An extension of the placebo‐based pattern‐mixture model

Pattern‐mixture models provide a general and flexible framework for sensitivity analyses of nonignorable missing data in longitudinal studies. The placebo‐based pattern‐mixture model handles missing data in a transparent and clinically interpretable manner. We extend this model to include a sensitivity parameter that characterizes the gradual departure of the missing data mechanism from being missing at random toward being missing not at random under the standard placebo‐based pattern‐mixture model. We derive the treatment effect implied by the extended model. We propose to utilize the primary analysis based on a mixed‐effects model for repeated measures to draw inference about the treatment effect under the extended placebo‐based pattern‐mixture model. We use simulation studies to confirm the validity of the proposed method. We apply the proposed method to a clinical study of major depressive disorders. Copyright © 2013 John Wiley & Sons, Ltd.     

Short notes on maximum likelihood inference for control‐based pattern‐mixture models

A likelihood‐based analytical approach has been proposed for the control‐based pattern‐mixture model and its extension. In this note, we derive equivalent but simpler analytical expressions for the treatment effect and its variance for these control‐based pattern mixture models. Our formulae are easier to use and interpret. An application of our formulae to an antidepressant trial is provided, in which the likelihood‐based analysis is compared with the multiple imputation approach. Copyright © 2015 John Wiley & Sons, Ltd.     

Skew-mixed effects model for multivariate longitudinal data with categorical outcomes and missingness

A longitudinal study commonly follows a set of variables, measured for each individual repeatedly over time, and usually suffers from incomplete data problem. A common approach for dealing with longitudinal categorical responses is to use the Generalized Linear Mixed Model (GLMM). This model induces the potential relation between response variables over time via a vector of random effects, assumed to be shared parameters in the non-ignorable missing mechanism. Most GLMMs assume that the random-effects parameters follow a normal or symmetric distribution and this leads to serious problems in real applications. In this paper, we propose GLMMs for the analysis of incomplete multivariate longitudinal categorical responses with a non-ignorable missing mechanism based on a shared parameter framework with the less restrictive assumption of skew-normality for the random effects. These models may contain incomplete data with monotone and non-monotone missing patterns. The performance of the model is evaluated using simulation studies and a well-known longitudinal data set extracted from a fluvoxamine trial is analyzed to determine the profile of fluvoxamine in ambulatory clinical psychiatric practice.     

Application of sensitivity analysis to incomplete longitudinal CD4 count data

In this paper, we investigate the effect of tuberculosis pericarditis (TBP) treatment on CD4 count changes over time and draw inferences in the presence of missing data. We accounted for missing data and conducted sensitivity analyses to assess whether inferences under missing at random (MAR) assumption are sensitive to not missing at random (NMAR) assumptions using the selection model (SeM) framework. We conducted sensitivity analysis using the local influence approach and stress-testing analysis. Our analyses showed that the inferences from the MAR are robust to the NMAR assumption and influential subjects do not overturn the study conclusions about treatment effects and the dropout mechanism. Therefore, the missing CD4 count measurements are likely to be MAR. The results also revealed that TBP treatment does not interact with HIV/AIDS treatment and that TBP treatment has no significant effect on CD4 count changes over time. Although the methods considered were applied to data in the IMPI trial setting, the methods can also be applied to clinical trials with similar settings.     

Data-driven sensitivity analysis to detect missing data mechanism with applications to structural equation modelling

Missing data are a common problem in almost all areas of empirical research. Ignoring the missing data mechanism, especially when data are missing not at random (MNAR), can result in biased and/or inefficient inference. Because MNAR mechanism is not verifiable based on the observed data, sensitivity analysis is often used to assess it. Current sensitivity analysis methods primarily assume a model for the response mechanism in conjunction with a measurement model and examine sensitivity to missing data mechanism via the parameters of the response model. Recently, Jamshidian and Mata (Post-modelling sensitivity analysis to detect the effect of missing data mechanism, Multivariate Behav. Res. 43 (2008), pp. 432–452) introduced a new method of sensitivity analysis that does not require the difficult task of modelling the missing data mechanism. In this method, a single measurement model is fitted to all of the data and to a sub-sample of the data. Discrepancy in the parameter estimates obtained from the the two data sets is used as a measure of sensitivity to missing data mechanism. Jamshidian and Mata describe their method mainly in the context of detecting data that are missing completely at random (MCAR). They used a bootstrap type method, that relies on heuristic input from the researcher, to test for the discrepancy of the parameter estimates. Instead of using bootstrap, the current article obtains confidence interval for parameter differences on two samples based on an asymptotic approximation. Because it does not use bootstrap, the developed procedure avoids likely convergence problems with the bootstrap methods. It does not require heuristic input from the researcher and can be readily implemented in statistical software. The article also discusses methods of obtaining sub-samples that may be used to test missing at random in addition to MCAR. An application of the developed procedure to a real data set, from the first wave of an ongoing longitudinal study on aging, is presented. Simulation studies are performed as well, using two methods of missing data generation, which show promise for the proposed sensitivity method. One method of missing data generation is also new and interesting in its own right.     

