Using a Box–Cox transformation in the analysis of longitudinal data with incomplete responses

We analyse longitudinal data on CD4 cell counts from patients who participated in clinical trials that compared two therapeutic treatments: zidovudine and didanosine. The investigators were interested in modelling the CD4 cell count as a function of treatment, age at base-line and disease stage at base-line. Serious concerns can be raised about the normality assumption of CD4 cell counts that is implicit in many methods and therefore an analysis may have to start with a transformation. Instead of assuming that we know the transformation (e.g. logarithmic) that makes the outcome normal and linearly related to the covariates, we estimate the transformation, by using maximum likelihood, within the Box–Cox family. There has been considerable work on the Box–Cox transformation for univariate regression models. Here, we discuss the Box–Cox transformation for longitudinal regression models when the outcome can be missing over time, and we also implement a maximization method for the likelihood, assumming that the missing data are missing at random.     

Smoothing combined estimating equations in quantile regression for longitudinal data

Quantile regression has become a powerful complement to the usual mean regression. A simple approach to use quantile regression in marginal analysis of longitudinal data is to assume working independence. However, this may incur potential efficiency loss. On the other hand, correctly specifying a working correlation in quantile regression can be difficult. We propose a new quantile regression model by combining multiple sets of unbiased estimating equations. This approach can account for correlations between the repeated measurements and produce more efficient estimates. Because the objective function is discrete and non-convex, we propose induced smoothing for fast and accurate computation of the parameter estimates, as well as their asymptotic covariance, using Newton-Raphson iteration. We further develop a robust quantile rank score test for hypothesis testing. We show that the resulting estimate is asymptotically normal and more efficient than the simple estimate using working independence. Extensive simulations and a real data analysis show the usefulness of the method.     

Quantile regression in heteroscedastic varying coefficient models

Varying coefficient models are flexible models to describe the dynamic structure in longitudinal data. Quantile regression, more than mean regression, gives partial information on the conditional distribution of the response given the covariates. In the literature, the focus has been so far mostly on homoscedastic quantile regression models, whereas there is an interest in looking into heteroscedastic modelling. This paper contributes to the area by modelling the heteroscedastic structure and estimating it from the data, together with estimating the quantile functions. The use of the proposed methods is illustrated on real-data applications. The finite-sample behaviour of the methods is investigated via a simulation study, which includes a comparison with an existing method.     

Bivariate modelling of longitudinal measurements of two human immunodeficiency type 1 disease progression markers in the presence of informative drop-outs

Summary.  The main statistical problem in many epidemiological studies which involve repeated measurements of surrogate markers is the frequent occurrence of missing data. Standard likelihood-based approaches like the linear random-effects model fail to give unbiased estimates when data are non-ignorably missing. In human immunodeficiency virus (HIV) type 1 infection, two markers which have been widely used to track progression of the disease are CD4 cell counts and HIV–ribonucleic acid (RNA) viral load levels. Repeated measurements of these markers tend to be informatively censored, which is a special case of non-ignorable missingness. In such cases, we need to apply methods that jointly model the observed data and the missingness process. Despite their high correlation, longitudinal data of these markers have been analysed independently by using mainly random-effects models. Touloumi and co-workers have proposed a model termed the joint multivariate random-effects model which combines a linear random-effects model for the underlying pattern of the marker with a log-normal survival model for the drop-out process. We extend the joint multivariate random-effects model to model simultaneously the CD4 cell and viral load data while adjusting for informative drop-outs due to disease progression or death. Estimates of all the model's parameters are obtained by using the restricted iterative generalized least squares method or a modified version of it using the EM algorithm as a nested algorithm in the case of censored survival data taking also into account non-linearity in the HIV–RNA trend. The method proposed is evaluated and compared with simpler approaches in a simulation study. Finally the method is applied to a subset of the data from the 'Concerted action on seroconversion to AIDS and death in Europe' study.     

Semiparametric analysis of panel count data with correlated observation and follow-up times

This paper discusses regression analysis of panel count data that often arise in longitudinal studies concerning occurrence rates of certain recurrent events. Panel count data mean that each study subject is observed only at discrete time points rather than under continuous observation. Furthermore, both observation and follow-up times can vary from subject to subject and may be correlated with the recurrent events. For inference, we propose some shared frailty models and estimating equations are developed for estimation of regression parameters. The proposed estimates are consistent and have asymptotically a normal distribution. The finite sample properties of the proposed estimates are investigated through simulation and an illustrative example from a cancer study is provided.     

Empirical likelihood for quantile regression models with longitudinal data

We develop two empirical likelihood-based inference procedures for longitudinal data under the framework of quantile regression. The proposed methods avoid estimating the unknown error density function and the intra-subject correlation involved in the asymptotic covariance matrix of the quantile estimators. By appropriately smoothing the quantile score function, the empirical likelihood approach is shown to have a higher-order accuracy through the Bartlett correction. The proposed methods exhibit finite-sample advantages over the normal approximation-based and bootstrap methods in a simulation study and the analysis of a longitudinal ophthalmology data set.     

