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 new framework is developed to intrinsically analyze sparsely observed Riemannian functional data. It features four innovative components: a frame-independent covariance function, a smooth vector bundle termed covariance vector bundle, a parallel transport and a smooth bundle metric on the covariance vector bundle. The introduced intrinsic covariance function links estimation of covariance structure to smoothing problems that involve raw covariance observations derived from sparsely observed Riemannian functional data, while the covariance vector bundle provides a rigorous mathematical founda…
Missing data on response variables are common in clinical studies. Corresponding to the uncertainty of missing mechanism, theoretical frameworks on controlled imputation have been developed. In practice, it is recommended to conduct a statistically valid analysis under the primary assumptions on missing data, followed by sensitivity analysis under alternative assumptions to assess the robustness of results. Due to the availability of software, controlled multiple imputation (MI) procedures, including delta-based and reference-based approaches, have become popular for analyzing continuous varia…
Extensions in the field of joint modeling of correlated data and dynamic predictions improve the development of prognosis research. The R package frailtypack provides estimations of various joint models for longitudinal data and survival events. In particular, it fits models for recurrent events and a terminal event (frailtyPenal), models for two survival outcomes for clustered data (frailtyPenal), models for two types of recurrent events and a terminal event (multivPenal), models for a longitudinal biomarker and a terminal event (longiPenal) and models for a longitudinal biomarker, recurrent …
The R package lcmm provides a series of functions to estimate statistical models based on linear mixed model theory. It includes the estimation of mixed models and latent class mixed models for Gaussian longitudinal outcomes (hlme), curvilinear and ordinal univariate longitudinal outcomes (lcmm) and curvilinear multivariate outcomes (multlcmm), as well as joint latent class mixed models (Jointlcmm) for a (Gaussian or curvilinear) longitudinal outcome and a time-to-event that can be possibly left-truncated right-censored and defined in a competing setting. Maximum likelihood esimators are obtai…
The article develops marginal models for multivariate longitudinal responses. Overall, the model consists of five regression submodels, one for the mean and four for the covariance matrix, with the latter resulting by considering various matrix decompositions. The decompositions that we employ are intuitive, easy to understand, and they do not rely on any assumptions such as the presence of an ordering among the multivariate responses. The regression submodels are semiparametric, with unknown functions represented by basis function expansions. We use spike-slap priors for the regression coeffi…
In this paper we propose a new template for empirical studies intended to assess causal effects: the outcome-wide longitudinal design. The approach is an extension of what is often done to assess the causal effects of a treatment or exposure using confounding control, but now, over numerous outcomes. We discuss the temporal and confounding control principles for such outcome-wide studies, metrics to evaluate robustness or sensitivity to potential unmeasured confounding for each outcome, and approaches to handle multiple testing. We argue that the outcome-wide longitudinal design has numerous a…
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…
A pressing challenge in medical research is to identify optimal treatments for individual patients. This is particularly challenging in mental health settings where mean responses are often similar across multiple treatments. For example, the mean longitudinal trajectories for patients treated with an active drug and placebo may be very similar but different treatments may exhibit distinctly different individual trajectory shapes. Most precision medicine approaches using longitudinal data often ignore information from the longitudinal data structure. This paper investigates a powerful precisio…
In semivarying coefficient models for longitudinal/clustered data, usually of primary interest is usually the parametric component which involves unknown constant coefficients. First, we study semiparametric efficiency bound for estimation of the constant coefficients in a general setup. It can be achieved by spline regression provided that the within-cluster covariance matrices are all known, which is an unrealistic assumption in reality. Thus, we propose an adaptive estimator of the constant coefficients when the covariance matrices are unknown and depend only on the index random variable, s…
Analyses of biomedical studies often necessitate modeling longitudinal causal effects. The current focus on personalized medicine and effect heterogeneity makes this task even more challenging. Towards this end, structural nested mean models (SNMMs) are fundamental tools for studying heterogeneous treatment effects in longitudinal studies. However, when outcomes are binary, current methods for estimating multiplicative and additive SNMM parameters suffer from variation dependence between the causal parameters and the non-causal nuisance parameters. This leads to a series of difficulties in int…
Joint models for longitudinal and survival data have gained a lot of attention in recent years, with the development of myriad extensions to the basic model, including those which allow for multivariate longitudinal data, competing risks and recurrent events. Several software packages are now also available for their implementation. Although mathematically straightforward, the inclusion of multiple longitudinal outcomes in the joint model remains computationally difficult due to the large number of random effects required, which hampers the practical application of this extension. We present a…