Missing data in clinical trials: from clinical assumptions to statistical analysis using pattern mixture models

The need to use rigorous, transparent, clearly interpretable, and scientifically justified methodology for preventing and dealing with missing data in clinical trials has been a focus of much attention from regulators, practitioners, and academicians over the past years. New guidelines and recommendations emphasize the importance of minimizing the amount of missing data and carefully selecting primary analysis methods on the basis of assumptions regarding the missingness mechanism suitable for the study at hand, as well as the need to stress‐test the results of the primary analysis under different sets of assumptions through a range of sensitivity analyses. Some methods that could be effectively used for dealing with missing data have not yet gained widespread usage, partly because of their underlying complexity and partly because of lack of relatively easy approaches to their implementation. In this paper, we explore several strategies for missing data on the basis of pattern mixture models that embody clear and realistic clinical assumptions. Pattern mixture models provide a statistically reasonable yet transparent framework for translating clinical assumptions into statistical analyses. Implementation details for some specific strategies are provided in an Appendix (available online as Supporting Information), whereas the general principles of the approach discussed in this paper can be used to implement various other analyses with different sets of assumptions regarding missing data. Copyright © 2013 John Wiley & Sons, Ltd.     

Maximum likelihood estimates in the multivariate normal with patterned mean and covariance via the em algorithm

The maximum likelihood equations for a multivariate normal model with structured mean and structured covariance matrix may not have an explicit solution. In some cases the model's error term may be decomposed as the sum of two independent error terms, each having a patterned covariance matrix, such that if one of the unobservable error terms is artificially treated as "missing data", the EM algorithm can be used to compute the maximum likelihood estimates for the original problem. Some decompositions produce likelihood equations which do not have an explicit solution at each iteration of the EM algorithm, but within-iteration explicit solutions are shown for two general classes of models including covariance component models used for analysis of longitudinal data.     

An R package for model fitting,model selection and the simulation for longitudinal data with dropout missingness

Abstract

Missing data arise frequently in clinical and epidemiological fields, in particular in longitudinal studies. This paper describes the core features of an R package wgeesel, which implements marginal model fitting (i.e., weighted generalized estimating equations, WGEE; doubly robust GEE) for longitudinal data with dropouts under the assumption of missing at random. More importantly, this package comprehensively provide existing information criteria for WGEE model selection on marginal mean or correlation structures. Also, it can serve as a valuable tool for simulating longitudinal data with missing outcomes. Lastly, a real data example and simulations are presented to illustrate and validate our package.     

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.     

Evaluation of incomplete multiple diagnostic tests,with an application in the colon cancer family registry study

Accurate diagnosis of a molecularly defined subtype of cancer is often an important step toward its effective control and treatment. For the diagnosis of some subtypes of a cancer, a gold standard with perfect sensitivity and specificity may be unavailable. In those scenarios, tumor subtype status is commonly measured by multiple imperfect diagnostic markers. Additionally, in many such studies, some subjects are only measured by a subset of diagnostic tests and the missing probabilities may depend on the unknown disease status. In this paper, we present statistical methods based on the EM algorithm to evaluate incomplete multiple imperfect diagnostic tests under a missing at random assumption and one missing not at random scenario. We apply the proposed methods to a real data set from the National Cancer Institute (NCI) colon cancer family registry on diagnosing microsatellite instability for hereditary non-polyposis colorectal cancer to estimate diagnostic accuracy parameters (i.e. sensitivities and specificities), prevalence, and potential differential missing probabilities for 11 biomarker tests. Simulations are also conducted to evaluate the small-sample performance of our methods.     

Sensitivity analysis for the identifiability with application to latent random effect model for the mixed data

In this paper, we study the indentifiability of a latent random effect model for the mixed correlated continuous and ordinal longitudinal responses. We derive conditions for the identifiability of the covariance parameters of the responses. Also, we proposed sensitivity analysis to investigate the perturbation from the non-identifiability of the covariance parameters, it is shown how one can use some elements of covariance structure. These elements associate conditions for identifiability of the covariance parameters of the responses. Influence of small perturbation of these elements on maximal normal curvature is also studied. The model is illustrated using medical data.     

