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.     

A comparison of various software tools for dealing with missing data via imputation

In real-life situations, we often encounter data sets containing missing observations. Statistical methods that address missingness have been extensively studied in recent years. One of the more popular approaches involves imputation of the missing values prior to the analysis, thereby rendering the data complete. Imputation broadly encompasses an entire scope of techniques that have been developed to make inferences about incomplete data, ranging from very simple strategies (e.g. mean imputation) to more advanced approaches that require estimation, for instance, of posterior distributions using Markov chain Monte Carlo methods. Additional complexity arises when the number of missingness patterns increases and/or when both categorical and continuous random variables are involved. Implementation of routines, procedures, or packages capable of generating imputations for incomplete data are now widely available. We review some of these in the context of a motivating example, as well as in a simulation study, under two missingness mechanisms (missing at random and missing not at random). Thus far, evaluation of existing implementations have frequently centred on the resulting parameter estimates of the prescribed model of interest after imputing the missing data. In some situations, however, interest may very well be on the quality of the imputed values at the level of the individual – an issue that has received relatively little attention. In this paper, we focus on the latter to provide further insight about the performance of the different routines, procedures, and packages in this respect.     

Coping with missing data in phase III pivotal registration trials: Tolvaptan in subjects with kidney disease,a case study

Missing data cause challenging issues, particularly in phase III registration trials, as highlighted by the European Medicines Agency (EMA) and the US National Research Council. We explore, as a case study, how the issues from missing data were tackled in a double‐blind phase III trial in subjects with autosomal dominant polycystic kidney disease. A total of 1445 subjects were randomized in a 2:1 ratio to receive active treatment (tolvaptan), or placebo. The primary outcome, the rate of change in total kidney volume, favored tolvaptan (P < .0001). The key secondary efficacy endpoints of clinical progression of disease and rate of decline in kidney function also favored tolvaptan. However, as highlighted by Food and Drug Administration and EMA, the interpretation of results was hampered by a high number of unevenly distributed dropouts, particularly early dropouts. In this paper, we outline the analyses undertaken to address the issue of missing data thoroughly. “Tipping point analyses” were performed to explore how extreme and detrimental outcomes among subjects with missing data must be to overturn the positive treatment effect attained in those subjects who had complete data. Nonparametric rank‐based analyses were also performed accounting for missing data. In conclusion, straightforward and transparent analyses directly taking into account missing data convincingly support the robustness of the preplanned analyses on the primary and secondary endpoints. Tolvaptan was confirmed to be effective in slowing total kidney volume growth, which is considered an efficacy endpoint by EMA, and in lessening the decline in renal function in patients with autosomal dominant polycystic kidney disease.     

Comparison of algorithms for replacing missing data in discriminant analysis

We examined the impact of different methods for replacing missing data in discriminant analyses conducted on randomly generated samples from multivariate normal and non-normal distributions. The probabilities of correct classification were obtained for these discriminant analyses before and after randomly deleting data as well as after deleted data were replaced using: (1) variable means, (2) principal component projections, and (3) the EM algorithm. Populations compared were: (1) multivariate normal with covariance matrices ∑₁=∑₂, (2) multivariate normal with ∑₁≠∑₂ and (3) multivariate non-normal with ∑₁=∑₂. Differences in the probabilities of correct classification were most evident for populations with small Mahalanobis distances or high proportions of missing data. The three replacement methods performed similarly but all were better than non - replacement.     

Hybrid pairwise‐likelihood estimation methods for incomplete longitudinal binary data

In longitudinal data, missing observations occur commonly with incomplete responses and covariates. Missing data can have a ‘missing not at random’ mechanism, a non‐monotone missing pattern, and moreover response and covariates can be missing not simultaneously. To avoid complexities in both modelling and computation, a two‐stage estimation method and a pairwise‐likelihood method are proposed. The two‐stage estimation method enjoys simplicities in computation, but incurs more severe efficiency loss. On the other hand, the pairwise approach leads to estimators with better efficiency, but can be cumbersome in computation. In this paper, we develop a compromise method using a hybrid pairwise‐likelihood framework. Our proposed approach has better efficiency than the two‐stage method, but its computational cost is still reasonable compared to the pairwise approach. The performance of the methods is evaluated empirically by means of simulation studies. Our methods are used to analyse longitudinal data obtained from the National Population Health Study.     

