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Massive Open Online Courses (MOOCs) have transformed the educational landscape, offering scalable and flexible learning opportunities, particularly in data-centric fields like data science and artificial intelligence. Incorporating AI and data science into MOOCs is a potential means of enhancing the learning experience through adaptive learning approaches. In this context, we introduce PyGlide, a proof-of-concept open-source MOOC delivery system that underscores autonomy, transparency, and collaboration in maintaining course content. We provide a user-friendly, step-by-step guide for PyGlide, emphasizing its distinct advantage of not requiring any local software installation for students. Highlighting its potential to enhance accessibility, inclusivity, and the manageability of course materials, we showcase PyGlide's practical application in a continuous integration pipeline on GitHub. We believe that PyGlide charts a promising course for the future of open-source MOOCs, effectively addressing crucial challenges in online education.

In this study, a density-on-density regression model is introduced, where the association between densities is elucidated via a warping function. The proposed model has the advantage of a being straightforward demonstration of how one density transforms into another. Using the Riemannian representation of density functions, which is the square-root function (or half density), the model is defined in the correspondingly constructed Riemannian manifold. To estimate the warping function, it is proposed to minimize the average Hellinger distance, which is equivalent to minimizing the average Fisher-Rao distance between densities. An optimization algorithm is introduced by estimating the smooth monotone transformation of the warping function. Asymptotic properties of the proposed estimator are discussed. Simulation studies demonstrate the superior performance of the proposed approach over competing approaches in predicting outcome density functions. Applying to a proteomic-imaging study from the Alzheimer's Disease Neuroimaging Initiative, the proposed approach illustrates the connection between the distribution of protein abundance in the cerebrospinal fluid and the distribution of brain regional volume. Discrepancies among cognitive normal subjects, patients with mild cognitive impairment, and Alzheimer's disease (AD) are identified and the findings are in line with existing knowledge about AD.

In this study, a longitudinal regression model for covariance matrix outcomes is introduced. The proposal considers a multilevel generalized linear model for regressing covariance matrices on (time-varying) predictors. This model simultaneously identifies covariate associated components from covariance matrices, estimates regression coefficients, and estimates the within-subject variation in the covariance matrices. Optimal estimators are proposed for both low-dimensional and high-dimensional cases by maximizing the (approximated) hierarchical likelihood function and are proved to be asymptotically consistent, where the proposed estimator is the most efficient under the low-dimensional case and achieves the uniformly minimum quadratic loss among all linear combinations of the identity matrix and the sample covariance matrix under the high-dimensional case. Through extensive simulation studies, the proposed approach achieves good performance in identifying the covariate related components and estimating the model parameters. Applying to a longitudinal resting-state fMRI dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the proposed approach identifies brain networks that demonstrate the difference between males and females at different disease stages. The findings are in line with existing knowledge of AD and the method improves the statistical power over the analysis of cross-sectional data.

A compositional tree refers to a tree structure on a set of random variables where each random variable is a node and composition occurs at each non-leaf node of the tree. As a generalization of compositional data, compositional trees handle more complex relationships among random variables and appear in many disciplines, such as brain imaging, genomics and finance. We consider the problem of sparse regression on data that are associated with a compositional tree and propose a transformation-free tree-based regularized regression method for component selection. The regularization penalty is designed based on the tree structure and encourages a sparse tree representation. We prove that our proposed estimator for regression coefficients is both consistent and model selection consistent. In the simulation study, our method shows higher accuracy than competing methods under different scenarios. By analyzing a brain imaging data set from studies of Alzheimer's disease, our method identifies meaningful associations between memory declination and volume of brain regions that are consistent with current understanding.

Brain segmentation at different levels is generally represented as hierarchical trees. Brain regional atrophy at specific levels was found to be marginally associated with Alzheimer's disease outcomes. In this study, we propose an L1-type regularization for predictors that follow a hierarchical tree structure. Considering a tree as a directed acyclic graph, we interpret the model parameters from a path analysis perspective. Under this concept, the proposed penalty regulates the total effect of each predictor on the outcome. With regularity conditions, it is shown that under the proposed regularization, the estimator of the model coefficient is consistent in L2-norm and the model selection is also consistent. By applying to a brain structural magnetic resonance imaging dataset acquired from the Alzheimer's Disease Neuroimaging Initiative, the proposed approach identifies brain regions where atrophy in these regions demonstrates the declination in memory. With regularization on the total effects, the findings suggest that the impact of atrophy on memory deficits is localized from small brain regions but at various levels of brain segmentation.

