Generalized Semiparametrically Structured Ordinal Models

The Annals of Applied Statistics, 2013

Diffusion tensor imaging provides important information on tissue structure and orientation of fiber tracts in brain white matter in vivo. It results in diffusion tensors, which are 3×3 symmetric positive definite (SPD) matrices, along fiber bundles. This paper develops a functional data analysis framework to model diffusion tensors along fiber tracts as functional data in a Riemannian manifold with a set of covariates of interest, such as age and gender. We propose a statistical model with varying coefficient functions to characterize the dynamic association between functional SPD matrix-valued responses and covariates. We calculate weighted least squares estimators of the varying coefficient functions for the Log-Euclidean metric in the space of SPD matrices. We also develop a global test statistic to test specific hypotheses about these coefficient functions and construct their simultaneous confidence bands. Simulated data are further used to examine the finite sample performance of the estimated varying coefficient functions. We apply our model to study potential gender differences and find a statistically significant aspect of the development of diffusion tensors along the right internal capsule tract in a clinical study of neurodevelopment.

2013 IEEE 10th International Symposium on Biomedical Imaging, 2013

The human brain undergoes rapid organization and structuring early in life. Longitudinal imaging enables the study of these changes over a developmental period within individuals through estimation of population growth trajectory and its variability. In this paper, we focus on maturation of white and gray matter as is depicted in structural and diffusion MRI of healthy subjects with repeated scans. We provide a framework for joint analysis of both structural MRI and DTI (Diffusion Tensor Imaging) using multivariate nonlinear mixed effect modeling of temporal changes. Our framework constructs normative growth models for all the modalities that take into account the correlation among the modalities and individuals, along with estimation of the variability of the population trends. We apply our method to study early brain development, and to our knowledge this is the first multimodel longitudinal modeling of diffusion and signal intensity changes for this growth stage. Results show the potential of our framework to study growth trajectories, as well as neurodevelopmental disorders through comparison against the constructed normative models of multimodal 4D MRI.

Lecture Notes in Computer Science, 2010

Diffusion tensor imaging (DTI) is important for characterizing the structure of white matter fiber bundles as well as detailed tissue properties along these fiber bundles in vivo. There has been extensive interest in the analysis of diffusion properties measured along fiber tracts as a function of age, diagnostic status, and gender, while controlling for other clinical variables. However, the existing methods have several limitations including the independent analysis of diffusion properties, a lack of method for accounting for multiple covariates, and a lack of formal statistical inference, such as estimation theory and hypothesis testing. This paper presents a statistical framework, called VCMTS, to specifically address these limitations. The VCMTS framework consists of four integrated components: a varying coefficient model for characterizing the association between fiber bundle diffusion properties and a set of covariates, the local polynomial kernel method for estimating smoothed multiple diffusion properties along individual fiber bundles, global and local test statistics for testing hypotheses of interest along fiber tracts, and a resampling method for approximating the p−value of the global test statistic. The proposed methodology is applied to characterizing the development of four diffusion properties along the splenium and genu of the corpus callosum tract in a study of neurodevelopment in healthy rhesus monkeys. Significant time effects on the four diffusion properties were found.

Biometrics, 2008

In this article we develop a nonparametric estimation procedure for the varying coefficient model when the within-subject covariance is unknown. Extending the idea of iterative reweighted least squares to the functional setting, we iterate between estimating the coefficients conditional on the covariance and estimating the functional covariance conditional on the coefficients. Smoothing splines for correlated errors are used to estimate the functional coefficients with smoothing parameters selected via the generalized maximum likelihood. The covariance is nonparametrically estimated using a penalized estimator with smoothing parameters chosen via a Kullback-Leibler criterion. Empirical properties of the proposed method are demonstrated in simulations and the method is applied to the data collected from an ovarian tumor study in mice to analyze the effects of different chemotherapy treatments on the volumes of two classes of tumors.

Neural Computation, 2005

In neuroimaging studies of human cognitive abilities, brain activation patterns that include regions that are strongly interactive in response to experimental task demands are of particular interest. Among the existing network analyses, partial least squares (PLS; McIntosh, 1999; McIntosh, Bookstein, Haxby, & Grady, 1996) has been highly successful, particularly in identifying group differences in regional functional connectivity, including differences as diverse as those associated with states of awareness and normal aging. However, we address the need for a within-group model that identifies patterns of regional functional connectivity that exhibit sustained activity across graduated changes in task parameters. For example, predictions of sustained connectivity are commonplace in studies of cognition that involve a series of tasks over which task difficulty increases (Baddeley, 2003). We designed ordinal trend analysis (OrT) to identify activation patterns that increase monotonically in their expression as the experimental task parameter increases, while the correlative relationships between brain regions remain constant. Of specific interest are patterns that express positive ordinal trends on a subject-by-subject basis. A unique feature of OrT is that it recovers information about functional connectivity based solely on experimental design variables. In particular, there is no requirement by OrT to provide either a quantitative model of the uncertain relationship between functional brain circuitry and subject variables (e.g., task performance and IQ) or partial information about the regions that are functionally connected. In this letter, we provide a step-by-step recipe of the computations performed in the new OrT analysis, including a description of the inferential statistical methods applied. Second, we describe applications of OrT to an event-related fMRI study of verbal working memory and H 2 15 O-PET study of visuomotor learning. In sum, OrT has potential applications to not only studies of young adults and their cognitive abilities, but also studies of normal aging and neurological and psychiatric disease.

