Modeling Longitudinal Obesity Data with Intermittent Missingness Using a New Latent Variable Model

We propose a latent variable model for informative missingness in longitudinal studies which is an extension of latent dropout class model. In our model, the value of the latent variable is affected by the missingness pattern and it is also used as a covariate in modeling the longitudinal response. So the latent variable links the longitudinal response and the missingness process. In our model, the latent variable is continuous instead of categorical and we assume that it is from a normal distribution. The EM algorithm is used to obtain the estimates of the parameter we are interested in and Gauss–Hermite quadrature is used to approximate the integration of the latent variable. The standard errors of the parameter estimates can be obtained from the bootstrap method or from the inverse of the Fisher information matrix of the final marginal likelihood. Comparisons are made to the mixed model and complete-case analysis in terms of a clinical trial dataset, which is Weight Gain Prevention among Women (WGPW) study. We use the generalized Pearson residuals to assess the fit of the proposed latent variable model.     

A nonlinear mixed-effects model for multivariate longitudinal data with partially observed outcomes with application to HIV disease dynamics

The measurable multiple bio-markers for a disease are used as indicators for studying the response variable of interest in order to monitor and model disease progression. However, it is common for subjects to drop out of the studies prematurely resulting in unbalanced data and hence complicating the inferences involving such data. In this paper we consider a case where data are unbalanced among subjects and also within a subject because for some reason only a subset of the multiple outcomes of the response variable are observed at any one occasion. We propose a nonlinear mixed-effects model for the multivariate response variable data and derive a joint likelihood function that takes into account the partial dropout of the outcomes of the response variable. We further show how the methodology can be used in the estimation of the parameters that characterise HIV disease dynamics. An approximation technique of the parameters is also given and illustrated using a routine observational HIV dataset.     

An Appraisal of Methods for the Analysis of Longitudinal Ordinal Response Data with Random Dropout Using a Nonhomogeneous Markov Model

There are many methods for analyzing longitudinal ordinal response data with random dropout. These include maximum likelihood (ML), weighted estimating equations (WEEs), and multiple imputations (MI). In this article, using a Markov model where the effect of previous response on the current response is investigated as an ordinal variable, the likelihood is partitioned to simplify the use of existing software. Simulated data, generated to present a three-period longitudinal study with random dropout, are used to compare performance of ML, WEE, and MI methods in terms of standardized bias and coverage probabilities. These estimation methods are applied to a real medical data set.     

Segmental modeling of changing immunologic response for CD4 data with skewness,missingness and dropout

In clinical practice, the profile of each subject's CD4 response from a longitudinal study may follow a ‘broken stick’ like trajectory, indicating multiple phases of increase and/or decline in response. Such multiple phases (changepoints) may be important indicators to help quantify treatment effect and improve management of patient care. Although it is a common practice to analyze complex AIDS longitudinal data using nonlinear mixed-effects (NLME) or nonparametric mixed-effects (NPME) models in the literature, NLME or NPME models become a challenge to estimate changepoint due to complicated structures of model formulations. In this paper, we propose a changepoint mixed-effects model with random subject-specific parameters, including the changepoint for the analysis of longitudinal CD4 cell counts for HIV infected subjects following highly active antiretroviral treatment. The longitudinal CD4 data in this study may exhibit departures from symmetry, may encounter missing observations due to various reasons, which are likely to be non-ignorable in the sense that missingness may be related to the missing values, and may be censored at the time of the subject going off study-treatment, which is a potentially informative dropout mechanism. Inferential procedures can be complicated dramatically when longitudinal CD4 data with asymmetry (skewness), incompleteness and informative dropout are observed in conjunction with an unknown changepoint. Our objective is to address the simultaneous impact of skewness, missingness and informative censoring by jointly modeling the CD4 response and dropout time processes under a Bayesian framework. The method is illustrated using a real AIDS data set to compare potential models with various scenarios, and some interested results are presented.     

Bias from the use of generalized estimating equations to analyze incomplete longitudinal binary data

Patient dropout is a common problem in studies that collect repeated binary measurements. Generalized estimating equations (GEE) are often used to analyze such data. The dropout mechanism may be plausibly missing at random (MAR), i.e. unrelated to future measurements given covariates and past measurements. In this case, various authors have recommended weighted GEE with weights based on an assumed dropout model, or an imputation approach, or a doubly robust approach based on weighting and imputation. These approaches provide asymptotically unbiased inference, provided the dropout or imputation model (as appropriate) is correctly specified. Other authors have suggested that, provided the working correlation structure is correctly specified, GEE using an improved estimator of the correlation parameters (‘modified GEE’) show minimal bias. These modified GEE have not been thoroughly examined. In this paper, we study the asymptotic bias under MAR dropout of these modified GEE, the standard GEE, and also GEE using the true correlation. We demonstrate that all three methods are biased in general. The modified GEE may be preferred to the standard GEE and are subject to only minimal bias in many MAR scenarios but in others are substantially biased. Hence, we recommend the modified GEE be used with caution.     

