Approximate bounded influence estimation for longitudinal data with outliers and measurement errors

Mixed effects models or random effects models are popular for the analysis of longitudinal data. In practice, longitudinal data are often complex since there may be outliers in both the response and the covariates and there may be measurement errors. The likelihood method is a common approach for these problems but it can be computationally very intensive and sometimes may even be computationally infeasible. In this article, we consider approximate robust methods for nonlinear mixed effects models to simultaneously address outliers and measurement errors. The approximate methods are computationally very efficient. We show the consistency and asymptotic normality of the approximate estimates. The methods can also be extended to missing data problems. An example is used to illustrate the methods and a simulation is conducted to evaluate the methods.     

A Semiparametric Bayesian Approach to Multivariate Longitudinal Data

We extend the standard multivariate mixed model by incorporating a smooth time effect and relaxing distributional assumptions. We propose a semiparametric Bayesian approach to multivariate longitudinal data using a mixture of Polya trees prior distribution. Usually, the distribution of random effects in a longitudinal data model is assumed to be Gaussian. However, the normality assumption may be suspect, particularly if the estimated longitudinal trajectory parameters exhibit multimodality and skewness. In this paper we propose a mixture of Polya trees prior density to address the limitations of the parametric random effects distribution. We illustrate the methodology by analyzing data from a recent HIV-AIDS study.     

Embedded experiments in repeated and overlapping surveys

Summary.  Statistical agencies make changes to the data collection methodology of their surveys to improve the quality of the data collected or to improve the efficiency with which they are collected. For reasons of cost it may not be possible to estimate the effect of such a change on survey estimates or response rates reliably, without conducting an experiment that is embedded in the survey which involves enumerating some respondents by using the new method and some under the existing method. Embedded experiments are often designed for repeated and overlapping surveys; however, previous methods use sample data from only one occasion. The paper focuses on estimating the effect of a methodological change on estimates in the case of repeated surveys with overlapping samples from several occasions. Efficient design of an embedded experiment that covers more than one time point is also mentioned. All inference is unbiased over an assumed measurement model, the experimental design and the complex sample design. Other benefits of the approach proposed include the following: it exploits the correlation between the samples on each occasion to improve estimates of treatment effects; treatment effects are allowed to vary over time; it is robust against incorrectly rejecting the null hypothesis of no treatment effect; it allows a wide set of alternative experimental designs. This paper applies the methodology proposed to the Australian Labour Force Survey to measure the effect of replacing pen-and-paper interviewing with computer-assisted interviewing. This application considered alternative experimental designs in terms of their statistical efficiency and their risks to maintaining a consistent series. The approach proposed is significantly more efficient than using only 1 month of sample data in estimation.     

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.     

Jointly modeling longitudinal proportional data and survival times with an application to the quality of life data in a breast cancer trial

Motivated by the joint analysis of longitudinal quality of life data and recurrence free survival times from a cancer clinical trial, we present in this paper two approaches to jointly model the longitudinal proportional measurements, which are confined in a finite interval, and survival data. Both approaches assume a proportional hazards model for the survival times. For the longitudinal component, the first approach applies the classical linear mixed model to logit transformed responses, while the second approach directly models the responses using a simplex distribution. A semiparametric method based on a penalized joint likelihood generated by the Laplace approximation is derived to fit the joint model defined by the second approach. The proposed procedures are evaluated in a simulation study and applied to the analysis of breast cancer data motivated this research.     

Testing homogeneity in clustered (longitudinal) count data regression model with over-dispersion

Clustered (longitudinal) count data arise in many bio-statistical practices in which a number of repeated count responses are observed on a number of individuals. The repeated observations may also represent counts over time from a number of individuals. One important problem that arises in practice is to test homogeneity within clusters (individuals) and between clusters (individuals). As data within clusters are observations of repeated responses, the count data may be correlated and/or over-dispersed. For over-dispersed count data with unknown over-dispersion parameter we derive two score tests by assuming a random intercept model within the framework of (i) the negative binomial mixed effects model and (ii) the double extended quasi-likelihood mixed effects model (Lee and Nelder, 2001). These two statistics are much simpler than a statistic derived by Jacqmin-Gadda and Commenges (1995) under the framework of the over-dispersed generalized linear model. The first statistic takes the over-dispersion more directly into the model and therefore is expected to do well when the model assumptions are satisfied and the other statistic is expected to be robust. Simulations show superior level property of the statistics derived under the negative binomial and double extended quasi-likelihood model assumptions. A data set is analyzed and a discussion is given.     