2011

Abstract. This paper develops a functional data analysis framework to model diffusion tensors along fiber bundles as functional responses with a set of covariates of interest, such as age, diagnostic status and gender. This framework has a wide range of clinical applications including the characterization of normal brain development, the neural bases of neuropsychiatric disorders, and the joint effects of environmental and genetic factors on white matter fiber bundles.

This paper studies estimation of a smooth function f (x, v) when we are given functional responses of the form f (x, ·) + error, but scientific interest centers on the collection of functions f (·, v) for different v. The motivation comes from studies of human brain development, in which x denotes age whereas v refers to brain locations. Analogously to varying-coefficient models, in which the mean response is linear in x, the "varying-smoother" models that we consider exhibit nonlinear dependence on x that varies smoothly with v. We discuss three approaches to estimating varying-smoother models: (a) methods that employ a tensor product penalty; (b) an approach based on smoothed functional principal component scores; and (c) two-step methods consisting of an initial smooth with respect to x at each v, followed by a postprocessing step. For the first approach, we derive an exact expression for a penalty proposed by Wood, and an adaptive penalty that allows smoothness to vary more flexibly with v. We also develop "pointwise degrees of freedom," a new tool for studying the complexity of estimates of f (·, v) at each v. The three approaches to varying-smoother models are compared in simulations and with a diffusion tensor imaging data set.

2012

For multivariate data, dependence beyond pair-wise can be important. This is true, for example, in using functional MRI (fMRI) data to investigate brain functional connectivity. When one has more than a few variables, however, the number of simple summaries of even third-order dependence can be unmanageably large. "Concurrence topology" is an apparently new nonparametric method for describing high-order dependence among up to dozens of dichotomous variables (e.g., seventh-order dependence in 32 variables). This method generally produces summaries of p th-order dependence of manageable size no matter how big p is. (But computing time can be lengthy.) For time series, this method can be applied in both the time and Fourier domains. Write each observation as a vector of 0's and 1's. A "concurrence" is a group of variables all "1" in the same observation. The collection of concurrences can be represented as a sequence of shapes ("filtration"). Holes in the filtration indicate weak or negative association among the variables. The pattern of the holes in the filtration can be analyzed using computational topology. This method is demonstrated on dichotomized fMRI data. The dataset includes subjects diagnosed with ADHD and healthy controls. In an exploratory analysis numerous group differences in the topology of the filtrations are found.

NeuroImage, 2012

We propose a semiparametric Bayesian local functional model (BFM) for the analysis of multiple diffusion properties (e.g., fractional anisotropy) along white matter fiber bundles with a set of covariates of interest, such as age and gender. BFM accounts for heterogeneity in the shape of the fiber bundle diffusion properties among subjects, while allowing the impact of the covariates to vary across subjects. A nonparametric Bayesian LPP2 prior facilitates global and local borrowings of information among subjects, while an infinite factor model flexibly represents low-dimensional structure. Local hypothesis testing and credible bands are developed to identify fiber segments, along which multiple diffusion properties are significantly associated with covariates of interest, while controlling for multiple comparisons. Moreover, BFM naturally group subjects into more homogeneous clusters. Posterior computation proceeds via an efficient Markov chain Monte Carlo algorithm. A simulation study is performed to evaluate the finite sample performance of BFM. We apply BFM to investigate the development of white matter diffusivities along the splenium of the corpus callosum tract and the right internal capsule tract in a clinical study of neurodevelopment in new born infants.

Lecture Notes in Computer Science, 2013

Many longitudinal imaging studies have been/are being widely conducted to use diffusion tensor imaging (DTI) to better understand white matter maturation in normal controls and diseased subjects. There is an urgent demand for the development of statistical methods for analyzing diffusion properties along major fiber tracts obtained from longitudinal DTI studies. Jointly analyzing fiber-tract diffusion properties and covariates from longitudinal studies raises several major challenges including (i) infinite-dimensional functional response data, (ii) complex spatialtemporal correlation structure, and (iii) complex spatial smoothness. To address these challenges, this article is to develop a longitudinal functional analysis framework (LFAF) to delineate the dynamic changes of diffusion properties along major fiber tracts and their association with a set of covariates of interest (e.g., age and group status) and the structure of the variability of these white matter tract properties in various longitudinal studies. Our LFAF consists of a functional mixed effects model for addressing all three challenges, an efficient method for spatially smoothing varying coefficient functions, an estimation method for estimating the spatial-temporal correlation structure, a test procedure with a global test statistic for testing hypotheses of interest associated with functional response, and a simultaneous confidence band for quantifying the uncertainty in the estimated coefficient functions. Simulated data are used to evaluate the finite sample performance of LFAF and to demonstrate that LFAF significantly outperforms a voxel-wise mixed model method. We apply LFAF to study the spatial-temporal dynamics of white-matter fiber tracts in a clinical study of neurodevelopment.

