SummaryObesity is a heterogeneous phenotype that is crudely measured by body mass index (BMI). There is a need for a more precise yet portable method of phenotyping and categorizing risk in large numbers of people with obesity to advance clinical care and drug development. Here, we used non-targeted metabolomics and whole-genome sequencing to identify metabolic and genetic signatures of obesity. We find that obesity results in profound perturbation of the metabolome; nearly a third of the assayed metabolites associated with changes in BMI. A metabolome signature identifies the healthy obese and lean individuals with abnormal metabolomes—these groups differ in health outcomes and underlying genetic risk. Specifically, an abnormal metabolome associated with a 2- to 5-fold increase in cardiovascular events when comparing individuals who were matched for BMI but had opposing metabolome signatures. Because metabolome profiling identifies clinically meaningful heterogeneity in obesity, this approach could help select patients for clinical trials.

Recently, a new robust adaptive beamforming (RAB) technique was proposed to remove the signal of interest (SOI) component from the sample covariance matrix based on interference-plus-noise covariance matrix reconstruction, which utilizes the Capon spectrum estimator integrated over a region separated from the direction of the SOI. However, the extreme condition of the reconstruction-based technique, that the precise information about the array structure is known in advance, is almost impossible in practice. In this paper, a novel method to reconstruct the interference-plus-noise covariance matrix is proposed. Considering the imprecise prior information about the array structure, which means that the array may be uncalibrated, we use an annulus uncertainty set to constrain the steering vectors of the interferences. Then we integrate the Capon spectrum over the surface of the annulus, by which we can obtain the reconstructed interference matrix without containing the SOI. Since the integral interval is a high-dimensional domain, which is very difficult to solve, we use a discrete sum method to calculate the integral approximately. With the reconstructed interference-plus-noise matrix, the nominal steering vector can be corrected via maximizing the beamformer output power by solving a quadratically constrained quadratic programming (QCQP) problem. The previous reconstruction method can be seen as a special case of the proposed one. The main advantage is that the proposed algorithm is robust against unknown arbitrary-type mismatches. Theoretical analysis and simulation results demonstrate the effectiveness and

Regression models for functional responses and scalar predictors are often fitted by means of basis functions, with quadratic roughness penalties applied to avoid overfitting. The fitting approach described by Ramsay and Silverman in the 1990s amounts to a penalized ordinary least squares (P-OLS) estimator of the coefficient functions. We recast this estimator as a generalized ridge regression estimator, and present a penalized generalized least squares (P-GLS) alternative. We describe algorithms by which both estimators can be implemented, with automatic selection of optimal smoothing parameters, in a more computationally efficient manner than has heretofore been available. We discuss pointwise confidence intervals for the coefficient functions, simultaneous inference by permutation tests, and model selection, including a novel notion of pointwise model selection. P-OLS and P-GLS are compared in a simulation study. Our methods are illustrated with an analysis of age effects in a functional magnetic resonance imaging data set, as well as a reanalysis of a now-classic Canadian weather data set. An R package implementing the methods is publicly available.

Objective measurement of physical activity using wearable devices such as accelerometers may provide tantalizing new insights into the association between activity and health outcomes. Accelerometers can record quasi-continuous activity information for many days and for hundreds of individuals. For example, in the Baltimore Longitudinal Study on Aging physical activity was recorded every minute for [Formula: see text] adults for an average of [Formula: see text] days per adult. An important scientific problem is to separate and quantify the systematic and random circadian patterns of physical activity as functions of time of day, age, and gender. To capture the systematic circadian pattern, we introduce a practical bivariate smoother and two crucial innovations: (i) estimating the smoothing parameter using leave-one-subject-out cross validation to account for within-subject correlation and (ii) introducing fast computational techniques that overcome problems both with the size of the data and with the cross-validation approach to smoothing. The age-dependent random patterns are analyzed by a new functional principal component analysis that incorporates both covariate dependence and multilevel structure. For the analysis, we propose a practical and very fast trivariate spline smoother to estimate covariate-dependent covariances and their spectra. Results reveal several interesting, previously unknown, circadian patterns associated with human aging and gender.

We develop scalar-on-image regression models when images are registered multidimensional manifolds. We propose a fast and scalable Bayes inferential procedure to estimate the image coefficient. The central idea is the combination of an Ising prior distribution, which controls a latent binary indicator map, and an intrinsic Gaussian Markov random field, which controls the smoothness of the nonzero coefficients. The model is fit using a single-site Gibbs sampler, which allows fitting within minutes for hundreds of subjects with predictor images containing thousands of locations. The code is simple and is provided in less than one page in the Appendix. We apply this method to a neuroimaging study where cognitive outcomes are regressed on measures of white matter microstructure at every voxel of the corpus callosum for hundreds of subjects.