A protective estimator for longitudinal binary data subject to non-ignorable non-monotone missingness

Summary.  In longitudinal studies missing data are the rule not the exception. We consider the analysis of longitudinal binary data with non-monotone missingness that is thought to be non-ignorable. In this setting a full likelihood approach is complicated algebraically and can be computationally prohibitive when there are many measurement occasions. We propose a 'protective' estimator that assumes that the probability that a response is missing at any occasion depends, in a completely unspecified way, on the value of that variable alone. Relying on this 'protectiveness' assumption, we describe a pseudolikelihood estimator of the regression parameters under non-ignorable missingness, without having to model the missing data mechanism directly. The method proposed is applied to CD4 cell count data from two longitudinal clinical trials of patients infected with the human immunodeficiency virus.     

Random coefficient models for binary longitudinal responses with attrition

We extend the approach introduced by Aitkin and Alfò (1998, Statistics and Computing, 4, pp. 289–307) to the general framework of random coefficient models and propose a class of conditional models to deal with binary longitudinal responses, including unknown sources of heterogeneity in the regression parameters as well as serial dependence of Markovian form.Furthermore, we discuss the extension of the proposed approach to the analysis of informative drop-outs, which represent a central problem in longitudinal studies, and define, as suggested by Follmann and Wu (1995, Biometrics, 51, pp. 151–168), a conditional specification of the full shared parameter model for the primary response and the missingness indicator. The model is applied to a dataset from a methadone maintenance treatment programme held in Sydney in 1986 and previously analysed by Chan et al. (1998, Australian & New Zealand Journal of Statistics, 40, pp. 1–10).All of the proposed models are estimated by means of an EM algorithm for nonparametric maximum likelihood, without assuming any specific parametric distribution for the random coefficients and for the drop-out process.A small scale simulation work is described to explore the behaviour of the extended approach in a number of different situations where informative drop-outs are present.     

A new look at the difference between the GEE and the GLMM when modeling longitudinal count responses

Poisson log-linear regression is a popular model for count responses. We examine two popular extensions of this model – the generalized estimating equations (GEE) and the generalized linear mixed-effects model (GLMM) – to longitudinal data analysis and complement the existing literature on characterizing the relationship between the two dueling paradigms in this setting. Unlike linear regression, the GEE and the GLMM carry significant conceptual and practical implications when applied to modeling count data. Our findings shed additional light on the differences between the two classes of models when used for count data. Our considerations are demonstrated by both real study and simulated data.     

Expected estimating equations to accommodate covariate measurement error

Estimating equations which are not necessarily likelihood-based score equations are becoming increasingly popular for estimating regression model parameters. This paper is concerned with estimation based on general estimating equations when true covariate data are missing for all the study subjects, but surrogate or mismeasured covariates are available instead. The method is motivated by the covariate measurement error problem in marginal or partly conditional regression of longitudinal data. We propose to base estimation on the expectation of the complete data estimating equation conditioned on available data. The regression parameters and other nuisance parameters are estimated simultaneously by solving the resulting estimating equations. The expected estimating equation (EEE) estimator is equal to the maximum likelihood estimator if the complete data scores are likelihood scores and conditioning is with respect to all the available data. A pseudo-EEE estimator, which requires less computation, is also investigated. Asymptotic distribution theory is derived. Small sample simulations are conducted when the error process is an order 1 autoregressive model. Regression calibration is extended to this setting and compared with the EEE approach. We demonstrate the methods on data from a longitudinal study of the relationship between childhood growth and adult obesity.     

Quantile regression in longitudinal studies with dropouts and measurement errors

ABSTRACT

Quantile regression models, as an important tool in practice, can describe effects of risk factors on the entire conditional distribution of the response variable with its estimates robust to outliers. However, there is few discussion on quantile regression for longitudinal data with both missing responses and measurement errors, which are commonly seen in practice. We develop a weighted and bias-corrected quantile loss function for the quantile regression with longitudinal data, which allows both missingness and measurement errors. Additionally, we establish the asymptotic properties of the proposed estimator. Simulation studies demonstrate the expected performance in correcting the bias resulted from missingness and measurement errors. Finally, we investigate the Lifestyle Education for Activity and Nutrition study and confirm the effective of intervention in producing weight loss after nine month at the high quantile.     

Quantile regression for longitudinal data based on latent Markov subject-specific parameters

We propose a latent Markov quantile regression model for longitudinal data with non-informative drop-out. The observations, conditionally on covariates, are modeled through an asymmetric Laplace distribution. Random effects are assumed to be time-varying and to follow a first order latent Markov chain. This latter assumption is easily interpretable and allows exact inference through an ad hoc EM-type algorithm based on appropriate recursions. Finally, we illustrate the model on a benchmark data set.     

