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Matching on a low dimensional vector of scalar covariates consists of constructing groups of individuals in which each individual in a group is within a pre-specified distance from an individual in another group. However, matching in high dimensional spaces is more challenging because the distance can be sensitive to implementation details, caliper width, and measurement error of observations. To partially address these problems, we propose to use extensive sensitivity analyses and identify the main sources of variation and bias. We illustrate these concepts by examining the racial disparity in all-cause mortality in the US using the National Health and Nutrition Examination Survey (NHANES 2003-2006). In particular, we match African Americans to Caucasian Americans on age, gender, BMI and objectively measured physical activity (PA). PA is measured every minute using accelerometers for up to seven days and then transformed into an empirical distribution of all of the minute-level observations. The Wasserstein metric is used as the measure of distance between these participant-specific distributions.

Continuous glucose monitoring (CGM) is a minimally invasive technology that allows continuous monitoring of an individual's blood glucose. We focus on a large clinical trial that collected CGM data every few minutes for 26 weeks and assumes that the basic observation unit is the distribution of CGM observations in a four-week interval. The resulting data structure is multilevel (because each individual has multiple months of data) and distributional (because the data for each four-week interval is represented as a distribution). The scientific goals are to: (1) identify and quantify the effects of factors that affect glycemic control in type 1 diabetes (T1D) patients; and (2) identify and characterize the patients who respond to treatment. To address these goals, we propose a new multilevel functional model that treats the CGM distributions as a response. Methods are motivated by and applied to data collected by The Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Group. Reproducible code for the methods introduced here is available on GitHub.

Between 2011 and 2014 NHANES collected objectively measured physical activity data using wrist-worn accelerometers for tens of thousands of individuals for up to seven days. Here we analyze the minute-level indicators of being active, which can be viewed as binary (because there is an active indicator at every minute), multilevel (because there are multiple days of data for each study participant), functional (because within-day data can be viewed as a function of time) data. To extract within- and between-participant directions of variation in the data, we introduce Generalized Multilevel Functional Principal Component Analysis (GM-FPCA), an approach based on the dimension reduction of the linear predictor. Scores associated with specific patterns of activity are shown to be strongly associated with time to death. Extensive simulation studies indicate that GM-FPCA provides accurate estimation of model parameters, is computationally stable, and is scalable in the number of study participants, visits, and observations within visits. R code for implementing the method is provided.

We consider the problem of predicting an individual's identity from accelerometry data collected during walking. In a previous paper we introduced an approach that transforms the accelerometry time series into an image by constructing its complete empirical autocorrelation distribution. Predictors derived by partitioning this image into grid cells were used in logistic regression to predict individuals. Here we: (1) implement machine learning methods for prediction using the grid cell-derived predictors; (2) derive inferential methods to screen for the most predictive grid cells; and (3) develop a novel multivariate functional regression model that avoids partitioning of the predictor space into cells. Prediction methods are compared on two open source data sets: (1) accelerometry data collected from $32$ individuals walking on a $1.06$ kilometer path; and (2) accelerometry data collected from six repetitions of walking on a $20$ meter path on two separate occasions at least one week apart for $153$ study participants. In the $32$-individual study, all methods achieve at least $95$% rank-1 accuracy, while in the $153$-individual study, accuracy varies from $41$% to $98$%, depending on the method and prediction task. Methods provide insights into why some individuals are easier to predict than others., Comment: 37 pages, 6 figures, 2 tables. Submitted to Journal of the American Statistical Association

We propose a new fast generalized functional principal components analysis (fast-GFPCA) algorithm for dimension reduction of non-Gaussian functional data. The method consists of: (1) binning the data within the functional domain; (2) fitting local random intercept generalized linear mixed models in every bin to obtain the initial estimates of the person-specific functional linear predictors; (3) using fast functional principal component analysis to smooth the linear predictors and obtain their eigenfunctions; and (4) estimating the global model conditional on the eigenfunctions of the linear predictors. An extensive simulation study shows that fast-GFPCA performs as well or better than existing state-of-the-art approaches, it is orders of magnitude faster than existing general purpose GFPCA methods, and scales up well with both the number of observed curves and observations per curve. Methods were motivated by and applied to a study of active/inactive physical activity profiles obtained from wearable accelerometers in the NHANES 2011-2014 study. The method can be implemented by any user familiar with mixed model software, though the R package fastGFPCA is provided for convenience.