AN APPROACH FOR JOINTLY MODELING MULTIVARIATE LONGITUDINAL MEASUREMENTS AND DISCRETE TIME-TO-EVENT DATA

In many medical studies, patients are followed longitudinally and interest is on assessing the relationship between longitudinal measurements and time to an event. Recently, various authors have proposed joint modeling approaches for longitudinal and time-to-event data for a single longitudinal variable. These joint modeling approaches become intractable with even a few longitudinal variables. In this paper we propose a regression calibration approach for jointly modeling multiple longitudinal measurements and discrete time-to-event data. Ideally, a two-stage modeling approach could be applied in which the multiple longitudinal measurements are modeled in the first stage and the longitudinal model is related to the time-to-event data in the second stage. Biased parameter estimation due to informative dropout makes this direct two-stage modeling approach problematic. We propose a regression calibration approach which appropriately accounts for informative dropout. We approximate the conditional distribution of the multiple longitudinal measurements given the event time by modeling all pairwise combinations of the longitudinal measurements using a bivariate linear mixed model which conditions on the event time. Complete data are then simulated based on estimates from these pairwise conditional models, and regression calibration is used to estimate the relationship between longitudinal data and time-to-event data using the complete data. We show that this approach performs well in estimating the relationship between multivariate longitudinal measurements and the time-to-event data and in estimating the parameters of the multiple longitudinal process subject to informative dropout. We illustrate this methodology with simulations and with an analysis of primary biliary cirrhosis (PBC) data.     

Least squares estimation of regression parameters in mixed effects models with unmeasured covariates

We consider mixed effects models for longitudinal, repeated measures or clustered data. Unmeasured or omitted covariates in such models may be correlated with the included covanates, and create model violations when not taken into account. Previous research and experience with longitudinal data sets suggest a general form of model which should be considered when omitted covariates are likely, such as in observational studies. We derive the marginal model between the response variable and included covariates, and consider model fitting using the ordinary and weighted least squares methods, which require simple non-iterative computation and no assumptions on the distribution of random covariates or error terms, Asymptotic properties of the least squares estimators are also discussed. The results shed light on the structure of least squares estimators in mixed effects models, and provide large sample procedures for statistical inference and prediction based on the marginal model. We present an example of the relationship between fluid intake and output in very low birth weight infants, where the model is found to have the assumed structure.     

Optimal Partitioning for Linear Mixed Effects Models: Applications to Identifying Placebo Responders

A long-standing problem in clinical research is distinguishing drug treated subjects that respond due to specific effects of the drug from those that respond to non-specific (or placebo) effects of the treatment. Linear mixed effect models are commonly used to model longitudinal clinical trial data. In this paper we present a solution to the problem of identifying placebo responders using an optimal partitioning methodology for linear mixed effects models. Since individual outcomes in a longitudinal study correspond to curves, the optimal partitioning methodology produces a set of prototypical outcome profiles. The optimal partitioning methodology can accommodate both continuous and discrete covariates. The proposed partitioning strategy is compared and contrasted with the growth mixture modelling approach. The methodology is applied to a two-phase depression clinical trial where subjects in a first phase were treated openly for 12 weeks with fluoxetine followed by a double blind discontinuation phase where responders to treatment in the first phase were randomized to either stay on fluoxetine or switched to a placebo. The optimal partitioning methodology is applied to the first phase to identify prototypical outcome profiles. Using time to relapse in the second phase of the study, a survival analysis is performed on the partitioned data. The optimal partitioning results identify prototypical profiles that distinguish whether subjects relapse depending on whether or not they stay on the drug or are randomized to a placebo.     

Bayesian analysis of competing risks with partially masked cause of failure

Summary. Bayesian analysis of system failure data from engineering applications under a competing risks framework is considered when the cause of failure may not have been exactly identified but has only been narrowed down to a subset of all potential risks. In statistical literature, such data are termed masked failure data. In addition to masking, failure times could be right censored owing to the removal of prototypes at a prespecified time or could be interval censored in the case of periodically acquired readings. In this setting, a general Bayesian formulation is investigated that includes most commonly used parametric lifetime distributions and that is sufficiently flexible to handle complex forms of censoring. The methodology is illustrated in two engineering applications with a special focus on model comparison issues.     