Dealing with selective dropout in clinical trials

Clinical trials in severely diseased populations often suffer from a high dropout rate that is related to the investigated target morbidity. These dropouts can bias estimates and treatment comparisons, particularly in the event of an imbalance. Methods to describe such selective dropout are presented that use the time in study distribution to generate so‐called population evolution charts. These charts show the development of a distribution of a covariate or the target morbidity measure as it changes as a result of the dropout process during the follow‐up time. The selectiveness of the dropout process with respect to a variable can be inferred from the change in its distribution. Different types of selective dropout are described with real data from several studies in metastatic bone disease, where marked effects can be seen. A general strategy to cope with selective dropout seems to be the inclusion of dropout events into the endpoint. Within a time‐to‐event analysis framework this simple approach can lead to valid conclusions and still retains conservative elements. Morbidity measures that are based on (recurrent) event counts react differently in the presence of selective dropout. They differ mainly in the way dropout is included. One simple measure achieves good performance under selective dropout by introducing a non‐specific penalty for premature study termination. The use of a prespecified scoring system to assign a weight for each works well. This simple and transparent approach performs well even in the presence of unbalanced selective dropout. Copyright © 2002 John Wiley & Sons, Ltd.     

Marginal and Conditional Distribution Estimation from Double‐sampled Semi‐competing Risks Data

Informative dropout is a vexing problem for any biomedical study. Most existing statistical methods attempt to correct estimation bias related to this phenomenon by specifying unverifiable assumptions about the dropout mechanism. We consider a cohort study in Africa that uses an outreach programme to ascertain the vital status for dropout subjects. These data can be used to identify a number of relevant distributions. However, as only a subset of dropout subjects were followed, vital status ascertainment was incomplete. We use semi‐competing risk methods as our analysis framework to address this specific case where the terminal event is incompletely ascertained and consider various procedures for estimating the marginal distribution of dropout and the marginal and conditional distributions of survival. We also consider model selection and estimation efficiency in our setting. Performance of the proposed methods is demonstrated via simulations, asymptotic study and analysis of the study data.     

Estimating low pay transition probabilities accounting for endogenous selection mechanisms

Summary.  We propose a model of transitions into and out of low paid employment that accounts for non-ignorable panel dropout, employment retention and base year low pay status ('initial conditions'). The model is fitted to data for men from the British Household Panel Survey. Initial conditions and employment retention are found to be non-ignorable selection processes. Whether panel dropout is found to be ignorable depends on how item non-response on pay is treated. Notwithstanding these results, we also find that models incorporating a simpler approach to accounting for non-ignorable selections provide estimates of covariate effects that differ very little from the estimates from the general model.     

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.     

Testing for qualitative interaction of multiple sources of informative dropout in longitudinal data

Longitudinal studies suffer from patient dropout. The dropout process may be informative if there exists an association between dropout patterns and the rate of change in the response over time. Multiple patterns are plausible in that different causes of dropout might contribute to different patterns. These multiple patterns can be dichotomized into two groups: quantitative and qualitative interaction. Quantitative interaction indicates that each of the multiple sources is biasing the estimate of the rate of change in the same direction, although with differing magnitudes. Alternatively, qualitative interaction results in the multiple sources biasing the estimate of the rate of change in opposing directions. Qualitative interaction is of special concern, since it is less likely to be detected by conventional methods and can lead to highly misleading slope estimates. We explore a test for qualitative interaction based on simultaneous confidence intervals. The test accommodates the realistic situation where reasons for dropout are not fully understood, or even entirely unknown. It allows for an additional level of clustering among participating subjects. We apply these methods to a study exploring tumor growth rates in mice as well as a longitudinal study exploring rates of change in cognitive functioning for Alzheimer's patients.     

A joint model for incomplete data in crossover trials

Crossover designs are popular in early phases of clinical trials and in bioavailability and bioequivalence studies. Assessment of carryover effects, in addition to the treatment effects, is a critical issue in crossover trails. The observed data from a crossover trial can be incomplete because of potential dropouts. A joint model for analyzing incomplete data from crossover trials is proposed in this article; the model includes a measurement model and an outcome dependent informative model for the dropout process. The informative-dropout model is compared with the ignorable-dropout model as specific cases of the latter are nested subcases of the proposed joint model. Markov chain sampling methods are used for Bayesian analysis of this model. The joint model is used to analyze depression score data from a clinical trial in women with late luteal phase dysphoric disorder. Interestingly, carryover effect is found to have a strong effect in the informative dropout model, but it is less significant when dropout is considered ignorable.     

