Studies of Alzheimer's disease (AD) often collect multiple longitudinal clinical outcomes, which are correlated and predictive of AD progression. It is of great scientific interest to investigate the association between the outcomes and time to AD onset. We model the multiple longitudinal outcomes as multivariate sparse functional data and propose a functional joint model linking multivariate functional data to event time data. In particular, we propose a multivariate functional mixed model (MFMM) to identify the shared progression pattern and outcome-specific progression patterns of the outcomes, which enables more interpretable modeling of associations between outcomes and AD onset. The proposed method is applied to the Alzheimer's Disease Neuroimaging Initiative study (ADNI) and the functional joint model sheds new light on inference of five longitudinal outcomes and their associations with AD onset. Simulation studies also confirm the validity of the proposed model.
We propose a new class of multivariate survival models based on archimedean copulas with margins modeled by the Yang and Prentice (YP) model. The Ali-Mikhail-Haq (AMH), Clayton, Frank, Gumbel-Hougaard (GH), and Joe copulas are employed to accommodate the dependency among marginal distributions. Baseline distributions are modeled semiparametrically by the piecewise exponential (PE) distribution and the Bernstein polynomials. The new class of models possesses some attractive features: i) the ability to take into account survival data with crossing survival curves; ii) the inclusion of the well-k…
Illness-death models are a class of stochastic models inside the multi-state framework. In those models, individuals are allowed to move over time between different states related to illness and death. They are of special interest when working with non-terminal diseases, as they not only consider the competing risk of death but also allow to study progression from illness to death. The intensity of each transition can be modelled including both fixed and random effects of covariates. In particular, spatially structured random effects or their multivariate versions can be used to assess spatial…
Joint modelling of longitudinal and time-to-event data is usually described by a joint model which uses shared or correlated latent effects to capture associations between the two processes. Under this framework, the joint distribution of the two processes can be derived straightforwardly by assuming conditional independence given the random effects. Alternative approaches to induce interdependency into sub-models have also been considered in the literature and one such approach is using copulas to introduce non-linear correlation between the marginal distributions of the longitudinal and time…
Covariance estimation is essential yet underdeveloped for analyzing multivariate functional data. We propose a fast covariance estimation method for multivariate sparse functional data using bivariate penalized splines. The tensor-product B-spline formulation of the proposed method enables a simple spectral decomposition of the associated covariance operator and explicit expressions of the resulting eigenfunctions as linear combinations of B-spline bases, thereby dramatically facilitating subsequent principal component analysis. We derive a fast algorithm for selecting the smoothing parameters…
For the analysis of clustered survival data, two different types of models that take the association into account, are commonly used: frailty models and copula models. Frailty models assume that conditional on a frailty term for each cluster, the hazard functions of individuals within that cluster are independent. These unknown frailty terms with their imposed distribution are used to express the association between the different individuals in a cluster. Copula models on the other hand assume that the joint survival function of the individuals within a cluster is given by a copula function, e…
We present a new method for the detection of gene pathways associated with a multivariate quantitative trait, and use it to identify causal pathways associated with an imaging endophenotype characteristic of longitudinal structural change in the brains of patients with Alzheimer's disease (AD). Our method, known as pathways sparse reduced-rank regression (PsRRR), uses group lasso penalised regression to jointly model the effects of genome-wide single nucleotide polymorphisms (SNPs), grouped into functional pathways using prior knowledge of gene-gene interactions. Pathways are ranked in order o…
Multivariate data occurs in a wide range of fields, with ever more flexible model specifications being proposed, often within a multivariate generalised linear mixed effects (MGLME) framework. In this article, we describe an extended framework, encompassing multiple outcomes of any type, each of which could be repeatedly measured (longitudinal), with any number of levels, and with any number of random effects at each level. Many standard distributions are described, as well as non-standard user-defined non-linear models. The extension focuses on a complex linear predictor for each outcome mode…
We are interested in survival analysis of hemodialysis patients for whom several biomarkers are recorded over time. Motivated by this challenging problem, we propose a general framework for multivariate joint longitudinal-survival modeling that can be used to examine the association between several longitudinally recorded covariates and a time-to-event endpoint. Our method allows for simultaneous modeling of longitudinal covariates by taking their correlation into account. This leads to a more efficient method for modeling their trajectories over time, and hence, it can better capture their re…
Mediation analysis seeks to identify and quantify the paths by which an exposure affects an outcome. Intermediate variables which are effected by the exposure and which effect the outcome are known as mediators. There exists extensive work on mediation analysis in the context of models with a single mediator and continuous and binary outcomes. However these methods are often not suitable for multi-omic data that include highly interconnected variables measuring biological mechanisms and various types of outcome variables such as censored survival responses. In this article, we develop a genera…
In statistical models for the analysis of time-to-event data, individual heterogeneity is usually accounted for by means of one or more random effects, also known as frailties. In the vast majority of the literature, the random effect is assumed to follow a continuous probability distribution. However, in some areas of application, a discrete frailty distribution may be more appropriate. We investigate and compare various existing families of discrete univariate and shared frailty models by taking as our focus the variance of the relative frailty distribution in survivors. The relative frailty…
Longitudinal and high-dimensional measurements have become increasingly common in biomedical research. However, methods to predict survival outcomes using covariates that are both longitudinal and high-dimensional are currently missing. In this article, we propose penalized regression calibration (PRC), a method that can be employed to predict survival in such situations. PRC comprises three modeling steps: First, the trajectories described by the longitudinal predictors are flexibly modeled through the specification of multivariate mixed effects models. Second, subject-specific summaries of t…