In this article, we consider the problem of recovering the underlying trajectory when the longitudinal data are sparsely and irregularly observed and noise-contaminated. Such data are popularly analyzed with functional principal component analysis via the Principal Analysis by Conditional Estimation (PACE) method. The PACE method may sometimes be numerically unstable because it involves the inverse of the covariance matrix. We propose a sparse orthonormal approximation (SOAP) method as an alternative. It estimates the optimal empirical basis functions in the best approximation framework rather…
A dynamic treatment regimen (DTR) is a pre-specified sequence of decision rules which maps baseline or time-varying measurements on an individual to a recommended intervention or set of interventions. Sequential multiple assignment randomized trials (SMARTs) represent an important data collection tool for informing the construction of effective DTRs. A common primary aim in a SMART is the marginal mean comparison between two or more of the DTRs embedded in the trial. This manuscript develops a mixed effects modeling and estimation approach for these primary aim comparisons based on a continuou…
Trial-based economic evaluations are typically performed on cross-sectional variables, derived from the responses for only the completers in the study, using methods that ignore the complexities of utility and cost data (e.g. skewness and spikes). We present an alternative and more efficient Bayesian parametric approach to handle missing longitudinal outcomes in economic evaluations, while accounting for the complexities of the data. We specify a flexible parametric model for the observed data and partially identify the distribution of the missing data with partial identifying restrictions and…
In mixed longitudinal studies, a group of subjects enter the study at different ages (cross-sectional) and are followed for successive years (longitudinal). In the context of such studies, we consider nonparametric covariance estimation with samples of noisy and partially observed functional trajectories. The proposed algorithm is based on a noniterative sequential-aggregation scheme with only basic matrix operations and closed-form solutions in each step. The good performance of the proposed method is supported by both theory and numerical experiments. We also apply the proposed procedure to …
Missing data is unavoidable in longitudinal clinical trials, and outcomes are not always normally distributed. In the presence of outliers or heavy-tailed distributions, the conventional multiple imputation with the mixed model with repeated measures analysis of the average treatment effect (ATE) based on the multivariate normal assumption may produce bias and power loss. Control-based imputation (CBI) is an approach for evaluating the treatment effect under the assumption that participants in both the test and control groups with missing outcome data have a similar outcome profile as those wi…
We propose a joint model for a time-to-event outcome and a quantile of a continuous response repeatedly measured over time. The quantile and survival processes are associated via shared latent and manifest variables. Our joint model provides a flexible approach to handle informative drop-out in quantile regression. A general Monte Carlo Expectation Maximization strategy based on importance sampling is proposed, which is directly applicable under any distributional assumption for the longitudinal outcome and random effects, and parametric and non-parametric assumptions for the baseline hazard. …
Consider estimating the G-formula for the counterfactual mean outcome under a given treatment regime in a longitudinal study. Bang and Robins provided an estimator for this quantity that relies on a sequential regression formulation of this parameter. This approach is doubly robust in that it is consistent if either the outcome regressions or the treatment mechanisms are consistently estimated. We define a stronger notion of double robustness, termed sequential double robustness, for estimators of the longitudinal G-formula. The definition emerges naturally from a more general definition of se…
Longitudinal Outcomes Truncated by Death: Causal Estimands and Bayesian Estimators
Amsterdam UMC（阿姆斯特丹大学医学中心）；Singapore University of Technology and Design（新加坡科技设计大学）；Massachusetts General Hospital（麻省总医院）；Harvard Medical School（哈佛医学院）
We propose a general framework for non-normal multivariate data analysis called multivariate covariance generalized linear models (McGLMs), designed to handle multivariate response variables, along with a wide range of temporal and spatial correlation structures defined in terms of a covariance link function combined with a matrix linear predictor involving known matrices. The method is motivated by three data examples that are not easily handled by existing methods. The first example concerns multivariate count data, the second involves response variables of mixed types, combined with repeate…
We propose a new, flexible model for inference of the effect of a binary treatment on a continuous outcome observed over subsequent time periods. The model allows to seperate association due to endogeneity of treatment selection from additional longitudinal association of the outcomes and hence unbiased estimation of dynamic treatment effects. We investigate the performance of the proposed method on simulated data and employ it to reanalyse data on the longitudinal effects of a long maternity leave on mothers' earnings after their return to the labour market.