Continuous glucose monitors (CGMs) are increasingly used to measure blood glucose levels and provide information about the treatment and management of diabetes. Our motivating study contains CGM data during sleep for 174 study participants with type II diabetes mellitus measured at a 5-minute frequency for an average of 10 nights. We aim to quantify the effects of diabetes medications and sleep apnea severity on glucose levels. Statistically, this is an inference question about the association between scalar covariates and functional responses. However, many characteristics of the data make analyses difficult, including (1) non-stationary within-day patterns; (2) substantial between-day heterogeneity, non-Gaussianity, and outliers; 3) large dimensionality due to the number of study participants, sleep periods, and time points. We evaluate and compare two methods: fast univariate inference (FUI) and functional additive mixed models (FAMM). We introduce a new approach for calculating p-values for testing a global null effect of covariates using FUI, and provide practical guidelines for speeding up FAMM computations, making it feasible for our data. While FUI and FAMM are philosophically different, they lead to similar point estimators in our study. In contrast to FAMM, FUI is fast, accounts for within-day correlations, and enables the construction of joint confidence intervals. Our analyses reveal that: (1) biguanide medication and sleep apnea severity significantly affect glucose trajectories during sleep, and (2) the estimated effects are time-invariant.

Background: We propose a method for estimating the timing of in-bed intervals using objective data in a large representative U.S. sample, and quantify the association between these intervals and age, sex, and day of the week. Methods: The study included 11,951 participants six years and older from the National Health and Nutrition Examination Survey (NHANES) 2003-2006, who wore accelerometers to measure physical activity for seven consecutive days. Participants were instructed to remove the device just before the nighttime sleep period and put it back on immediately after. This nighttime period of non-wear was defined in this paper as the objective bedtime (OBT), an objectively estimated record of the in-bed-interval. For each night of the week, we estimated two measures: the duration of the OBT (OBT-D) and, as a measure of the chronotype, the midpoint of the OBT (OBT-M). We estimated day-of-the-week-specific OBT-D and OBT-M using gender-specific population percentile curves. Differences in OBT-M (chronotype) and OBT-D (the amount of time spent in bed) by age and sex were estimated using regression models. Results: The estimates of OBT-M and their differences among age groups were consistent with the estimates of chronotype obtained via self-report in European populations. The average OBT-M varied significantly by age, while OBT-D was less variable with age. The most pronounced differences were observed between OBT-M of weekday and weekend nights. Conclusions: The proposed measures, OBT-D and OBT-M, provide useful information of time in bed and chronotype in NHANES 2003-2006. They identify within-week patterns of bedtime and can be used to study associations between the bedtime and the large number of health outcomes collected in NHANES 2003-2006.

Background. Wearable accelerometry devices allow collection of high-density activity data in large epidemiological studies both in-the-lab as well as in-the-wild (free-living). Such data can be used to detect and identify periods of sustained harmonic walking. This report aims to establish whether the micro- and macro-features of walking identified in the laboratory and free-living environments are associated with measures of physical function, mobility, fatigability, and fitness. Methods. Fifty-one older adults (median age 77.5) enrolled in the Developmental Epidemiologic Cohort Study in Pittsburgh, Pennsylvania were included in the analyses. The study included an in-the-lab component as well as 7 days of monitoring in-the-wild. Participants were equipped with hip-worn Actigraph GT3X+ activity monitors, which collect high-density raw accelerometry data. We applied a walking identification algorithm to the data and defined features of walking, such as participant-specific walking acceleration and cadence. The association between these walking features and physical function, mobility, fatigability, and fitness was quantified using linear regression analysis. Results. Micro-scale features of walking (acceleration and cadence) estimated from in-the-lab and in-the-wild data were associated with measures of physical function, mobility, fatigability, and fitness. In-the-lab median walking acceleration was strongly inversely associated with physical function, mobility, fatigability and fitness. Additionally, in-the-wild daily walking time was inversely associated with usual- and fast-paced 400m walking time. Conclusions. The proposed accelerometry-derived walking features are significantly associated with measures of physical function, mobility, fatigability, and fitness, which provides evidence of convergent validity.

