Genome-wide association analysis of secondary imaging phenotypes from the Alzheimer's disease neuroimaging initiative study

The aim of this paper is to systematically evaluate a biased sampling issue associated with genome-wide association analysis (GWAS) of imaging phenotypes for most imaging genetic studies, including the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Specifically, the original sampling scheme of these imaging genetic studies is primarily the retrospective case-control design, whereas most existing statistical analyses of these studies ignore such sampling scheme by directly correlating imaging phenotypes (called the secondary traits) with genotype. Although it has been well documented in genetic epidemiology that ignoring the case-control sampling scheme can produce highly biased estimates, and subsequently lead to misleading results and suspicious associations, such findings are not well documented in imaging genetics. We use extensive simulations and a large-scale imaging genetic data analysis of the Alzheimer’s Disease Neuroimag-ing Initiative (ADNI) data to evaluate the effects of the case-control sampling scheme on GWAS results based on some standard statistical methods, such as linear regression methods, while comparing it with several advanced statistical methods that appropriately adjust for the case-control sampling scheme

Advanced Analysis Methods for Large-Scale Structured Data

In the era of ’big data’, advanced storage and computing technologies allow people to build and process large-scale datasets, which promote the development of many fields such as speech recognition, natural language processing and computer vision. Traditional approaches can not handle the heterogeneity and complexity of some novel data structures. In this dissertation, we want to explore how to combine different tools to develop new methodologies in analyzing certain kinds of structured data, motivated by real-world problems. Multi-group design, such as the Alzheimer’s Disease Neuroimaging Initiative (ADNI), has been undertaken by recruiting subjects based on their multi-class primary disease status, while some extensive secondary outcomes are also collected. Analysis by standard approaches is usually distorted because of the unequal sampling rates of different classes. In the first part of the dissertation, we develop a general regression framework for the analysis of secondary phenotypes collected in multi-group association studies. Our regression framework is built on a conditional model for the secondary outcome given the multi-group status and covariates and its relationship with the population regression of interest of the secondary outcome given the covariates. Then, we develop generalized estimation equations to estimate the parameters of interest. We use simulations and a large-scale imaging genetic data analysis of the ADNI data to evaluate the effect of the multi-group sampling scheme on standard genome-wide association analyses based on linear regression methods, while comparing it with our statistical methods that appropriately adjust for the multi-group sampling scheme. In the past few decades, network data has been increasingly collected and studied in diverse areas, including neuroimaging, social networks and knowledge graphs. In the second part of the dissertation, we investigate the graph-based semi-supervised learning problem with nonignorable nonresponses. We propose a Graph-based joint model with Nonignorable Missingness (GNM) and develop an imputation and inverse probability weighting estimation approach. We further use graph neural networks (GNN) to model nonlinear link functions and then use a gradient descent (GD) algorithm to estimate all the parameters of GNM. We propose a novel identifiability for the GNM model with neural network structures, and validate its predictive performance in both simulations and real data analysis through comparing with models ignoring or misspecifying the missingness mechanism. Our method can achieve up to 7.5% improvement than the baseline model for the document classification task on the Cora dataset. Predictions of Origin-Destination (OD) flow data is an important instrument in transportation studies. However, most existing methods ignore the network structure of OD flow data. In the last part of the dissertation, we propose a spatial-temporal origin-destination (STOD) model, with a novel CNN filter to learn the spatial features from the perspective of graphs and an attention mechanism to capture the long term periodicity. Experiments on a real customer request dataset with available OD information from a ride-sharing platform demonstrates the advantage of STOD in achieving a more accurate and stable prediction performance compared to some state-of-the-art methods.Doctor of Philosoph

Recent publications from the Alzheimer's Disease Neuroimaging Initiative: Reviewing progress toward improved AD clinical trials

INTRODUCTION: The Alzheimer's Disease Neuroimaging Initiative (ADNI) has continued development and standardization of methodologies for biomarkers and has provided an increased depth and breadth of data available to qualified researchers. This review summarizes the over 400 publications using ADNI data during 2014 and 2015. METHODS: We used standard searches to find publications using ADNI data. RESULTS: (1) Structural and functional changes, including subtle changes to hippocampal shape and texture, atrophy in areas outside of hippocampus, and disruption to functional networks, are detectable in presymptomatic subjects before hippocampal atrophy; (2) In subjects with abnormal β-amyloid deposition (Aβ+), biomarkers become abnormal in the order predicted by the amyloid cascade hypothesis; (3) Cognitive decline is more closely linked to tau than Aβ deposition; (4) Cerebrovascular risk factors may interact with Aβ to increase white-matter (WM) abnormalities which may accelerate Alzheimer's disease (AD) progression in conjunction with tau abnormalities; (5) Different patterns of atrophy are associated with impairment of memory and executive function and may underlie psychiatric symptoms; (6) Structural, functional, and metabolic network connectivities are disrupted as AD progresses. Models of prion-like spreading of Aβ pathology along WM tracts predict known patterns of cortical Aβ deposition and declines in glucose metabolism; (7) New AD risk and protective gene loci have been identified using biologically informed approaches; (8) Cognitively normal and mild cognitive impairment (MCI) subjects are heterogeneous and include groups typified not only by "classic" AD pathology but also by normal biomarkers, accelerated decline, and suspected non-Alzheimer's pathology; (9) Selection of subjects at risk of imminent decline on the basis of one or more pathologies improves the power of clinical trials; (10) Sensitivity of cognitive outcome measures to early changes in cognition has been improved and surrogate outcome measures using longitudinal structural magnetic resonance imaging may further reduce clinical trial cost and duration; (11) Advances in machine learning techniques such as neural networks have improved diagnostic and prognostic accuracy especially in challenges involving MCI subjects; and (12) Network connectivity measures and genetic variants show promise in multimodal classification and some classifiers using single modalities are rivaling multimodal classifiers. DISCUSSION: Taken together, these studies fundamentally deepen our understanding of AD progression and its underlying genetic basis, which in turn informs and improves clinical trial desig