterior cingulate gyrus, lingual gyrus and caudate regions, in line with results reported in previous findings. A relatively high classification accuracy of 91.89 % is also achieved, with an increment of 5.4 % compared to the fully-connected, non-directional Pearson-correlation-based functional connectivity approach

Learning Discriminative Bayesian Networks from High-dimensional Continuous Neuroimaging Data

Due to its causal semantics, Bayesian networks (BN) have been widely employed to discover the underlying data relationship in exploratory studies, such as brain research. Despite its success in modeling the probability distribution of variables, BN is naturally a generative model, which is not necessarily discriminative. This may cause the ignorance of subtle but critical network changes that are of investigation values across populations. In this paper, we propose to improve the discriminative power of BN models for continuous variables from two different perspectives. This brings two general discriminative learning frameworks for Gaussian Bayesian networks (GBN). In the first framework, we employ Fisher kernel to bridge the generative models of GBN and the discriminative classifiers of SVMs, and convert the GBN parameter learning to Fisher kernel learning via minimizing a generalization error bound of SVMs. In the second framework, we employ the max-margin criterion and build it directly upon GBN models to explicitly optimize the classification performance of the GBNs. The advantages and disadvantages of the two frameworks are discussed and experimentally compared. Both of them demonstrate strong power in learning discriminative parameters of GBNs for neuroimaging based brain network analysis, as well as maintaining reasonable representation capacity. The contributions of this paper also include a new Directed Acyclic Graph (DAG) constraint with theoretical guarantee to ensure the graph validity of GBN.Comment: 16 pages and 5 figures for the article (excluding appendix

Hyper-connectivity of functional networks for brain disease diagnosis

Exploring structural and functional interactions among various brain regions enables better understanding of pathological underpinnings of neurological disorders. Brain connectivity network, as a simplified representation of those structural and functional interactions, has been widely used for diagnosis and classification of neurodegenerative diseases, especially for Alzheimer’s disease (AD) and its early stage - mild cognitive impairment (MCI). However, the conventional functional connectivity network is usually constructed based on the pairwise correlation among different brain regions and thus ignores their higher-order relationships. Such loss of high-order information could be important for disease diagnosis, since neurologically a brain region predominantly interacts with more than one other brain regions. Accordingly, in this paper, we propose a novel framework for estimating the hyper-connectivity network of brain functions and then use this hyper-network for brain disease diagnosis. Here, the functional connectivity hyper-network denotes a network where each of its edges representing the interactions among multiple brain regions (i.e., an edge can connect with more than two brain regions), which can be naturally represented by a hyper-graph. Specifically, we first construct connectivity hyper-networks from the resting-state fMRI (R-fMRI) time series by using sparse representation. Then, we extract three sets of brain-region specific features from the connectivity hyper-networks, and further exploit a manifold regularized multi-task feature selection method to jointly select the most discriminative features. Finally, we use multi-kernel support vector machine (SVM) for classification. The experimental results on both MCI dataset and attention deficit hyperactivity disorder (ADHD) dataset demonstrate that, compared with the conventional connectivity network-based methods, the proposed method can not only improve the classification performance, but also help discover disease-related biomarkers important for disease diagnosis

Machine Learning for Multiclass Classification and Prediction of Alzheimer\u27s Disease

Alzheimer\u27s disease (AD) is an irreversible neurodegenerative disorder and a common form of dementia. This research aims to develop machine learning algorithms that diagnose and predict the progression of AD from multimodal heterogonous biomarkers with a focus placed on the early diagnosis. To meet this goal, several machine learning-based methods with their unique characteristics for feature extraction and automated classification, prediction, and visualization have been developed to discern subtle progression trends and predict the trajectory of disease progression. The methodology envisioned aims to enhance both the multiclass classification accuracy and prediction outcomes by effectively modeling the interplay between the multimodal biomarkers, handle the missing data challenge, and adequately extract all the relevant features that will be fed into the machine learning framework, all in order to understand the subtle changes that happen in the different stages of the disease. This research will also investigate the notion of multitasking to discover how the two processes of multiclass classification and prediction relate to one another in terms of the features they share and whether they could learn from one another for optimizing multiclass classification and prediction accuracy. This research work also delves into predicting cognitive scores of specific tests over time, using multimodal longitudinal data. The intent is to augment our prospects for analyzing the interplay between the different multimodal features used in the input space to the predicted cognitive scores. Moreover, the power of modality fusion, kernelization, and tensorization have also been investigated to efficiently extract important features hidden in the lower-dimensional feature space without being distracted by those deemed as irrelevant. With the adage that a picture is worth a thousand words, this dissertation introduces a unique color-coded visualization system with a fully integrated machine learning model for the enhanced diagnosis and prognosis of Alzheimer\u27s disease. The incentive here is to show that through visualization, the challenges imposed by both the variability and interrelatedness of the multimodal features could be overcome. Ultimately, this form of visualization via machine learning informs on the challenges faced with multiclass classification and adds insight into the decision-making process for a diagnosis and prognosis

