Influence of human immunodeficiency virus infection on neurological impairment: an analysis of longitudinal binary data with informative drop-out

A study to investigate the human immunodeficiency virus (HIV) status on the course of neurological impairment, conducted by the HIV Center at Columbia University, followed a cohort of HIV positive and negative gay men for 5 years and assessed the presence or absence of neurological impairment every 6 months. Almost half of the subjects dropped out before the end of the study for reasons that might have been related to the missing neurological data. We propose likelihood-based methods for analysing such binary longitudinal data under informative and non-informative drop-out. A transition model is assumed for the binary response, and several models for the drop-out processes are considered which are functions of the response variable (neurological impairment). The likelihood ratio test is used to compare models with informative and non-informative drop-out mechanisms. Using simulations, we investigate the percentage bias and mean-squared error (MSE) of the parameter estimates in the transition model under various assumptions for the drop-out. We find evidence for informative drop-out in the study, and we illustrate that the bias and MSE for the parameters of the transition model are not directly related to the observed drop-out or missing data rates. The effect of HIV status on the neurological impairment is found to be statistically significant under each of the models considered for the drop-out, although the regression coefficient may be biased in certain cases. The presence and relative magnitude of the bias depend on factors such as the probability of drop-out conditional on the presence of neurological impairment and the prevalence of neurological impairment in the population under study.     

A hierarchical modelling approach to analysing longitudinal data with drop-out and non-compliance, with application to an equivalence trial in paediatric acquired immune deficiency syndrome

Longitudinal clinical trials with long follow-up periods almost invariably suffer from a loss to follow-up and non-compliance with the assigned therapy. An example is protocol 128 of the AIDS Clinical Trials Group, a 5-year equivalency trial comparing reduced dose zidovudine with the standard dose for treatment of paediatric acquired immune deficiency syndrome patients. This study compared responses to treatment by using both clinical and cognitive outcomes. The cognitive outcomes are of particular interest because the effects of human immunodeficiency virus infection of the central nervous system can be more acute in children than in adults. We formulate and apply a Bayesian hierarchical model to estimate both the intent-to-treat effect and the average causal effect of reducing the prescribed dose of zidovudine by 50%. The intent-to-treat effect quantifies the causal effect of assigning the lower dose, whereas the average causal effect represents the causal effect of actually taking the lower dose. We adopt a potential outcomes framework where, for each individual, we assume the existence of a different potential outcomes process at each level of time spent on treatment. The joint distribution of the potential outcomes and the time spent on assigned treatment is formulated using a hierarchical model: the potential outcomes distribution is given at the first level, and dependence between the outcomes and time on treatment is specified at the second level by linking the time on treatment to subject-specific effects that characterize the potential outcomes processes. Several distributional and structural assumptions are used to identify the model from observed data, and these are described in detail. A detailed analysis of AIDS Clinical Trials Group protocol 128 is given; inference about both the intent-to-treat effect and average causal effect indicate a high probability of dose equivalence with respect to cognitive functioning.     

A cautionary note on generalized linear models for covariance of unbalanced longitudinal data

Missing data in longitudinal studies can create enormous challenges in data analysis when coupled with the positive-definiteness constraint on a covariance matrix. For complete balanced data, the Cholesky decomposition of a covariance matrix makes it possible to remove the positive-definiteness constraint and use a generalized linear model setup to jointly model the mean and covariance using covariates (Pourahmadi, 2000). However, this approach may not be directly applicable when the longitudinal data are unbalanced, as coherent regression models for the dependence across all times and subjects may not exist. Within the existing generalized linear model framework, we show how to overcome this and other challenges by embedding the covariance matrix of the observed data for each subject in a larger covariance matrix and employing the familiar EM algorithm to compute the maximum likelihood estimates of the parameters and their standard errors. We illustrate and assess the methodology using real data sets and simulations.     

Analysis of censored longitudinal data with skewness and a terminal event

In HIV/AIDS study, the measurements viral load are often highly skewed and left-censored because of a lower detection limit. Furthermore, a terminal event (e.g., death) stops the follow-up process. The time to terminal event may be dependent on the viral load measurements. In this article, we present a joint analysis framework to model the censored longitudinal data with skewness and a terminal event process. The estimation is carried out by adaptive Gaussian quadrature techniques in SAS procedure NLMIXED. The proposed model is evaluated by a simulation study and is applied to the motivating Multicenter AIDS Cohort Study (MACS).     

