A Comparative Study of Approaches for Predicting Prostate Cancer from Longitudinal Data

Disease prediction based on longitudinal data can be done using various modeling approaches. Alternative approaches are compared using data from a longitudinal study to predict the onset of disease. The data are modeled using linear mixed-effects models. Posterior probabilities of group membership are computed starting with the first observation and sequentially adding observations until the subject is classified as developing the disease or until the last measurement is used. Individuals are classified by computing posterior probabilities using the marginal distributions of the mixed-effects models, the conditional distributions (conditional on the group-specific random effects), and the distributions of the random effects.     

A modified two-stage approach for joint modelling of longitudinal and time-to-event data

Joint models for longitudinal and time-to-event data have been applied in many different fields of statistics and clinical studies. However, the main difficulty these models have to face with is the computational problem. The requirement for numerical integration becomes severe when the dimension of random effects increases. In this paper, a modified two-stage approach has been proposed to estimate the parameters in joint models. In particular, in the first stage, the linear mixed-effects models and best linear unbiased predictorsare applied to estimate parameters in the longitudinal submodel. In the second stage, an approximation of the fully joint log-likelihood is proposed using the estimated the values of these parameters from the longitudinal submodel. Survival parameters are estimated bymaximizing the approximation of the fully joint log-likelihood. Simulation studies show that the approach performs well, especially when the dimension of random effects increases. Finally, we implement this approach on AIDS data.     

Mixture of linear mixed models using multivariate t distribution

Linear mixed models are widely used when multiple correlated measurements are made on each unit of interest. In many applications, the units may form several distinct clusters, and such heterogeneity can be more appropriately modelled by a finite mixture linear mixed model. The classical estimation approach, in which both the random effects and the error parts are assumed to follow normal distribution, is sensitive to outliers, and failure to accommodate outliers may greatly jeopardize the model estimation and inference. We propose a new mixture linear mixed model using multivariate t distribution. For each mixture component, we assume the response and the random effects jointly follow a multivariate t distribution, to conveniently robustify the estimation procedure. An efficient expectation conditional maximization algorithm is developed for conducting maximum likelihood estimation. The degrees of freedom parameters of the t distributions are chosen data adaptively, for achieving flexible trade-off between estimation robustness and efficiency. Simulation studies and an application on analysing lung growth longitudinal data showcase the efficacy of the proposed approach.     

Bayesian analysis of skew-normal independent linear mixed models with heterogeneity in the random-effects population

We present a new class of models to fit longitudinal data, obtained with a suitable modification of the classical linear mixed-effects model. For each sample unit, the joint distribution of the random effect and the random error is a finite mixture of scale mixtures of multivariate skew-normal distributions. This extension allows us to model the data in a more flexible way, taking into account skewness, multimodality and discrepant observations at the same time. The scale mixtures of skew-normal form an attractive class of asymmetric heavy-tailed distributions that includes the skew-normal, skew-Student-t, skew-slash and the skew-contaminated normal distributions as special cases, being a flexible alternative to the use of the corresponding symmetric distributions in this type of models. A simple efficient MCMC Gibbs-type algorithm for posterior Bayesian inference is employed. In order to illustrate the usefulness of the proposed methodology, two artificial and two real data sets are analyzed.     

贝叶斯非线性混合效应模型及其应用研究

由于常用的线性混合效应模型对具有非线性关系的纵向数据建模具有一定的局限性,因此对线性混合效应模型进行扩展,根据变量间的非线性关系建立不同的非线性混合效应模型,并根据因变量的分布特征建立混合分布模型。基于一组实际的保险损失数据,建立多项式混合效应模型、截断多项式混合效应模型和B样条混合效应模型。研究结果表明,非线性混合效应模型能够显著改进对保险损失数据的建模效果,对非寿险费率厘定具有重要参考价值。     

Some factors affecting statistical power of approximate tests in the linear mixed model for longitudinal data