Discovering Causal Relations and Equations from Data

Physics is a field of science that has traditionally used the scientific method to answer questions about why natural phenomena occur and to make testable models that explain the phenomena. Discovering equations, laws and principles that are invariant, robust and causal explanations of the world has been fundamental in physical sciences throughout the centuries. Discoveries emerge from observing the world and, when possible, performing interventional studies in the system under study. With the advent of big data and the use of data-driven methods, causal and equation discovery fields have grown and made progress in computer science, physics, statistics, philosophy, and many applied fields. All these domains are intertwined and can be used to discover causal relations, physical laws, and equations from observational data. This paper reviews the concepts, methods, and relevant works on causal and equation discovery in the broad field of Physics and outlines the most important challenges and promising future lines of research. We also provide a taxonomy for observational causal and equation discovery, point out connections, and showcase a complete set of case studies in Earth and climate sciences, fluid dynamics and mechanics, and the neurosciences. This review demonstrates that discovering fundamental laws and causal relations by observing natural phenomena is being revolutionised with the efficient exploitation of observational data, modern machine learning algorithms and the interaction with domain knowledge. Exciting times are ahead with many challenges and opportunities to improve our understanding of complex systems.Comment: 137 page

Sparse feature learning for image analysis in segmentation, classification, and disease diagnosis.

The success of machine learning algorithms generally depends on intermediate data representation, called features that disentangle the hidden factors of variation in data. Moreover, machine learning models are required to be generalized, in order to reduce the specificity or bias toward the training dataset. Unsupervised feature learning is useful in taking advantage of large amount of unlabeled data, which is available to capture these variations. However, learned features are required to capture variational patterns in data space. In this dissertation, unsupervised feature learning with sparsity is investigated for sparse and local feature extraction with application to lung segmentation, interpretable deep models, and Alzheimer\u27s disease classification. Nonnegative Matrix Factorization, Autoencoder and 3D Convolutional Autoencoder are used as architectures or models for unsupervised feature learning. They are investigated along with nonnegativity, sparsity and part-based representation constraints for generalized and transferable feature extraction

Dealing with heterogeneity in the prediction of clinical diagnosis

Le diagnostic assisté par ordinateur est un domaine de recherche en émergence et se situe à l’intersection de l’imagerie médicale et de l’apprentissage machine. Les données médi- cales sont de nature très hétérogène et nécessitent une attention particulière lorsque l’on veut entraîner des modèles de prédiction. Dans cette thèse, j’ai exploré deux sources d’hétérogénéité, soit l’agrégation multisites et l’hétérogénéité des étiquettes cliniques dans le contexte de l’imagerie par résonance magnétique (IRM) pour le diagnostic de la maladie d’Alzheimer (MA). La première partie de ce travail consiste en une introduction générale sur la MA, l’IRM et les défis de l’apprentissage machine en imagerie médicale. Dans la deuxième partie de ce travail, je présente les trois articles composant la thèse. Enfin, la troisième partie porte sur une discussion des contributions et perspectives fu- tures de ce travail de recherche. Le premier article de cette thèse montre que l’agrégation des données sur plusieurs sites d’acquisition entraîne une certaine perte, comparative- ment à l’analyse sur un seul site, qui tend à diminuer plus la taille de l’échantillon aug- mente. Le deuxième article de cette thèse examine la généralisabilité des modèles de prédiction à l’aide de divers schémas de validation croisée. Les résultats montrent que la formation et les essais sur le même ensemble de sites surestiment la précision du modèle, comparativement aux essais sur des nouveaux sites. J’ai également montré que l’entraînement sur un grand nombre de sites améliore la précision sur des nouveaux sites. Le troisième et dernier article porte sur l’hétérogénéité des étiquettes cliniques et pro- pose un nouveau cadre dans lequel il est possible d’identifier un sous-groupe d’individus qui partagent une signature homogène hautement prédictive de la démence liée à la MA. Cette signature se retrouve également chez les patients présentant des symptômes mod- érés. Les résultats montrent que 90% des sujets portant la signature ont progressé vers la démence en trois ans. Les travaux de cette thèse apportent ainsi de nouvelles con- tributions à la manière dont nous approchons l’hétérogénéité en diagnostic médical et proposent des pistes de solution pour tirer profit de cette hétérogénéité.Computer assisted diagnosis has emerged as a popular area of research at the intersection of medical imaging and machine learning. Medical data are very heterogeneous in nature and therefore require careful attention when one wants to train prediction models. In this thesis, I explored two sources of heterogeneity, multisite aggregation and clinical label heterogeneity, in an application of magnetic resonance imaging to the diagnosis of Alzheimer’s disease. In the process, I learned about the feasibility of multisite data aggregation and how to leverage that heterogeneity in order to improve generalizability of prediction models. Part one of the document is a general context introduction to Alzheimer’s disease, magnetic resonance imaging, and machine learning challenges in medical imaging. In part two, I present my research through three articles (two published and one in preparation). Finally, part three provides a discussion of my contributions and hints to possible future developments. The first article shows that data aggregation across multiple acquisition sites incurs some loss, compared to single site analysis, that tends to diminish as the sample size increase. These results were obtained through semisynthetic Monte-Carlo simulations based on real data. The second article investigates the generalizability of prediction models with various cross-validation schemes. I showed that training and testing on the same batch of sites over-estimates the accuracy of the model, compared to testing on unseen sites. However, I also showed that training on a large number of sites improves the accuracy on unseen sites. The third article, on clinical label heterogeneity, proposes a new framework where we can identify a subgroup of individuals that share a homogeneous signature highly predictive of AD dementia. That signature could also be found in patients with mild symptoms, 90% of whom progressed to dementia within three years. The thesis thus makes new contributions to dealing with heterogeneity in medical diagnostic applications and proposes ways to leverage that heterogeneity to our benefit