A joint marginalized multilevel model for longitudinal outcomes

The shared-parameter model and its so-called hierarchical or random-effects extension are widely used joint modeling approaches for a combination of longitudinal continuous, binary, count, missing, and survival outcomes that naturally occurs in many clinical and other studies. A random effect is introduced and shared or allowed to differ between two or more repeated measures or longitudinal outcomes, thereby acting as a vehicle to capture association between the outcomes in these joint models. It is generally known that parameter estimates in a linear mixed model (LMM) for continuous repeated measures or longitudinal outcomes allow for a marginal interpretation, even though a hierarchical formulation is employed. This is not the case for the generalized linear mixed model (GLMM), that is, for non-Gaussian outcomes. The aforementioned joint models formulated for continuous and binary or two longitudinal binomial outcomes, using the LMM and GLMM, will naturally have marginal interpretation for parameters associated with the continuous outcome but a subject-specific interpretation for the fixed effects parameters relating covariates to binary outcomes. To derive marginally meaningful parameters for the binary models in a joint model, we adopt the marginal multilevel model (MMM) due to Heagerty [13] and Heagerty and Zeger [14] and formulate a joint MMM for two longitudinal responses. This enables to (1) capture association between the two responses and (2) obtain parameter estimates that have a population-averaged interpretation for both outcomes. The model is applied to two sets of data. The results are compared with those obtained from the existing approaches such as generalized estimating equations, GLMM, and the model of Heagerty [13]. Estimates were found to be very close to those from single analysis per outcome but the joint model yields higher precision and allows for quantifying the association between outcomes. Parameters were estimated using maximum likelihood. The model is easy to fit using available tools such as the SAS NLMIXED procedure.     

Estimated estimating equations: semiparametric inference for clustered and longitudinal data

Summary.  We introduce a flexible marginal modelling approach for statistical inference for clustered and longitudinal data under minimal assumptions. This estimated estimating equations approach is semiparametric and the proposed models are fitted by quasi-likelihood regression, where the unknown marginal means are a function of the fixed effects linear predictor with unknown smooth link, and variance–covariance is an unknown smooth function of the marginal means. We propose to estimate the nonparametric link and variance–covariance functions via smoothing methods, whereas the regression parameters are obtained via the estimated estimating equations. These are score equations that contain nonparametric function estimates. The proposed estimated estimating equations approach is motivated by its flexibility and easy implementation. Moreover, if data follow a generalized linear mixed model, with either a specified or an unspecified distribution of random effects and link function, the model proposed emerges as the corresponding marginal (population-average) version and can be used to obtain inference for the fixed effects in the underlying generalized linear mixed model, without the need to specify any other components of this generalized linear mixed model. Among marginal models, the estimated estimating equations approach provides a flexible alternative to modelling with generalized estimating equations. Applications of estimated estimating equations include diagnostics and link selection. The asymptotic distribution of the proposed estimators for the model parameters is derived, enabling statistical inference. Practical illustrations include Poisson modelling of repeated epileptic seizure counts and simulations for clustered binomial responses.     

A more general methodology for fitting global cross-ratio models for discrete longitudinal responses

In this paper, we focus on repeated measurement problems, comprising an interesting research area in statistics. We study longitudinal data which arise when outcomes are observed repeatedly on each experimental subject at several points. We focus on a marginal approach for this type of data with lack of independence among the observations proposed by Dale [Global cross-ratio models for bivariate, discrete, ordered responses. Biometrics. 1986;42(4):909–917] for bivariate, discrete, ordered responses. We propose an alternative estimation based on divergence measures to the full likelihood method proposed in that paper. Finally, a wide simulation study and a data example that illustrates the new methodology is provided.     

Distance-based approach in univariate longitudinal data analysis

In this paper, we propose a methodology to analyze longitudinal data through distances between pairs of observations (or individuals) with regard to the explanatory variables used to fit continuous response variables. Restricted maximum-likelihood and generalized least squares are used to estimate the parameters in the model. We applied this new approach to study the effect of gender and exposure on the deviant behavior variable with respect to tolerance for a group of youths studied over a period of 5 years. Were performed simulations where we compared our distance-based method with classic longitudinal analysis with both AR(1) and compound symmetry correlation structures. We compared them under Akaike and Bayesian information criterions, and the relative efficiency of the generalized variance of the errors of each model. We found small gains in the proposed model fit with regard to the classical methodology, particularly in small samples, regardless of variance, correlation, autocorrelation structure and number of time measurements.     

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.     

Joint modeling of multivariate longitudinal mixed measurements and time to event data using a Bayesian approach

In many longitudinal studies multiple characteristics of each individual, along with time to occurrence of an event of interest, are often collected. In such data set, some of the correlated characteristics may be discrete and some of them may be continuous. In this paper, a joint model for analysing multivariate longitudinal data comprising mixed continuous and ordinal responses and a time to event variable is proposed. We model the association structure between longitudinal mixed data and time to event data using a multivariate zero-mean Gaussian process. For modeling discrete ordinal data we assume a continuous latent variable follows the logistic distribution and for continuous data a Gaussian mixed effects model is used. For the event time variable, an accelerated failure time model is considered under different distributional assumptions. For parameter estimation, a Bayesian approach using Markov Chain Monte Carlo is adopted. The performance of the proposed methods is illustrated using some simulation studies. A real data set is also analyzed, where different model structures are used. Model comparison is performed using a variety of statistical criteria.     