A joint model for longitudinal data profiles and associated event risks with application to a depression study

Summary.  In many longitudinal studies, a subject's response profile is closely associated with his or her risk of experiencing a related event. Examples of such event risks include recurrence of disease, relapse, drop-out and non-compliance. When evaluating the effect of a treatment, it is sometimes of interest to consider the joint process consisting of both the response and the risk of an associated event. Motivated by a prevention of depression study among patients with malignant melanoma, we examine a joint model that incorporates the risk of discontinuation into the analysis of serial depression measures. We present a maximum likelihood estimator for the mean response and event risk vectors. We test hypotheses about functions of mean depression and withdrawal risk profiles from our joint model, predict depression from updated patient histories, characterize associations between components of the joint process and estimate the probability that a patient's depression and risk of withdrawal exceed specified levels. We illustrate the application of our joint model by using the depression data.     

Semiparametric statistical inferences for longitudinal data with nonparametric covariance modelling

In this paper, semiparametric modelling for longitudinal data with an unstructured error process is considered. We propose a partially linear additive regression model for longitudinal data in which within-subject variances and covariances of the error process are described by unknown univariate and bivariate functions, respectively. We provide an estimating approach in which polynomial splines are used to approximate the additive nonparametric components and the within-subject variance and covariance functions are estimated nonparametrically. Both the asymptotic normality of the resulting parametric component estimators and optimal convergence rate of the resulting nonparametric component estimators are established. In addition, we develop a variable selection procedure to identify significant parametric and nonparametric components simultaneously. We show that the proposed SCAD penalty-based estimators of non-zero components have an oracle property. Some simulation studies are conducted to examine the finite-sample performance of the proposed estimation and variable selection procedures. A real data set is also analysed to demonstrate the usefulness of the proposed method.     

Empirical likelihood for parameters in an additive partially linear errors-in-variables model with longitudinal data

Empirical likelihood inferences for the parameter component in an additive partially linear errors-in-variables model with longitudinal data are investigated in this article. A corrected-attenuation block empirical likelihood procedure is used to estimate the regression coefficients, a corrected-attenuation block empirical log-likelihood ratio statistic is suggested and its asymptotic distribution is obtained. Compared with the method based on normal approximations, our proposed method does not require any consistent estimator for the asymptotic variance and bias. Simulation studies indicate that our proposed method performs better than the method based on normal approximations in terms of relatively higher coverage probabilities and smaller confidence regions. Furthermore, an example of an air pollution and health data set is used to illustrate the performance of the proposed method.     

Marginal methods for clustered longitudinal binary data with incomplete covariates

Many analyses for incomplete longitudinal data are directed to examining the impact of covariates on the marginal mean responses. We consider the setting in which longitudinal responses are collected from individuals nested within clusters. We discuss methods for assessing covariate effects on the mean and association parameters when covariates are incompletely observed. Weighted first and second order estimating equations are constructed to obtain consistent estimates of mean and association parameters when covariates are missing at random. Empirical studies demonstrate that estimators from the proposed method have negligible finite sample biases in moderate samples. An application to the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) demonstrates the utility of the proposed method.     

Analysis of longitudinal data using a finite mixture model

This paper considers a finite mixture model for longitudinal data, which can be used to study the dependency of the shape of the respective follow-up curves on treatments or other influential factors and to classify these curves. An EM-algorithm to achieve the ml-estimate of the model is given. The potencies of the model are demonstrated using data of a clinical trial.     

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.     

Generalized empirical likelihood inference in partially linear model for longitudinal data with missing response variables and error-prone covariates

In this article, we consider statistical inference for longitudinal partial linear models when the response variable is sometimes missing with missingness probability depending on the covariate that is measured with error. A generalized empirical likelihood (GEL) method is proposed by combining correction attenuation and quadratic inference functions. The method that takes into consideration the correlation within groups is used to estimate the regression coefficients. Furthermore, residual-adjusted empirical likelihood (EL) is employed for estimating the baseline function so that undersmoothing is avoided. The empirical log-likelihood ratios are proven to be asymptotically Chi-squared, and the corresponding confidence regions for the parameters of interest are then constructed. Compared with methods based on NAs, the GEL does not require consistent estimators for the asymptotic variance and bias. The numerical study is conducted to compare the performance of the EL and the normal approximation-based method, and a real example is analysed.     