A structured framework for assessing sensitivity to missing data assumptions in longitudinal clinical trials

The objective of this research was to demonstrate a framework for drawing inference from sensitivity analyses of incomplete longitudinal clinical trial data via a re‐analysis of data from a confirmatory clinical trial in depression. A likelihood‐based approach that assumed missing at random (MAR) was the primary analysis. Robustness to departure from MAR was assessed by comparing the primary result to those from a series of analyses that employed varying missing not at random (MNAR) assumptions (selection models, pattern mixture models and shared parameter models) and to MAR methods that used inclusive models. The key sensitivity analysis used multiple imputation assuming that after dropout the trajectory of drug‐treated patients was that of placebo treated patients with a similar outcome history (placebo multiple imputation). This result was used as the worst reasonable case to define the lower limit of plausible values for the treatment contrast. The endpoint contrast from the primary analysis was ? 2.79 (p = .013). In placebo multiple imputation, the result was ? 2.17. Results from the other sensitivity analyses ranged from ? 2.21 to ? 3.87 and were symmetrically distributed around the primary result. Hence, no clear evidence of bias from missing not at random data was found. In the worst reasonable case scenario, the treatment effect was 80% of the magnitude of the primary result. Therefore, it was concluded that a treatment effect existed. The structured sensitivity framework of using a worst reasonable case result based on a controlled imputation approach with transparent and debatable assumptions supplemented a series of plausible alternative models under varying assumptions was useful in this specific situation and holds promise as a generally useful framework. Copyright © 2012 John Wiley & Sons, Ltd.     

An application of the mixed-effects model and pattern mixture model to treatment groups with differential missingness suspected not-missing-at-random

Likelihood-based, mixed-effects models for repeated measures (MMRMs) are occasionally used in primary analyses for group comparisons of incomplete continuous longitudinal data. Although MMRM analysis is generally valid under missing-at-random assumptions, it is invalid under not-missing-at-random (NMAR) assumptions. We consider the possibility of bias of estimated treatment effect using standard MMRM analysis in a motivational case, and propose simple and easily implementable pattern mixture models within the framework of mixed-effects modeling, to handle the NMAR data with differential missingness between treatment groups. The proposed models are a new form of pattern mixture model that employ a categorical time variable when modeling the outcome and a continuous time variable when modeling the missingness-data patterns. The models can directly provide an overall estimate of the treatment effect of interest using the average of the distribution of the missingness indicator and a categorical time variable in the same manner as MMRM analysis. Our simulation results indicate that the bias of the treatment effect for MMRM analysis was considerably larger than that for the pattern mixture model analysis under NMAR assumptions. In the case study, it would be dangerous to interpret only the results of the MMRM analysis, and the proposed pattern mixture model would be useful as a sensitivity analysis for treatment effect evaluation.     

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.     

Efficient inverse probability weighting method for quantile regression with nonignorable missing data

Quantitle regression (QR) is a popular approach to estimate functional relations between variables for all portions of a probability distribution. Parameter estimation in QR with missing data is one of the most challenging issues in statistics. Regression quantiles can be substantially biased when observations are subject to missingness. We study several inverse probability weighting (IPW) estimators for parameters in QR when covariates or responses are subject to missing not at random. Maximum likelihood and semiparametric likelihood methods are employed to estimate the respondent probability function. To achieve nice efficiency properties, we develop an empirical likelihood (EL) approach to QR with the auxiliary information from the calibration constraints. The proposed methods are less sensitive to misspecified missing mechanisms. Asymptotic properties of the proposed IPW estimators are shown under general settings. The efficiency gain of EL-based IPW estimator is quantified theoretically. Simulation studies and a data set on the work limitation of injured workers from Canada are used to illustrated our proposed methodologies.     

Missing data in clinical trials: control‐based mean imputation and sensitivity analysis

In some randomized (drug versus placebo) clinical trials, the estimand of interest is the between‐treatment difference in population means of a clinical endpoint that is free from the confounding effects of “rescue” medication (e.g., HbA1c change from baseline at 24 weeks that would be observed without rescue medication regardless of whether or when the assigned treatment was discontinued). In such settings, a missing data problem arises if some patients prematurely discontinue from the trial or initiate rescue medication while in the trial, the latter necessitating the discarding of post‐rescue data. We caution that the commonly used mixed‐effects model repeated measures analysis with the embedded missing at random assumption can deliver an exaggerated estimate of the aforementioned estimand of interest. This happens, in part, due to implicit imputation of an overly optimistic mean for “dropouts” (i.e., patients with missing endpoint data of interest) in the drug arm. We propose an alternative approach in which the missing mean for the drug arm dropouts is explicitly replaced with either the estimated mean of the entire endpoint distribution under placebo (primary analysis) or a sequence of increasingly more conservative means within a tipping point framework (sensitivity analysis); patient‐level imputation is not required. A supplemental “dropout = failure” analysis is considered in which a common poor outcome is imputed for all dropouts followed by a between‐treatment comparison using quantile regression. All analyses address the same estimand and can adjust for baseline covariates. Three examples and simulation results are used to support our recommendations.     