2013

Many longitudinal imaging studies have collected repeated diffusion tensor magnetic resonance imaging data to understand white matter maturation and structural connectivity pattern in normal controls and diseased subjects. There is an urgent demand for the development of statistical methods for the analysis of diffusion properties along fiber tracts and clinical data obtained from longitudinal studies. Jointly analyzing repeated fiber-tract diffusion properties and covariates (e.g., age or gender) raises several major challenges including (i) infinite-dimensional functional response data, (ii) complex spatial-temporal correlation structure, and (iii) complex spatial smoothness. To address these challenges, this article is to develop a functional mixed effects modeling (FMEM) framework to delineate the dynamic changes of diffusion properties along major fiber tracts and their association with a set of covariates of interest and the structure of the variability of these white matter tract properties in various longitudinal studies. Our FMEM consists of a functional mixed effects model for addressing all three challenges, an efficient method for spatially smoothing varying coefficient functions, an estimation method for estimating the spatial-temporal correlation structure, a test procedure with local and global test statistics for testing hypotheses of interest associated with functional response, and a simultaneous confidence band for quantifying the uncertainty in the estimated coefficient functions. Simulated data are used to evaluate the finite sample performance of FMEM and to demonstrate that FMEM significantly

2008

Normative modeling aims to quantify the degree to which an individual's brain deviates from a reference sample with respect to one or more variables, which can be used as a potential biomarker of a healthy brain and as a tool to study heterogeneity of psychiatric disorders. The application of normative models is hindered by methodological challenges and lacks standards for the usage and evaluation of normative models. In this paper, we present generalized additive models for location scale and shape (GAMLSS) for normative modeling of neuroimaging data, a flexible modeling framework that can model heteroskedasticity, non-linear effects of variables, and hierarchical structure of the data. It can model non-Gaussian distributions, and it allows for an automatic model order selection, thus improving the accuracy of normative models while mitigating problems of overfitting. Furthermore, we describe measures and diagnostic tools suitable for evaluating normative models and step-by-ste...

The Annals of Statistics, 2015

In the low-dimensional case, the generalized additive coefficient model (GACM) proposed by Xue and Yang [Statist. Sinica 16 (2006) 1423-1446] has been demonstrated to be a powerful tool for studying nonlinear interaction effects of variables. In this paper, we propose estimation and inference procedures for the GACM when the dimension of the variables is high. Specifically, we propose a groupwise penalization based procedure to distinguish significant covariates for the "large p small n" setting. The procedure is shown to be consistent for model structure identification. Further, we construct simultaneous confidence bands for the coefficient functions in the selected model based on a refined two-step spline estimator. We also discuss how to choose the tuning parameters. To estimate the standard deviation of the functional estimator, we adopt the smoothed bootstrap method. We conduct simulation experiments to evaluate the numerical performance of the proposed methods and analyze an obesity data set from a genome-wide association study as an illustration.

Journal of the Royal Statistical Society: Series C (Applied Statistics), 2019

Neurobiological data such as EEG measurements pose a statistical challenge due to low spatial resolution and poor signal-to-noise ratio, as well as large variability from subject to subject. We propose a new modeling framework for this type of data based on stochastic processes. Stochastic differential equations with mixed effects are a popular framework for modeling biomedical data, e.g., in pharmacological studies. While the inherent stochasticity of diffusion models accounts for prevalent model uncertainty or misspecification, random effects take care of the inter-subject variability. The 2-layer stochasticity, however, renders parameter inference challenging. This is especially true for more complex model dynamics, and only few theoretical investigations on the asymptotic behavior of estimates exist. This article adds to filling this gap by examining asymptotics (number of subjects going to infinity) of Maximum Likelihood estimators in multidimensional, nonlinear and non-homogeneous stochastic differential equations with random effects and included covariates. Estimates are based on the discretized continuous-time likelihood and we investigate finite-sample and discretization bias. In applications, the comparison of, e.g., different experimental conditions such as placebo vs. treatment, is often of interest. We suggest a hypothesis testing approach and evaluate the test's performance by simulations. Finally, we apply the framework to a statistical investigation of EEG recordings from epileptic patients.