Non parametric space-time modeling of SO2 in presence of many missing data

Given pollution measurement from a network of monitoring sites in the area of a city and over an extended period of time, an important problem is to identify the spatial and temporal structure of the data. In this paper we focus on the identification and estimate of a statistical non parametric model to analyse the SO₂ in the city of Padua, where data are collected by some fixed stations and some mobile stations moving without any specific rule in different new locations. The impact of the use of mobile stations is that for each location there are times when data was not collected. Assuming temporal stationarity and spatial isotropy for the residuals of an additive model for the logarithm of SO₂ concentration, we estimate the semivariogram using a kernel-type estimator. Attempts are made to avoid the assumption of spatial isotropy. Bootstrap confidence bands are obtained for the spatial component of the additive model that is a deterministic function which defines the spatial structure. Finally, an example is proposed to design an optimal network for the mobiles monitoring stations in a fixed future time, given all the information available.     

Penalized spline joint models for longitudinal and time-to-event data

The joint models for longitudinal data and time-to-event data have recently received numerous attention in clinical and epidemiologic studies. Our interest is in modeling the relationship between event time outcomes and internal time-dependent covariates. In practice, the longitudinal responses often show non linear and fluctuated curves. Therefore, the main aim of this paper is to use penalized splines with a truncated polynomial basis to parameterize the non linear longitudinal process. Then, the linear mixed-effects model is applied to subject-specific curves and to control the smoothing. The association between the dropout process and longitudinal outcomes is modeled through a proportional hazard model. Two types of baseline risk functions are considered, namely a Gompertz distribution and a piecewise constant model. The resulting models are referred to as penalized spline joint models; an extension of the standard joint models. The expectation conditional maximization (ECM) algorithm is applied to estimate the parameters in the proposed models. To validate the proposed algorithm, extensive simulation studies were implemented followed by a case study. In summary, the penalized spline joint models provide a new approach for joint models that have improved the existing standard joint models.     

A Bayesian hierarchical model for categorical longitudinal data from a social survey of immigrants

Summary.  The paper investigates a Bayesian hierarchical model for the analysis of categorical longitudinal data from a large social survey of immigrants to Australia. Data for each subject are observed on three separate occasions, or waves, of the survey. One of the features of the data set is that observations for some variables are missing for at least one wave. A model for the employment status of immigrants is developed by introducing, at the first stage of a hierarchical model, a multinomial model for the response and then subsequent terms are introduced to explain wave and subject effects. To estimate the model, we use the Gibbs sampler, which allows missing data for both the response and the explanatory variables to be imputed at each iteration of the algorithm, given some appropriate prior distributions. After accounting for significant covariate effects in the model, results show that the relative probability of remaining unemployed diminished with time following arrival in Australia.     

A pseudo likelihood approach to analyze rate difference of binary response data in longitudinal factorial studies

Although Fan showed that the mixed-effects model for repeated measures (MMRM) is appropriate to analyze complete longitudinal binary data in terms of the rate difference, they focused on using the generalized estimating equations (GEE) to make statistical inference. The current article emphasizes validity of the MMRM when the normal-distribution-based pseudo likelihood approach is used to make inference for complete longitudinal binary data. For incomplete longitudinal binary data with missing at random missing mechanism, however, the MMRM, using either the GEE or the normal-distribution-based pseudo likelihood inferential procedure, gives biased results in general and should not be used for analysis.     