This manuscript presents an approach to perform generalized linear regression with multiple high dimensional covariance matrices as the outcome. Model parameters are proposed to be estimated by maximizing a pseudo-likelihood. When the data are high dimensional, the normal likelihood function is ill-posed as the sample covariance matrix is rank-deficient. Thus, a well-conditioned linear shrinkage estimator of the covariance matrix is introduced. With multiple covariance matrices, the shrinkage coefficients are proposed to be common across matrices. Theoretical studies demonstrate that the proposed covariance matrix estimator is optimal achieving the uniformly minimum quadratic loss asymptotically among all linear combinations of the identity matrix and the sample covariance matrix. Under regularity conditions, the proposed estimator of the model parameters is consistent. The superior performance of the proposed approach over existing methods is illustrated through simulation studies. Implemented to a resting-state functional magnetic resonance imaging study acquired from the Alzheimer's Disease Neuroimaging Initiative, the proposed approach identified a brain network within which functional connectivity is significantly associated with Apolipoprotein E $\varepsilon$4, a strong genetic marker for Alzheimer's disease., Comment: 21 pages of main text and references, 3 figures

Independent component analysis is commonly applied to functional magnetic resonance imaging (fMRI) data to extract independent components (ICs) representing functional brain networks. While ICA produces reliable group-level estimates, single-subject ICA often produces noisy results. Template ICA (tICA) is a hierarchical ICA model using empirical population priors to produce reliable subject-level IC estimates. However, this and other hierarchical ICA models assume unrealistically that subject effects are spatially independent. Here, we propose spatial template ICA (stICA), which incorporates spatial process priors into tICA. This results in greater estimation efficiency of ICs and subject effects. Additionally, the joint posterior distribution can be used to identify engaged areas using an excursions set approach. By leveraging spatial dependencies and avoiding massive multiple comparisons, stICA has high power to detect true effects. We derive an efficient expectation-maximization algorithm to obtain maximum likelihood estimates of the model parameters and posterior moments of the latent fields. Based on analysis of simulated data and fMRI data from the Human Connectome Project, we find that stICA produces estimates that are more accurate and reliable than benchmark approaches, and identifies larger and more reliable areas of engagement. The algorithm is quite tractable, achieving convergence within 7 hours in our fMRI analysis., Comment: 32 pages, 16 figures

In this study, we propose a two-stage procedure for hypothesis testing, where the first stage is conventional hypothesis testing and the second is an equivalence testing procedure using an introduced Empirical Equivalence Bound. In 2016, the American Statistical Association released a policy statement on P-values to clarify the proper use and interpretation in response to the criticism of reproducibility and replicability in scientific findings. A recent solution to improve reproducibility and transparency in statistical hypothesis testing is to integrate P-values (or confidence intervals) with practical or scientific significance. Similar ideas have been proposed via the equivalence test, where the goal is to infer equality under a presumption (null) of inequality of parameters. However, in these testing procedures, the definition of scientific significance/equivalence can be subjective. To circumvent this drawback, we introduce a B-value and the Empirical Equivalence Bound, which are both estimated from the data. Performing a second-stage equivalence test, our procedure offers an opportunity to correct for false positive discoveries and improve the reproducibility in findings across studies.

With fast advancements in technologies, the collection of multiple types of measurements on a common set of subjects is becoming routine in science. Some notable examples include multimodal neuroimaging studies for the simultaneous investigation of brain structure and function, and multi-omics studies for combining genetic and genomic information. Integrative analysis of multimodal data allows scientists to interrogate new mechanistic questions. However, the data collection and generation of integrative hypotheses is outpacing available methodology for joint analysis of multimodal measurements. In this article, we study high-dimensional multimodal data integration in the context of mediation analysis. We aim to understand the roles different data modalities play as possible mediators in the pathway between an exposure variable and an outcome. We propose a mediation model framework with two data types serving as separate sets of mediators, and develop a penalized optimization approach for parameter estimation. We study both the theoretical properties of the estimator through an asymptotic analysis, and its finite-sample performance through simulations. We illustrate our method with a multimodal brain pathway analysis having both structural and functional connectivities as mediators in the association between sex and language processing.

Large brain imaging databases contain a wealth of information on brain organization in the populations they target, and on individual variability. While such databases have been used to study group-level features of populations directly, they are currently underutilized as a resource to inform single-subject analysis. Here, we propose leveraging the information contained in large functional magnetic resonance imaging (fMRI) databases by establishing population priors to employ in an empirical Bayesian framework. We focus on estimation of brain networks as source signals in independent component analysis (ICA). We formulate a hierarchical "template" ICA model where source signals---including known population brain networks and subject-specific signals---are represented as latent variables. For estimation, we derive an expectation maximization (EM) algorithm having an explicit solution. However, as this solution is computationally intractable, we also consider an approximate subspace algorithm and a faster two-stage approach. Through extensive simulation studies, we assess performance of both methods and compare with dual regression, a popular but ad-hoc method. The two proposed algorithms have similar performance, and both dramatically outperform dual regression. We also conduct a reliability study utilizing the Human Connectome Project and find that template ICA achieves substantially better performance than dual regression, achieving 75-250% higher intra-subject reliability.