Different longitudinal study designs require different statistical analysis methods and different methods of sample size determination. Statistical power analysis is a flexible approach to sample size determination for longitudinal studies. However, different power analyses are required for different statistical tests which arises from the difference between different statistical methods. In this paper, the simulation-based power calculations of F-tests with Containment, Kenward-Roger or Satterthwaite approximation of degrees of freedom are examined for sample size determination in the context of a special case of linear mixed models (LMMs), which is frequently used in the analysis of longitudinal data. Essentially, the roles of some factors, such as variance–covariance structure of random effects [unstructured UN or factor analytic FA0], autocorrelation structure among errors over time [independent IND, first-order autoregressive AR1 or first-order moving average MA1], parameter estimation methods [maximum likelihood ML and restricted maximum likelihood REML] and iterative algorithms [ridge-stabilized Newton-Raphson and Quasi-Newton] on statistical power of approximate F-tests in the LMM are examined together, which has not been considered previously. The greatest factor affecting statistical power is found to be the variance–covariance structure of random effects in the LMM. It appears that the simulation-based analysis in this study gives an interesting insight into statistical power of approximate F-tests for fixed effects in LMMs for longitudinal data.     

Joint modelling of longitudinal and repeated time-to-event data using nonlinear mixed-effects models and the stochastic approximation expectation–maximization algorithm

We propose a nonlinear mixed-effects framework to jointly model longitudinal and repeated time-to-event data. A parametric nonlinear mixed-effects model is used for the longitudinal observations and a parametric mixed-effects hazard model for repeated event times. We show the importance for parameter estimation of properly calculating the conditional density of the observations (given the individual parameters) in the presence of interval and/or right censoring. Parameters are estimated by maximizing the exact joint likelihood with the stochastic approximation expectation–maximization algorithm. This workflow for joint models is now implemented in the Monolix software, and illustrated here on five simulated and two real datasets.     

医疗费用预测的贝叶斯多项式混合效应模型

医疗费用预测是健康保险费率厘定的前提和基础。对于多年期的医疗费用数据,通常使用线性混合效应模型对其进行拟合,但线性混合效应模型对非线性关系的纵向数据建模具有一定的局限性。本文对线性混合效应模型进行扩展,根据医疗费用数据中变量之间的非线性关系,建立了多项式混合效应模型,并将其应用于一组医疗费用数据进行实证研究。结果表明,多项式混合效应模型对住院医疗费用的拟合效果显著优于通常使用的线性混合模型,在医疗费用管理和健康保险的费率厘定中具有重要的应用价值。     

Parameter estimation of nonlinear mixed-effects models using first-order conditional linearization and the EM algorithm

Nonlinear mixed-effects (NLME) models are flexible enough to handle repeated-measures data from various disciplines. In this article, we propose both maximum-likelihood and restricted maximum-likelihood estimations of NLME models using first-order conditional expansion (FOCE) and the expectation–maximization (EM) algorithm. The FOCE-EM algorithm implemented in the ForStat procedure SNLME is compared with the Lindstrom and Bates (LB) algorithm implemented in both the SAS macro NLINMIX and the S-Plus/R function nlme in terms of computational efficiency and statistical properties. Two realworld data sets an orange tree data set and a Chinese fir (Cunninghamia lanceolata) data set, and a simulated data set were used for evaluation. FOCE-EM converged for all mixed models derived from the base model in the two realworld cases, while LB did not, especially for the models in which random effects are simultaneously considered in several parameters to account for between-subject variation. However, both algorithms had identical estimated parameters and fit statistics for the converged models. We therefore recommend using FOCE-EM in NLME models, particularly when convergence is a concern in model selection.     

Robust variance estimators for fixed-effect estimates with hierarchical-likelihood

In longitudinal studies, robust sandwich variance estimators are often used, and are especially useful when model assumptions are in doubt. However, the usual sandwich estimator does not allow for models with crossed random effects. The hierarchical likelihood extends the idea of the sandwich estimator to models not currently covered. By simulation studies, we show that the new sandwich estimator is robust against heteroscedastic errors and against misspecification of overdispersion in the y | v component.     

A Statistical Method for the Determination of the Appropriate Order in a General Class of Time Series Models

Abstract

We propose a method to determine the order q of a model in a general class of time series models. For the subset of linear moving average models (MA(q)), our method is compared with that of the sample autocorrelations. Since the sample autocorrelation is meant to detect a linear structure of dependence between random variables, it turns out to be more suitable for the linear case. However, our method presents a competitive option in that case, and for nonlinear models (NLMA(q)) it is shown to work better. The main advantages of our approach are that it does not make assumptions on the existence of moments and on the distribution of the noise involved in the moving average models. We also include an example with real data corresponding to the daily returns of the exchange rate process of mexican pesos and american dollars.     