Inference in Semi‐Parametric Dynamic Models for Repeated Count Data

This paper deals with a longitudinal semi‐parametric regression model in a generalised linear model setup for repeated count data collected from a large number of independent individuals. To accommodate the longitudinal correlations, we consider a dynamic model for repeated counts which has decaying auto‐correlations as the time lag increases between the repeated responses. The semi‐parametric regression function involved in the model contains a specified regression function in some suitable time‐dependent covariates and a non‐parametric function in some other time‐dependent covariates. As far as the inference is concerned, because the non‐parametric function is of secondary interest, we estimate this function consistently using the independence assumption‐based well‐known quasi‐likelihood approach. Next, the proposed longitudinal correlation structure and the estimate of the non‐parametric function are used to develop a semi‐parametric generalised quasi‐likelihood approach for consistent and efficient estimation of the regression effects in the parametric regression function. The finite sample performance of the proposed estimation approach is examined through an intensive simulation study based on both large and small samples. Both balanced and unbalanced cluster sizes are incorporated in the simulation study. The asymptotic performances of the estimators are given. The estimation methodology is illustrated by reanalysing the well‐known health care utilisation data consisting of counts of yearly visits to a physician by 180 individuals for four years and several important primary and secondary covariates.     

Extending the Box–Cox transformation to the linear mixed model

Summary.  For a univariate linear model, the Box–Cox method helps to choose a response transformation to ensure the validity of a Gaussian distribution and related assumptions. The desire to extend the method to a linear mixed model raises many vexing questions. Most importantly, how do the distributions of the two sources of randomness (pure error and random effects) interact in determining the validity of assumptions? For an otherwise valid model, we prove that the success of a transformation may be judged solely in terms of how closely the total error follows a Gaussian distribution. Hence the approach avoids the complexity of separately evaluating pure errors and random effects. The extension of the transformation to the mixed model requires an exploration of its potential effect on estimation and inference of the model parameters. Analysis of longitudinal pulmonary function data and Monte Carlo simulations illustrate the methodology discussed.     

Analysis of longitudinal data unbalanced over time

Summary.  The paper considers modelling, estimating and diagnostically verifying the response process generating longitudinal data, with emphasis on association between repeated meas-ures from unbalanced longitudinal designs. Our model is based on separate specifications of the moments for the mean, standard deviation and correlation, with different components possibly sharing common parameters. We propose a general class of correlation structures that comprise random effects, measurement errors and a serially correlated process. These three elements are combined via flexible time-varying weights, whereas the serial correlation can depend flexibly on the mean time and lag. When the measurement schedule is independent of the response process, our estimation procedure yields consistent and asymptotically normal estimates for the mean parameters even when the standard deviation and correlation are misspecified, and for the standard deviation parameters even when the correlation is misspecified. A generic diagnostic method is developed for verifying the models for the mean, standard deviation and, in particular, the correlation, which is applicable even when the data are severely unbalanced. The methodology is illustrated by an analysis of data from a longitudinal study that was designed to characterize pulmonary growth in girls.     

Semiparametric Bayesian hierarchical models for heterogeneous population in nonlinear mixed effect model: application to gastric emptying studies

Gastric emptying studies are frequently used in medical research, both human and animal, when evaluating the effectiveness and determining the unintended side-effects of new and existing medications, diets, and procedures or interventions. It is essential that gastric emptying data be appropriately summarized before making comparisons between study groups of interest and to allow study the comparisons. Since gastric emptying data have a nonlinear emptying curve and are longitudinal data, nonlinear mixed effect (NLME) models can accommodate both the variation among measurements within individuals and the individual-to-individual variation. However, the NLME model requires strong assumptions that are often not satisfied in real applications that involve a relatively small number of subjects, have heterogeneous measurement errors, or have large variation among subjects. Therefore, we propose three semiparametric Bayesian NLMEs constructed with Dirichlet process priors, which automatically cluster sub-populations and estimate heterogeneous measurement errors. To compare three semiparametric models with the parametric model we propose a penalized posterior Bayes factor. We compare the performance of our semiparametric hierarchical Bayesian approaches with that of the parametric Bayesian hierarchical approach. Simulation results suggest that our semiparametric approaches are more robust and flexible. Our gastric emptying studies from equine medicine are used to demonstrate the advantage of our approaches.