A Novel Synergistic Model Fusing Electroencephalography and Functional Magnetic Resonance Imaging for Modeling Brain Activities

Study of the human brain is an important and very active area of research. Unraveling the way the human brain works would allow us to better understand, predict and prevent brain related diseases that affect a significant part of the population. Studying the brain response to certain input stimuli can help us determine the involved brain areas and understand the mechanisms that characterize behavioral and psychological traits. In this research work two methods used for the monitoring of brain activities, Electroencephalography (EEG) and functional Magnetic Resonance (fMRI) have been studied for their fusion, in an attempt to bridge together the advantages of each one. In particular, this work has focused in the analysis of a specific type of EEG and fMRI recordings that are related to certain events and capture the brain response under specific experimental conditions. Using spatial features of the EEG we can describe the temporal evolution of the electrical field recorded in the scalp of the head. This work introduces the use of Hidden Markov Models (HMM) for modeling the EEG dynamics. This novel approach is applied for the discrimination of normal and progressive Mild Cognitive Impairment patients with significant results. EEG alone is not able to provide the spatial localization needed to uncover and understand the neural mechanisms and processes of the human brain. Functional Magnetic Resonance imaging (fMRI) provides the means of localizing functional activity, without though, providing the timing details of these activations. Although, at first glance it is apparent that the strengths of these two modalities, EEG and fMRI, complement each other, the fusion of information provided from each one is a challenging task. A novel methodology for fusing EEG spatiotemporal features and fMRI features, based on Canonical Partial Least Squares (CPLS) is presented in this work. A HMM modeling approach is used in order to derive a novel feature-based representation of the EEG signal that characterizes the topographic information of the EEG. We use the HMM model in order to project the EEG data in the Fisher score space and use the Fisher score to describe the dynamics of the EEG topography sequence. The correspondence between this new feature and the fMRI is studied using CPLS. This methodology is applied for extracting features for the classification of a visual task. The results indicate that the proposed methodology is able to capture task related activations that can be used for the classification of mental tasks. Extensions on the proposed models are examined along with future research directions and applications

Functional Organization of the Brain at Rest and During Complex Tasks Using fMRI

How and why functional connectivity (FC), which captures the correlations among brain regions and/or networks, differs in various brain states has been incompletely understood. I review high-level background on this problem and how it relates to 1) the contributions of task-evoked activity, 2) white-matter fMRI, and 3) disease states in Chapter 1. In Chapter 2, based on the notion that brain activity during a task reflects an unknown mixture of spontaneous activity and task-evoked responses, we uncovered that the difference in FC between a task state (a naturalistic movie) and resting state only marginally (3-15%) reflects task-evoked connectivity. Instead, these changes may reflect changes in spontaneously emerging networks. In Chapter 3, we were able to show subtle task-related differences in the white matter using fMRI, which has only rarely been used to study functions in this tissue type. In doing so, we also demonstrated that white matter independent components were also hierarchically organized into axonal fiber bundles, challenging the conventional practice of taking white-matter signals as noise or artifacts. Finally, in Chapter 4, we examined the utility of combining FC with task-activation studies in uncovering changes in brain activity during preclinical Alzheimer\u27s Disease (mild cognitive impairment (MCI) and subjective cognitive decline (SCD) populations), based on data collected at the Indiana University School of Medicine. We found a reduction in neural task-based activations and resting-state FC that appeared to be directly related to diagnostic severity. Taken together, the work presented in this dissertation paves the way for a novel framework for understanding neural dynamics in health and disease

Causal Discovery from Temporal Data: An Overview and New Perspectives

Temporal data, representing chronological observations of complex systems, has always been a typical data structure that can be widely generated by many domains, such as industry, medicine and finance. Analyzing this type of data is extremely valuable for various applications. Thus, different temporal data analysis tasks, eg, classification, clustering and prediction, have been proposed in the past decades. Among them, causal discovery, learning the causal relations from temporal data, is considered an interesting yet critical task and has attracted much research attention. Existing casual discovery works can be divided into two highly correlated categories according to whether the temporal data is calibrated, ie, multivariate time series casual discovery, and event sequence casual discovery. However, most previous surveys are only focused on the time series casual discovery and ignore the second category. In this paper, we specify the correlation between the two categories and provide a systematical overview of existing solutions. Furthermore, we provide public datasets, evaluation metrics and new perspectives for temporal data casual discovery.Comment: 52 pages, 6 figure