Generalized linear mixed joint model for longitudinal and survival outcomes

Longitudinal studies often entail categorical outcomes as primary responses. When dropout occurs, non-ignorability is frequently accounted for through shared parameter models (SPMs). In this context, several extensions from Gaussian to non-Gaussian longitudinal processes have been proposed. In this paper, we formulate an approach for non-Gaussian longitudinal outcomes in the framework of joint models. As an extension of SPMs, based on shared latent effects, we assume that the history of the response up to current time may have an influence on the risk of dropout. This history is represented by the current, expected, value of the response. Since the time a subject spends in the study is continuous, we parametrize the dropout process through a proportional hazard model. The resulting model is referred to as Generalized Linear Mixed Joint Model (GLMJM). To estimate model parameters, we adopt a maximum likelihood approach via the EM algorithm. In this context, the maximization of the observed data log-likelihood requires numerical integration over the random effect posterior distribution, which is usually not straightforward; under the assumption of Gaussian random effects, we compare Gauss-Hermite and Pseudo-Adaptive Gaussian quadrature rules. We investigate in a simulation study the behaviour of parameter estimates in the case of Poisson and Binomial longitudinal responses, and apply the GLMJM to a benchmark dataset.     

Joint Modeling of Event Time and Nonignorable Missing Longitudinal Data

Survival studies usually collect on each participant, both duration until some terminal event and repeated measures of a time-dependent covariate. Such a covariate is referred to as an internal time-dependent covariate. Usually, some subjects drop out of the study before occurence of the terminal event of interest. One may then wish to evaluate the relationship between time to dropout and the internal covariate. The Cox model is a standard framework for that purpose. Here, we address this problem in situations where the value of the covariate at dropout is unobserved. We suggest a joint model which combines a first-order Markov model for the longitudinaly measured covariate with a time-dependent Cox model for the dropout process. We consider maximum likelihood estimation in this model and show how estimation can be carried out via the EM-algorithm. We state that the suggested joint model may have applications in the context of longitudinal data with nonignorable dropout. Indeed, it can be viewed as generalizing Diggle and Kenward's model (1994) to situations where dropout may occur at any point in time and may be censored. Hence we apply both models and compare their results on a data set concerning longitudinal measurements among patients in a cancer clinical trial.     

Bias in the last observation carried forward method under informative dropout

Subject dropout is an inevitable problem in longitudinal studies. It makes the analysis challenging when the main interest is the change in outcome from baseline to endpoint of study. The last observation carried forward (LOCF) method is a very common approach for handling this problem. It assumes that the last measured outcome is frozen in time after the point of dropout, an unrealistic assumption given any time trends. Though existence and direction of the bias can sometimes be anticipated, the more important statistical question involves the actual magnitude of the bias and this requires computation. This paper provides explicit expressions for the exact bias in the LOCF estimates of mean change and its variance when the longitudinal data follow a linear mixed-effects model with linear time trajectories. General dropout patterns are considered that may depend on treatment group, subject-specific trajectories and follow different time to dropout distributions. In our case studies, the magnitude of bias for mean change estimators linearly increases as time to dropout decreases. The bias depends heavily on the dropout interval. The variance term is always underestimated.     

Bayesian Analysis of Ordinal Survey Data Using the Dirichlet Process to Account for Respondent Personality Traits

This article presents a Bayesian latent variable model used to analyze ordinal response survey data by taking into account the characteristics of respondents. The ordinal response data are viewed as multivariate responses arising from continuous latent variables with known cut-points. Each respondent is characterized by two parameters that have a Dirichlet process as their joint prior distribution. The proposed mechanism adjusts for classes of personalities. The model is applied to student survey data in course evaluations. Goodness-of-fit (GoF) procedures are developed for assessing the validity of the model. The proposed GoF procedures are simple, intuitive, and do not seem to be a part of current Bayesian practice.     

A latent variable regression model for asymmetric bivariate ordered categorical data

In many areas of medical research, especially in studies that involve paired organs, a bivariate ordered categorical response should be analyzed. Using a bivariate continuous distribution as the latent variable is an interesting strategy for analyzing these data sets. In this context, the bivariate standard normal distribution, which leads to the bivariate cumulative probit regression model, is the most common choice. In this paper, we introduce another latent variable regression model for modeling bivariate ordered categorical responses. This model may be an appropriate alternative for the bivariate cumulative probit regression model, when postulating a symmetric form for marginal or joint distribution of response data does not appear to be a valid assumption. We also develop the necessary numerical procedure to obtain the maximum likelihood estimates of the model parameters. To illustrate the proposed model, we analyze data from an epidemiologic study to identify some of the most important risk indicators of periodontal disease among students 15-19 years in Tehran, Iran.     