Analysis of longitudinal data with irregular, outcome-dependent follow-up

Summary.  A frequent problem in longitudinal studies is that subjects may miss scheduled visits or be assessed at self-selected points in time. As a result, observed outcome data may be highly unbalanced and the availability of the data may be directly related to the outcome measure and/or some auxiliary factors that are associated with the outcome. If the follow-up visit and outcome processes are correlated, then marginal regression analyses will produce biased estimates. Building on the work of Robins, Rotnitzky and Zhao, we propose a class of inverse intensity-of-visit process-weighted estimators in marginal regression models for longitudinal responses that may be observed in continuous time. This allows us to handle arbitrary patterns of missing data as embedded in a subject's visit process. We derive the large sample distribution for our inverse visit-intensity-weighted estimators and investigate their finite sample behaviour by simulation. Our approach is illustrated with a data set from a health services research study in which homeless people with mental illness were randomized to three different treatments and measures of homelessness (as percentage days homeless in the past 3 months) and other auxiliary factors were recorded at follow-up times that are not fixed by design.     

Handling drop-out in longitudinal clinical trials: a comparison of the LOCF and MMRM approaches

This study compares two methods for handling missing data in longitudinal trials: one using the last-observation-carried-forward (LOCF) method and one based on a multivariate or mixed model for repeated measurements (MMRM). Using data sets simulated to match six actual trials, I imposed several drop-out mechanisms, and compared the methods in terms of bias in the treatment difference and power of the treatment comparison. With equal drop-out in Active and Placebo arms, LOCF generally underestimated the treatment effect; but with unequal drop-out, bias could be much larger and in either direction. In contrast, bias with the MMRM method was much smaller; and whereas MMRM rarely caused a difference in power of greater than 20%, LOCF caused a difference in power of greater than 20% in nearly half the simulations. Use of the LOCF method is therefore likely to misrepresent the results of a trial seriously, and so is not a good choice for primary analysis. In contrast, the MMRM method is unlikely to result in serious misinterpretation, unless the drop-out mechanism is missing not at random (MNAR) and there is substantially unequal drop-out. Moreover, MMRM is clearly more reliable and better grounded statistically. Neither method is capable of dealing on its own with trials involving MNAR drop-out mechanisms, for which sensitivity analysis is needed using more complex methods.     

A practical extension of the generalized estimating equation approach for longitudinal data

Liang and Zeger (1986) proposed an extension of generalized linear models to the analysis of longitudinal data. In their formulation, a common dispersion parameter assumption across observation times is required. However, this assumption is not expected to hold in most situations. Park (1993) proposed a simple extension of Liang and Zeger's formulation to allow for different dispersion parameters for each time point. The proposed model is easy to apply without heavy computations and useful to handle the cases when variations in over-dispersion over time exist. In this paper, we focus on evaluating the effect of additional dispersion parameters on the estimators of model parameters. Through a Monte Carlo simulation study, efficiency of Park's method is compared with the Liang and Zeger's method.     

Bayesian methods for dealing with missing data problems

Missing data, a common but challenging issue in most studies, may lead to biased and inefficient inferences if handled inappropriately. As a natural and powerful way for dealing with missing data, Bayesian approach has received much attention in the literature. This paper reviews the recent developments and applications of Bayesian methods for dealing with ignorable and non-ignorable missing data. We firstly introduce missing data mechanisms and Bayesian framework for dealing with missing data, and then introduce missing data models under ignorable and non-ignorable missing data circumstances based on the literature. After that, important issues of Bayesian inference, including prior construction, posterior computation, model comparison and sensitivity analysis, are discussed. Finally, several future issues that deserve further research are summarized and concluded.     

Model checks for nonparametric regression with missing data: a comparative study

ABSTRACT

This paper analyses the behaviour of the goodness-of-fit tests for regression models. To this end, it uses statistics based on an estimation of the integrated regression function with missing observations either in the response variable or in some of the covariates. It proposes several versions of one empirical process, constructed from a previous estimation, that uses only the complete observations or replaces the missing observations with imputed values. In the case of missing covariates, a link model is used to fill the missing observations with other complete covariates. In all the situations, Bootstrap methodology is used to calibrate the distribution of the test statistics. A broad simulation study compares the different procedures based on empirical regression methodology, with smoothed tests previously studied in the literature. The comparison reflects the effect of the correlation between the covariates in the tests based on the imputed sample for missing covariates. In addition, the paper proposes a computational binning strategy to evaluate the tests based on an empirical process for large data sets. Finally, two applications to real data illustrate the performance of the tests.