We propose simple inferential approaches for the fixed effects in complex functional mixed effects models. We estimate the fixed effects under the independence of functional residuals assumption and then bootstrap independent units (e.g. subjects) to estimate the variability of and conduct inference in the form of hypothesis testing on the fixed effects parameters. Simulations show excellent coverage probability of the confidence intervals and size of tests. Methods are motivated by and applied to the Baltimore Longitudinal Study of Aging (BLSA), though they are applicable to other studies that collect correlated functional data.

Many epidemiological and clinical studies use accelerometry to objectively measure physical activity using the activity counts, vector magnitude, or number of steps. These measures use just a fraction of the information in the raw accelerometry data as they are typically summarized at the minute level. To address this problem we define and estimate two gait measures of temporal stride-to-stride variability based on raw accelerometry data: Amplitude Deviation (AD) and Phase Deviation (PD). We explore the sensitivity of our approach to on-body placement of the accelerometer by comparing hip, left and right wrist placements. We illustrate the approach by estimating AD and PD in 46 elderly participants in the Developmental Epidemiologic Cohort Study (DECOS) who worn accelerometers during a 400 meter walk test. We also show that AD and PD have a statistically significant association with the gait speed and sit-to-stand test performance

Smoothing of noisy sample covariances is an important component in functional data analysis. We propose a novel covariance smoothing method based on penalized splines and associated software. The proposed method is a bivariate spline smoother that is designed for covariance smoothing and can be used for sparse functional or longitudinal data. We propose a fast algorithm for covariance smoothing using leave-one-subject-out cross validation. Our simulations show that the proposed method compares favorably against several commonly used methods. The method is applied to a study of child growth led by one of coauthors and to a public dataset of longitudinal CD4 counts., Comment: 29 pages, 8 figures

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.

Structural magnetic resonance imaging (MRI) can be used to detect lesions in the brains of multiple sclerosis (MS) patients. The formation of these lesions is a complex process involving inflammation, tissue damage, and tissue repair, all of which are visible on MRI. Here we characterize the lesion formation process on longitudinal, multi-sequence structural MRI from 34 MS patients and relate the longitudinal changes we observe within lesions to therapeutic interventions. In this article, we first outline a pipeline to extract voxel level, multi-sequence longitudinal profiles from four MRI sequences within lesion tissue. We then propose two models to relate clinical covariates to the longitudinal profiles. The first model is a principal component analysis (PCA) regression model, which collapses the information from all four profiles into a scalar value. We find that the score on the first PC identifies areas of slow, long-term intensity changes within the lesion at a voxel level, as validated by two experienced clinicians, a neuroradiologist and a neurologist. On a quality scale of 1 to 4 (4 being the highest) the neuroradiologist gave the score on the first PC a median rating of 4 (95% CI: [4,4]), and the neurologist gave it a median rating of 3 (95% CI: [3,3]). In the PCA regression model, we find that treatment with disease modifying therapies (p-value < 0.01), steroids (p-value < 0.01), and being closer to the boundary of abnormal signal intensity (p-value < 0.01) are associated with a return of a voxel to intensity values closer to that of normal-appearing tissue. The second model is a function-on-scalar regression, which allows for assessment of the individual time points at which the covariates are associated with the profiles. In the function-on-scalar regression both age and distance to the boundary were found to have a statistically significant association with the profiles.

Objective. Using raw, sub-second level, accelerometry data, we propose and validate a method for identifying and characterizing walking in the free-living environment. We focus on the sustained harmonic walking (SHW), which we define as walking for at least 10 seconds with low variability of step frequency. Approach. We utilize the harmonic nature of SHW and quantify local periodicity of the tri-axial raw accelerometry data. We also estimate fundamental frequency of observed signals and link it to the instantaneous walking (step-to-step) frequency (IWF). Next, we report total time spent in SHW, number and durations of SHW bouts, time of the day when SHW occurred and IWF for 49 healthy, elderly individuals. Main results. Sensitivity of the proposed classification method was found to be 97%, while specificity ranged between 87% and 97% and prediction accuracy between 94% and 97%. We report total time in SHW between 140 and 10 minutes-per-day distributed between 340 and 50 bouts. We estimate the average IWF to be 1.7 steps-per-second. Significance. We propose a simple approach for detection of SHW and estimation of IWF, based on Fourier decomposition. The resulting approach is fast and allows processing of a week-long raw accelerometry data (approx. 150 million measurements) in relatively short time (~half an hour) on a common laptop computer (2.8 GHz Intel Core i7, 16 GB DDR3 RAM).

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)