Partially Collapsed Gibbs Sampling for Linear Mixed-effects Models

This article presents a novel Bayesian analysis for linear mixed-effects models. The analysis is based on the method of partial collapsing that allows some components to be partially collapsed out of a model. The resulting partially collapsed Gibbs (PCG) sampler constructed to fit linear mixed-effects models is expected to exhibit much better convergence properties than the corresponding Gibbs sampler. In order to construct the PCG sampler without complicating component updates, we consider the reparameterization of model components by expressing a between-group variance in terms of a within-group variance in a linear mixed-effects model. The proposed method of partial collapsing with reparameterization is applied to the Merton’s jump diffusion model as well as general linear mixed-effects models with proper prior distributions and illustrated using simulated data and longitudinal data on sleep deprivation.     

Smooth-Threshold GEE Variable Selection in High-Dimensional Partially Linear Models with Longitudinal Data

We consider the problem of variable selection in high-dimensional partially linear models with longitudinal data. A variable selection procedure is proposed based on the smooth-threshold generalized estimating equation (SGEE). The proposed procedure automatically eliminates inactive predictors by setting the corresponding parameters to be zero, and simultaneously estimates the nonzero regression coefficients by solving the SGEE. We establish the asymptotic properties in a high-dimensional framework where the number of covariates p_n increases as the number of clusters n increases. Extensive Monte Carlo simulation studies are conducted to examine the finite sample performance of the proposed variable selection procedure.     

Comparison of Mixed-Effects Models for Skew-Normal Responses with an Application to AIDS Data: A Bayesian Approach

The potency of antiretroviral agents in AIDS clinical trials can be assessed on the basis of a viral response such as viral decay rate or change in viral load (number of HIV RNA copies in plasma). Linear, nonlinear, and nonparametric mixed-effects models have been proposed to estimate such parameters in viral dynamic models. However, there are two critical questions that stand out: whether these models achieve consistent estimates for viral decay rates, and which model is more appropriate for use in practice. Moreover, one often assumes that a model random error is normally distributed, but this assumption may be unrealistic, obscuring important features of within- and among-subject variations. In this article, we develop a skew-normal (SN) Bayesian linear mixed-effects (SN-BLME) model, an SN Bayesian nonlinear mixed-effects (SN-BNLME) model, and an SN Bayesian semiparametric nonlinear mixed-effects (SN-BSNLME) model that relax the normality assumption by considering model random error to have an SN distribution. We compare the performance of these SN models, and also compare their performance with the corresponding normal models. An AIDS dataset is used to test the proposed models and methods. It was found that there is a significant incongruity in the estimated viral decay rates. The results indicate that SN-BSNLME model is preferred to the other models, implying that an arbitrary data truncation is not necessary. The findings also suggest that it is important to assume a model with an SN distribution in order to achieve reasonable results when the data exhibit skewness.     

Modification of GEE1 and linear mixed-effects models for heteroscedastic longitudinal Gaussian data

A characterization of GLMs is given. Modification of the Gaussian GEE1, modified GEE1, was applied to heteroscedastic longitudinal data, to which linear mixed-effects models are usually applied. The modified GEE1 models scale multivariate data to homoscedastic data maintaining the correlation structure and apply usual GEE1 to homoscedastic data, which needs no-diagnostics for diagonal variances. Relationships among multivariate linear regression methods, ordinary/generalized LS, naïve/modified GEE1, and linear mixed-effects models were discussed. An application showed modified GEE1 gave most efficient parameter estimation. Correct specification of the main diagonals of heteroscedastic data variance appears to be more important for efficient mean parameter estimation.     

Bayesian modelling of the mean and covariance matrix in normal nonlinear models

An important problem in statistics is the study of longitudinal data taking into account the effect of other explanatory variables such as treatments and time. In this paper, a new Bayesian approach for analysing longitudinal data is proposed. This innovative approach takes into account the possibility of having nonlinear regression structures on the mean and linear regression structures on the variance–covariance matrix of normal observations, and it is based on the modelling strategy suggested by Pourahmadi [M. Pourahmadi, Joint mean-covariance models with applications to longitudinal data: Unconstrained parameterizations, Biometrika, 87 (1999), pp. 667–690.]. We initially extend the classical methodology to accommodate the fitting of nonlinear mean models then we propose our Bayesian approach based on a generalization of the Metropolis–Hastings algorithm of Cepeda [E.C. Cepeda, Variability modeling in generalized linear models, Unpublished Ph.D. Thesis, Mathematics Institute, Universidade Federal do Rio de Janeiro, 2001]. Finally, we illustrate the proposed methodology by analysing one example, the cattle data set, that is used to study cattle growth.     