Clinicians and researchers alike are increasingly interested in how best to personalize interventions. A dynamic treatment regimen (DTR) is a sequence of pre-specified decision rules which can be used to guide the delivery of a sequence of treatments or interventions that are tailored to the changing needs of the individual. The sequential multiple-assignment randomized trial (SMART) is a research tool which allows for the construction of effective DTRs. We derive easy-to-use formulae for computing the total sample size for three common two-stage SMART designs in which the primary aim is to co…
In electronic health records (EHRs), latent subgroups of patients may exhibit distinctive patterning in their longitudinal health trajectories. For such data, growth mixture models (GMMs) enable classifying patients into different latent classes based on individual trajectories and hypothesized risk factors. However, the application of GMMs is hindered by the special missing data problem in EHRs, which manifests two patient-led missing data processes: the visit process and the response process for an EHR variable conditional on a patient visiting the clinic. If either process is associated wit…
Longitudinal analysis is important in many disciplines, such as the study of behavioral transitions in social science. Only very recently, feature selection has drawn adequate attention in the context of longitudinal modeling. Standard techniques, such as generalized estimating equations, have been modified to select features by imposing sparsity-inducing regularizers. However, they do not explicitly model how a dependent variable relies on features measured at proximal time points. Recent graphical Granger modeling can select features in lagged time points but ignores the temporal correlation…
Random forests is a state-of-the-art supervised machine learning method which behaves well in high-dimensional settings although some limitations may happen when $p$, the number of predictors, is much larger than the number of observations $n$. Repeated measurements can help by offering additional information but no approach has been proposed for high-dimensional longitudinal data. Random forests have been adapted to standard (i.e., $n > p$) longitudinal data by using a semi-parametric mixed-effects model, in which the non-parametric part is estimated using random forests. We first propose a s…
Longitudinal gene expression profiles of patients are collected in some clinical studies to monitor disease progression and understand disease etiology. The identification of gene sets that have coordinated changes with relevant clinical outcomes over time from these data could provide significant insights into the molecular basis of disease progression and hence may lead to better treatments. In this article, we propose a Distance-Correlation based Gene Set Analysis (dcGSA) method for longitudinal gene expression data. dcGSA is a non-parametric approach, statistically robust, and can capture …
We propose an inferential approach for maximum likelihood estimation of the hidden Markov models for continuous responses. We extend to the case of longitudinal observations the finite mixture model of multivariate Gaussian distributions with Missing At Random (MAR) outcomes, also accounting for possible dropout. The resulting hidden Markov model accounts for different types of missing pattern: (i) partially missing outcomes at a given time occasion; (ii) completely missing outcomes at a given time occasion (intermittent pattern); (iii) dropout before the end of the period of observation (mono…
In this paper, we consider the problem of estimating the eigenvalues and eigenfunctions of the covariance kernel (i.e., the functional principal components) from sparse and irregularly observed longitudinal data. We approach this problem through a maximum likelihood method assuming that the covariance kernel is smooth and finite dimensional. We exploit the smoothness of the eigenfunctions to reduce dimensionality by restricting them to a lower dimensional space of smooth functions. The estimation scheme is developed based on a Newton-Raphson procedure using the fact that the basis coefficients…
Health exams determine a patient's health status by comparing the patient's measurement with a population reference range, a 95% interval derived from a homogeneous reference population. Similarly, most of the established relation among health problems are assumed to hold for the entire population. We use data from the 2009 - 2010 National Health and Nutrition Examination Survey (NHANES) on four major health problems in the U.S. and apply a joint mean and covariance model to study how the reference ranges and associations of those health outcomes could vary among subpopulations. We discuss gui…