We propose a novel personalized concept for the optimal treatment selection for a situation where the response is a multivariate vector, that could contain right-censored variables such as survival time. The proposed method can be applied with any number of treatments and outcome variables, under a broad set of models. Following a working semiparametric Single Index Model that relates covariates and responses, we first define a patient-specific composite score, constructed from individual covariates. We then estimate conditional means of each response, given the patient score, correspond to ea…
Motivated by recent data analyses in biomedical imaging studies, we consider a class of image-on-scalar regression models for imaging responses and scalar predictors. We propose using flexible multivariate splines over triangulations to handle the irregular domain of the objects of interest on the images, as well as other characteristics of images. The proposed estimators of the coefficient functions are proved to be root-n consistent and asymptotically normal under some regularity conditions. We also provide a consistent and computationally efficient estimator of the covariance function. Asym…
A case-control family study is a study where individuals with a disease of interest (case probands) and individuals without the disease (control probands) are randomly sampled from a well-defined population. Possibly right-censored age at onset and disease status are observed for both probands and their relatives. Correlation among the outcomes within a family is induced by factors such as inherited genetic susceptibility, shared environment, and common behavior patterns. For this setting, we present a nonparametric estimator of the marginal survival function, based on local linear estimation …
As other neurodegenerative diseases, Alzheimer's disease, the most frequent dementia in the elderly, is characterized by multiple progressive impairments in the brain structure and in clinical functions such as cognitive functioning and functional disability. Until recently, these components were mostly studied independently since no joint model for multivariate longitudinal data and time to event was available in the statistical community. Yet, these components are fundamentally inter-related in the degradation process towards dementia and should be analyzed together. We thus propose a joint …
Many biomedical studies have identified important imaging biomarkers that are associated with both repeated clinical measures and a survival outcome. The functional joint model (FJM) framework, proposed in Li and Luo (2017), investigates the association between repeated clinical measures and survival data, while adjusting for both high-dimensional images and low-dimensional covariates based upon the functional principal component analysis (FPCA). In this paper, we propose a novel algorithm for the estimation of FJM based on the functional partial least squares (FPLS). Our numerical studies dem…
This paper considers canonical correlation analysis for two longitudinal variables that are possibly sampled at different time resolutions with irregular grids. We modeled trajectories of the multivariate variables using random effects and found the most correlated sets of linear combinations in the latent space. Our numerical simulations showed that the longitudinal canonical correlation analysis effectively recovers underlying correlation patterns between two high-dimensional longitudinal data sets. We applied the proposed LCCA to data from the Alzheimer's Disease Neuroimaging Initiative and…
merlin can do a lot of things. From simple stuff, like fitting a linear regression or a Weibull survival model, to a three-level logistic mixed effects model, or a multivariate joint model of multiple longitudinal outcomes (of different types) and a recurrent event and survival with non-linear effects...the list is rather endless. merlin can do things I haven't even thought of yet. I'll take a single dataset, and attempt to show you the full range of capabilities of merlin, and discuss some future directions for the implementation in Stata.
A new non-parametric test for multivariate paired data from pair matching or paired designs
School of Data Science, Fudan University（复旦大学数据科学学院）；Department of Statistics, University of California, Davis（加州大学戴维斯分校统计系）；Beijing International Center for Mathematical Research and School of Public Health, Peking University（北京大学北京国际数学研究中心与公共卫生学院）
We develop a multivariate cure survival model to estimate lifetime patterns of colorectal cancer screening. Screening data cover long periods of time, with sparse observations for each person. Some events may occur before the study begins or after the study ends, so the data are both left- and right-censored, and some individuals are never screened (the "cured" population). We propose a multivariate parametric cure model that can be used with left- and right-censored data. Our model allows for the estimation of the time to screening as well as the average number of times individuals will be sc…
It is important to characterize the temporal trajectories of disease-related biomarkers in order to monitor progression and identify potential points of intervention. This is especially important for neurodegenerative diseases, as therapeutic intervention is most likely to be effective in the preclinical disease stages prior to significant neuronal damage. Longitudinal neuroimaging allows for the measurement of structural, functional, and metabolic integrity of the brain over time at the level of voxels. However, commonly used longitudinal analysis approaches, such as linear mixed effects mode…
We consider a parametric modelling approach for survival data where covariates are allowed to enter the model through multiple distributional parameters, i.e., scale and shape. This is in contrast with the standard convention of having a single covariate-dependent parameter, typically the scale. Taking what is referred to as a multi-parameter regression (MPR) approach to modelling has been shown to produce flexible and robust models with relatively low model complexity cost. However, it is very common to have clustered data arising from survival analysis studies, and this is something that is …
A new class of copulas, termed the MGL copula class, is introduced. The new copula originates from extracting the dependence function of the multivariate generalized log-Moyal-gamma distribution whose marginals follow the univariate generalized log-Moyal-gamma (GLMGA) distribution as introduced in \citet{li2019jan}. The MGL copula can capture nonelliptical, exchangeable, and asymmetric dependencies among marginal coordinates and provides a simple formulation for regression applications. We discuss the probabilistic characteristics of MGL copula and obtain the corresponding extreme-value copula…
We develop a Bayesian bivariate spatial model for multivariate regression analysis applicable to studies examining the influence of genetic variation on brain structure. Our model is motivated by an imaging genetics study of the Alzheimer's Disease Neuroimaging Initiative (ADNI), where the objective is to examine the association between images of volumetric and cortical thickness values summarizing the structure of the brain as measured by magnetic resonance imaging (MRI) and a set of 486 SNPs from 33 Alzheimer's Disease (AD) candidate genes obtained from 632 subjects. A bivariate spatial proc…
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…