Α Markov model for longitudinal studies with incomplete dichotomous outcomes

Missing outcome data constitute a serious threat to the validity and precision of inferences from randomized controlled trials. In this paper, we propose the use of a multistate Markov model for the analysis of incomplete individual patient data for a dichotomous outcome reported over a period of time. The model accounts for patients dropping out of the study and also for patients relapsing. The time of each observation is accounted for, and the model allows the estimation of time‐dependent relative treatment effects. We apply our methods to data from a study comparing the effectiveness of 2 pharmacological treatments for schizophrenia. The model jointly estimates the relative efficacy and the dropout rate and also allows for a wide range of clinically interesting inferences to be made. Assumptions about the missingness mechanism and the unobserved outcomes of patients dropping out can be incorporated into the analysis. The presented method constitutes a viable candidate for analyzing longitudinal, incomplete binary data.     

Type I error rates from likelihood‐based repeated measures analyses of incomplete longitudinal data

The last observation carried forward (LOCF) approach is commonly utilized to handle missing values in the primary analysis of clinical trials. However, recent evidence suggests that likelihood‐based analyses developed under the missing at random (MAR) framework are sensible alternatives. The objective of this study was to assess the Type I error rates from a likelihood‐based MAR approach – mixed‐model repeated measures (MMRM) – compared with LOCF when estimating treatment contrasts for mean change from baseline to endpoint (Δ). Data emulating neuropsychiatric clinical trials were simulated in a 4 × 4 factorial arrangement of scenarios, using four patterns of mean changes over time and four strategies for deleting data to generate subject dropout via an MAR mechanism. In data with no dropout, estimates of Δ and SE_Δ from MMRM and LOCF were identical. In data with dropout, the Type I error rates (averaged across all scenarios) for MMRM and LOCF were 5.49% and 16.76%, respectively. In 11 of the 16 scenarios, the Type I error rate from MMRM was at least 1.00% closer to the expected rate of 5.00% than the corresponding rate from LOCF. In no scenario did LOCF yield a Type I error rate that was at least 1.00% closer to the expected rate than the corresponding rate from MMRM. The average estimate of SE_Δ from MMRM was greater in data with dropout than in complete data, whereas the average estimate of SE_Δ from LOCF was smaller in data with dropout than in complete data, suggesting that standard errors from MMRM better reflected the uncertainty in the data. The results from this investigation support those from previous studies, which found that MMRM provided reasonable control of Type I error even in the presence of MNAR missingness. No universally best approach to analysis of longitudinal data exists. However, likelihood‐based MAR approaches have been shown to perform well in a variety of situations and are a sensible alternative to the LOCF approach. MNAR methods can be used within a sensitivity analysis framework to test the potential presence and impact of MNAR data, thereby assessing robustness of results from an MAR method. Copyright © 2004 John Wiley & Sons, Ltd.     

On the estimation of a binary response model in a selected population

A generalization of the Probit model is presented, with the extended skew-normal cumulative distribution as a link function, which can be used for modelling a binary response variable in the presence of selectivity bias. The estimate of the parameters via ML is addressed, and inference on the parameters expressing the degree of selection is discussed. The assumption underlying the model is that the selection mechanism influences the unmeasured factors and does not affect the explanatory variables. When this assumption is violated, but other conditional independencies hold, then the model proposed here is derived. In particular, the instrumental variable formula still applies and the model results at the second stage of the estimating procedure.     

Refusal to Answer Specific Questions in a Survey: A Case Study

It is well known that non ignorable item non response may occur when the cause of the non response is the value of the latent variable of interest. In these cases, a refusal by a respondent to answer specific questions in a survey should be treated sometimes as a non ignorable item non response. The Rasch-Rasch model (RRM) is a new two-dimensional item response theory model for addressing non ignorable non response. This article demonstrates the use of the RRM on data from an Italian survey focused on assessment of healthcare workers’ knowledge about sudden infant death syndrome (that is, a context in which non response is presumed to be more likely among individuals with a low level of competence). We compare the performance of the RRM with other models within the Rasch model family that assume the unidimensionality of the latent trait. We conclude that this assumption should be considered unreliable for the data at hand, whereas the RRM provides a better fit of the data.