Causal mediation analysis aims to quantify the intermediate effect of a mediator on the causal pathway from treatment to outcome. With multiple mediators, which are potentially causally dependent, the possible decomposition of pathway effects grows exponentially with the number of mediators. Huang and Pan (2016) introduced a principal component analysis (PCA) based approach to address this challenge, in which the transformed mediators are conditionally independent given the orthogonality of the PCs. However, the transformed mediator PCs, which are linear combinations of original mediators, are difficult to interpret. In this study, we propose a sparse high-dimensional mediation analysis approach by adopting the sparse PCA method introduced by Zou and others (2006) to the mediation setting. We apply the approach to a task-based functional magnetic resonance imaging study, and show that our proposed method is able to detect biologically meaningful results related to the identified mediator., Comment: 24 pages, 3 figures, 1 table

Mediation analysis has become an important tool in the behavioral sciences for investigating the role of intermediate variables that lie in the path between a randomized treatment and an outcome variable. The influence of the intermediate variable on the outcome is often explored using structural equation models (SEMs), with model coefficients interpreted as possible effects. While there has been significant research on the topic in recent years, little work has been done on mediation analysis when the intermediate variable (mediator) is a high-dimensional vector. In this work we present a new method for exploratory mediation analysis in this setting called the directions of mediation (DMs). The first DM is defined as the linear combination of the elements of a high-dimensional vector of potential mediators that maximizes the likelihood of the SEM. The subsequent DMs are defined as linear combinations of the elements of the high-dimensional vector that are orthonormal to the previous DMs and maximize the likelihood of the SEM. We provide an estimation algorithm and establish the asymptotic properties of the obtained estimators. This method is well suited for cases when many potential mediators are measured. Examples of high-dimensional potential mediators are brain images composed of hundreds of thousands of voxels, genetic variation measured at millions of SNPs, or vectors of thousands of variables in large-scale epidemiological studies. We demonstrate the method using a functional magnetic resonance imaging (fMRI) study of thermal pain where we are interested in determining which brain locations mediate the relationship between the application of a thermal stimulus and self-reported pain.

High-dimensional time-series data are becoming increasingly abundant across a wide variety of domains, spanning economics, neuroscience, particle physics, and cosmology. Fitting statistical models to such data, to enable parameter estimation and time-series prediction, is an important computational primitive. Existing methods, however, are unable to cope with the high-dimensional nature of these problems, due to both computational and statistical reasons. We mitigate both kinds of issues via proposing an M-estimator for Reduced-rank System IDentification (MR. SID). A combination of low-rank approximations, L-1 and L-2 penalties, and some numerical linear algebra tricks, yields an estimator that is computationally efficient and numerically stable. Simulations and real data examples demonstrate the utility of this approach in a variety of problems. In particular, we demonstrate that MR. SID can estimate spatial filters, connectivity graphs, and time-courses from native resolution functional magnetic resonance imaging data. Other applications and extensions are immediately available, as our approach is a generalization of the classical Kalman Filter-Smoother Expectation-Maximization algorithm.

We develop a flexible framework for modeling high-dimensional imaging data observed longitudinally. The approach decomposes the observed variability of repeatedly measured high-dimensional observations into three additive components: a subject-specific imaging random intercept that quantifies the cross-sectional variability, a subject-specific imaging slope that quantifies the dynamic irreversible deformation over multiple realizations, and a subject-visit-specific imaging deviation that quantifies exchangeable effects between visits. The proposed method is very fast, scalable to studies including ultrahigh-dimensional data, and can easily be adapted to and executed on modest computing infrastructures. The method is applied to the longitudinal analysis of diffusion tensor imaging (DTI) data of the corpus callosum of multiple sclerosis (MS) subjects. The study includes $176$ subjects observed at $466$ visits. For each subject and visit the study contains a registered DTI scan of the corpus callosum at roughly 30,000 voxels., Comment: Published in at http://dx.doi.org/10.1214/14-AOAS748 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org)

Data reproducibility is a critical issue in all scientific experiments. In this manuscript, we consider the problem of quantifying the reproducibility of graphical measurements. We generalize the concept of image intra-class correlation coefficient (I2C2) and propose the concept of the graphical intra-class correlation coefficient (GICC) for such purpose. The concept of GICC is based on multivariate probit-linear mixed effect models. We will present a Markov Chain EM (MCEM) algorithm for estimating the GICC. Simulations results with varied settings are demonstrated and our method is applied to the KIRBY21 test-retest dataset., Comment: 14 pages, 3 figures, 1 table

The Sleep Heart Health Study (SHHS) is a comprehensive landmark study of sleep and its impacts on health outcomes. A primary metric of the SHHS is the in-home polysomnogram, which includes two electroencephalographic (EEG) channels for each subject, at two visits. The volume and importance of this data presents enormous challenges for analysis. To address these challenges, we introduce multilevel functional principal component analysis (MFPCA), a novel statistical methodology designed to extract core intra- and inter-subject geometric components of multilevel functional data. Though motivated by the SHHS, the proposed methodology is generally applicable, with potential relevance to many modern scientific studies of hierarchical or longitudinal functional outcomes. Notably, using MFPCA, we identify and quantify associations between EEG activity during sleep and adverse cardiovascular outcomes., Comment: Published in at http://dx.doi.org/10.1214/08-AOAS206 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org)