Mixed-effects Models with Skewed Distributions for Time-varying Decay Rate in HIV Dynamics

After initiation of treatment, HIV viral load has multiphasic changes, which indicates that the viral decay rate is a time-varying process. Mixed-effects models with different time-varying decay rate functions have been proposed in literature. However, there are two unresolved critical issues: (i) it is not clear which model is more appropriate for practical use, and (ii) the model random errors are commonly assumed to follow a normal distribution, which may be unrealistic and can obscure important features of within- and among-subject variations. Because asymmetry of HIV viral load data is still noticeable even after transformation, it is important to use a more general distribution family that enables the unrealistic normal assumption to be relaxed. We developed skew-elliptical (SE) Bayesian mixed-effects models by considering the model random errors to have an SE distribution. We compared the performance among five SE models that have different time-varying decay rate functions. For each model, we also contrasted the performance under different model random error assumptions such as normal, Student-t, skew-normal, or skew-t distribution. Two AIDS clinical trial datasets were used to illustrate the proposed models and methods. The results indicate that the model with a time-varying viral decay rate that has two exponential components is preferred. Among the four distribution assumptions, the skew-t and skew-normal models provided better fitting to the data than normal or Student-t model, suggesting that it is important to assume a model with a skewed distribution in order to achieve reasonable results when the data exhibit skewness.     

Linear Transformations of Linear Mixed-Effects Models

A number of articles have discussed the way lower order polynomial and interaction terms should be handled in linear regression models. Only if all lower order terms are included in the model will the regression model be invariant with respect to coding transformations of the variables. If lower order terms are omitted, the regression model will not be well formulated. In this paper, we extend this work to examine the implications of the ordering of variables in the linear mixed-effects model. We demonstrate how linear transformations of the variables affect the model and tests of significance of fixed effects in the model. We show how the transformations modify the random effects in the model, as well as their covariance matrix and the value of the restricted log-likelihood. We suggest a variable selection strategy for the linear mixed-effects model.     

Perturbation diagnostics of autocorrelation coefficients in non linear mixed-effects models with AR(1) errors based on M-estimation

In this work we propose and analyze non linear mixed-effects models for longitudinal data, which are widely used in the fields of economics, biopharmaceuticals, agriculture, and so on. A robust method to obtain maximum likelihood estimates for the parameters is presented, as well as perturbation diagnostics of autocorrelation coefficient in non linear models based on robust estimates and influence curvature. The obtained results are illustrated by plasma concentrations data presented in Davidian and Giltinan, which was analyzed under the non robust situation.     

Joint modeling of hierarchically clustered and overdispersed non‐gaussian continuous outcomes for comet assay data

Multivariate longitudinal or clustered data are commonly encountered in clinical trials and toxicological studies. Typically, there is no single standard endpoint to assess the toxicity or efficacy of the compound of interest, but co‐primary endpoints are available to assess the toxic effects or the working of the compound. Modeling the responses jointly is thus appealing to draw overall inferences using all responses and to capture the association among the responses. Non‐Gaussian outcomes are often modeled univariately using exponential family models. To accommodate both the overdispersion and hierarchical structure in the data, Molenberghs et al. A family of generalized linear models for repeated measures with normal and conjugate random effects. Statistical Science 2010; 25:325–347 proposed using two separate sets of random effects. This papers considers a model for multivariate data with hierarchically clustered and overdispersed non‐Gaussian data. Gamma random effect for the over‐dispersion and normal random effects for the clustering in the data are being used. The two outcomes are jointly analyzed by assuming that the normal random effects for both endpoints are correlated. The association structure between the response is analytically derived. The fit of the joint model to data from a so‐called comet assay are compared with the univariate analysis of the two outcomes. Copyright © 2012 John Wiley & Sons, Ltd.