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.     

Robust testing with generalized partial linear models for longitudinal data

By approximating the nonparametric component using a regression spline in generalized partial linear models (GPLM), robust generalized estimating equations (GEE), involving bounded score function and leverage-based weighting function, can be used to estimate the regression parameters in GPLM robustly for longitudinal data or clustered data. In this paper, score test statistics are proposed for testing the regression parameters with robustness, and their asymptotic distributions under the null hypothesis and a class of local alternative hypotheses are studied. The proposed score tests reply on the estimation of a smaller model without the testing parameters involved, and perform well in the simulation studies and real data analysis conducted in this paper.     

Longitudinal perspectives on event history analysis

We discuss event histories from the point of view of longitudinal data analysis, comparing several possible inferential objectives. We show that the Nelson–Aalen estimate of a cumulative intensity may be derived as a limiting solution to a sequence of generalized estimating equations for intermittently observed longitudinal count data. We outline a potential use for the theory in interval-censored recurrent-event models, and demonstrate its applicability using data from a Toronto arthritis clinic. We also discuss connections with rate models, along with some implications for the longitudinal analyst.     

Robust estimation of covariance parameters in partial linear model for longitudinal data

For longitudinal data, the within-subject dependence structure and covariance parameters may be of practical and theoretical interests. The estimation of covariance parameters has received much attention and been studied mainly in the framework of generalized estimating equations (GEEs). The GEEs method, however, is sensitive to outliers. In this paper, an alternative set of robust generalized estimating equations for both the mean and covariance parameters are proposed in the partial linear model for longitudinal data. The asymptotic properties of the proposed estimators of regression parameters, non-parametric function and covariance parameters are obtained. Simulation studies are conducted to evaluate the performance of the proposed estimators under different contaminations. The proposed method is illustrated with a real data analysis.     

On the assessment of various factors effecting the improvement in CD4 count of aids patients undergoing antiretroviral therapy using generalized Poisson regression

An important marker for identifying the progression of human immunodeficiency virus (HIV) infection in an individual is the CD4 cell count. Antiretroviral therapy (ART) is a treatment for HIV/AIDS (AIDS, acquired immune-deficiency syndrome) which prolongs and improves the lives of patients by improving the CD4 cell count and strengthen the immune system. This strengthening of the immune system in terms of CD4 count, not only depends on various biological factors, but also other behavioral factors. Previous studies have shown the effect of CD4 count on the mortality, but nobody has attempted to study the factors which are likely to influence the improvement in CD4 count of patients diagnosed of AIDS and undergoing ART. In this paper, we use Poisson regression model (GPR) for exploring the effect of various socio-demographic covariates such as age, gender, geographical location, and drug usage on the improvement in the CD4 count of AIDS patients. However, if the CD4 count data suffers from under or overdispersion, we use GPR model and compare it with negative binomial distribution. Finally, the model is applied for the analysis of data on patients undergoing the ART in the Ram Manohar Lohia Hospital, Delhi, India. The data exhibited overdispersion and hence, GPR model provided the best fit.     

Bayesian quantile regression for ordinal longitudinal data

Since the pioneering work by Koenker and Bassett [27], quantile regression models and its applications have become increasingly popular and important for research in many areas. In this paper, a random effects ordinal quantile regression model is proposed for analysis of longitudinal data with ordinal outcome of interest. An efficient Gibbs sampling algorithm was derived for fitting the model to the data based on a location-scale mixture representation of the skewed double-exponential distribution. The proposed approach is illustrated using simulated data and a real data example. This is the first work to discuss quantile regression for analysis of longitudinal data with ordinal outcome.     

Joint Mean-Covariance Models with Applications to Longitudinal Data in Partially Linear Model

Semiparametric regression models and estimating covariance functions are very useful in longitudinal study. Unfortunately, challenges arise in estimating the covariance function of longitudinal data collected at irregular time points. In this article, for mean term, a partially linear model is introduced and for covariance structure, a modified Cholesky decomposition approach is proposed to heed the positive-definiteness constraint. We estimate the regression function by using the local linear technique and propose quasi-likelihood estimating equations for both the mean and covariance structures. Moreover, asymptotic normality of the resulting estimators is established. Finally, simulation study and real data analysis are used to illustrate the proposed approach.     

Estimation and variable selection in single-index composite quantile regression

In this article, a new composite quantile regression estimation approach is proposed for estimating the parametric part of single-index model. We use local linear composite quantile regression (CQR) for estimating the nonparametric part of single-index model (SIM) when the error distribution is symmetrical. The weighted local linear CQR is proposed for estimating the nonparametric part of SIM when the error distribution is asymmetrical. Moreover, a new variable selection procedure is proposed for SIM. Under some regularity conditions, we establish the large sample properties of the proposed estimators. Simulation studies and a real data analysis are presented to illustrate the behavior of the proposed estimators.