A monte carlo comparison of the smoothing,scoring and em algorithms for dispersion matrix estimation with incomplete growth curve data

Incomplete growth curve data often result from missing or mistimed observations in a repeated measures design. Virtually all methods of analysis rely on the dispersion matrix estimates. A Monte Carlo simulation was used to compare three methods of estimation of dispersion matrices for incomplete growth curve data. The three methods were: 1) maximum likelihood estimation with a smoothing algorithm, which finds the closest positive semidefinite estimate of the pairwise estimated dispersion matrix; 2) a mixed effects model using the EM (estimation maximization) algorithm; and 3) a mixed effects model with the scoring algorithm. The simulation included 5 dispersion structures, 20 or 40 subjects with 4 or 8 observations per subject and 10 or 30% missing data. In all the simulations, the smoothing algorithm was the poorest estimator of the dispersion matrix. In most cases, there were no significant differences between the scoring and EM algorithms. The EM algorithm tended to be better than the scoring algorithm when the variances of the random effects were close to zero, especially for the simulations with 4 observations per subject and two random effects.     

An index of local sensitivity to non-ignorability for parametric survival models with potential non-random missing covariate: an application to the SEER cancer registry data

Several survival regression models have been developed to assess the effects of covariates on failure times. In various settings, including surveys, clinical trials and epidemiological studies, missing data may often occur due to incomplete covariate data. Most existing methods for lifetime data are based on the assumption of missing at random (MAR) covariates. However, in many substantive applications, it is important to assess the sensitivity of key model inferences to the MAR assumption. The index of sensitivity to non-ignorability (ISNI) is a local sensitivity tool to measure the potential sensitivity of key model parameters to small departures from the ignorability assumption, needless of estimating a complicated non-ignorable model. We extend this sensitivity index to evaluate the impact of a covariate that is potentially missing, not at random in survival analysis, using parametric survival models. The approach will be applied to investigate the impact of missing tumor grade on post-surgical mortality outcomes in individuals with pancreas-head cancer in the Surveillance, Epidemiology, and End Results data set. For patients suffering from cancer, tumor grade is an important risk factor. Many individuals in these data with pancreas-head cancer have missing tumor grade information. Our ISNI analysis shows that the magnitude of effect for most covariates (with significant effect on the survival time distribution), specifically surgery and tumor grade as some important risk factors in cancer studies, highly depends on the missing mechanism assumption of the tumor grade. Also a simulation study is conducted to evaluate the performance of the proposed index in detecting sensitivity of key model parameters.     

Conditional simulation from highly structured Gaussian systems, with application to blocking-MCMC for the Bayesian analysis of very large linear models

This paper examines strategies for simulating exactly from large Gaussian linear models conditional on some Gaussian observations. Local computation strategies based on the conditional independence structure of the model are developed in order to reduce costs associated with storage and computation. Application of these algorithms to simulation from nested hierarchical linear models is considered, and the construction of efficient MCMC schemes for Bayesian inference in high-dimensional linear models is outlined.     

Joint modeling of multivariate censored longitudinal and event time data with application to the Genetic Markers of Inflammation Study

The Genetic Markers of Inflammation Study (GenIMS) was conceived to investigate the role of severe sepsis, which is typically defined as system-wide multi-organ failure, on survival. One major hypothesis for this systemic collapse, and reduction in survival, is a cascade of pro-inflammatory and anti-inflammatory cytokines. In this paper, we devised a novel joint modeling strategy to evaluate the joint effect of longitudinal anti-inflammatory marker IL-6 and pro-inflammatory marker IL-10 on 90-day survival. We found that, on average, patients with high initial values of both IL-6 and IL-10, that tend to increase over time, are associated with a reduction in survival expectancy and that accounting for their assumed correlation was justified.     

A generalization of the Grizzle model to the estimation of treatment effects in crossover trials with non-compliance

Compliance with one specified dosing strategy of assigned treatments is a common problem in randomized drug clinical trials. Recently, there has been much interest in methods used for analysing treatment effects in randomized clinical trials that are subject to non-compliance. In this paper, we estimate and compare treatment effects based on the Grizzle model (GM) (ignorable non-compliance) as the custom model and the generalized Grizzle model (GGM) (non-ignorable non-compliance) as the new model. A real data set based on the treatment of knee osteoarthritis is used to compare these models. The results based on the likelihood ratio statistics and simulation study show the advantage of the proposed model (GGM) over the custom model (GGM).