Empirical likelihood and Wilks phenomenon for data with nonignorable missing values

Wilks's theorem is useful for constructing confidence regions. When applying the popular empirical likelihood to data with nonignorable nonresponses, Wilks's phenomenon does not hold. This paper unveils that this is caused by the extra estimation of the nuisance parameter in the nonignorable nonresponse propensity. Motivated by this result, we propose an adjusted empirical likelihood for which Wilks's theorem holds. Asymptotic results are presented and supplemented by simulation results for finite sample performance of the point estimators and confidence regions. An analysis of a data set is included for illustration.     

Pseudo likelihood-based estimation and testing of missingness mechanism function in nonignorable missing data problems

In nonignorable missing response problems, we study a semiparametric model with unspecified missingness mechanism model and a exponential family model for response conditional density. Even though existing methods are available to estimate the parameters in exponential family, estimation or testing of the missingness mechanism model nonparametrically remains to be an open problem. By defining a “synthesis" density involving the unknown missingness mechanism model and the known baseline “carrier" density in the exponential family model, we treat this “synthesis" density as a legitimate one with biased sampling version. We develop maximum pseudo likelihood estimation procedures and the resultant estimators are consistent and asymptotically normal. Since the “synthesis" cumulative distribution is a functional of the missingness mechanism model and the known carrier density, proposed method can be used to test the correctness of the missingness mechanism model nonparametrically andindirectly. Simulation studies and real example demonstrate the proposed methods perform very well.     

The impact of missing data on the results of a schizophrenia study

Missing data pose a serious challenge to the integrity of randomized clinical trials, especially of treatments for prolonged illnesses such as schizophrenia, in which long‐term impact assessment is of great importance, but the follow‐up rates are often no more than 50%. Sensitivity analysis using Bayesian modeling for missing data offers a systematic approach to assessing the sensitivity of the inferences made on the basis of observed data. This paper uses data from an 18‐month study of veterans with schizophrenia to demonstrate this approach. Data were obtained from a randomized clinical trial involving 369 patients diagnosed with schizophrenia that compared long‐acting injectable risperidone with a psychiatrist's choice of oral treatment. Bayesian analysis utilizing a pattern‐mixture modeling approach was used to validate the reported results by detecting bias due to non‐random patterns of missing data. The analysis was applied to several outcomes including standard measures of schizophrenia symptoms, quality of life, alcohol use, and global mental status. The original study results for several measures were confirmed against a wide range of patterns of non‐random missingness. Robustness of the conclusions was assessed using sensitivity parameters. The missing data in the trial did not likely threaten the validity of previously reported results. Copyright © 2014 John Wiley & Sons, Ltd.     

Modern variable selection for longitudinal semi-parametric models with missing data

Penalized methods for variable selection such as the Smoothly Clipped Absolute Deviation penalty have been increasingly applied to aid variable section in regression analysis. Much of the literature has focused on parametric models, while a few recent studies have shifted the focus and developed their applications for the popular semi-parametric, or distribution-free, generalized estimating equations (GEEs) and weighted GEE (WGEE). However, although the WGEE is composed of one main and one missing-data module, available methods only focus on the main module, with no variable selection for the missing-data module. In this paper, we develop a new approach to further extend the existing methods to enable variable selection for both modules. The approach is illustrated by both real and simulated study data.     

Performances of Bayesian model selection criteria for generalized linear models with non-ignorably missing covariates

This article deals with model comparison as an essential part of generalized linear modelling in the presence of covariates missing not at random (MNAR). We provide an evaluation of the performances of some of the popular model selection criteria, particularly of deviance information criterion (DIC) and weighted L (WL) measure, for comparison among a set of candidate MNAR models. In addition, we seek to provide deviance and quadratic loss-based model selection criteria with alternative penalty terms targeting directly the MNAR models. This work is motivated by the need in the literature to understand the performances of these important model selection criteria for comparison among a set of MNAR models. A Monte Carlo simulation experiment is designed to assess the finite sample performances of these model selection criteria in the context of interest under different scenarios for missingness amounts. Some naturally driven DIC and WL extensions are also discussed and evaluated.     

Comparing diagnostic tests with missing data

When missing data occur in studies designed to compare the accuracy of diagnostic tests, a common, though naive, practice is to base the comparison of sensitivity, specificity, as well as of positive and negative predictive values on some subset of the data that fits into methods implemented in standard statistical packages. Such methods are usually valid only under the strong missing completely at random (MCAR) assumption and may generate biased and less precise estimates. We review some models that use the dependence structure of the completely observed cases to incorporate the information of the partially categorized observations into the analysis and show how they may be fitted via a two-stage hybrid process involving maximum likelihood in the first stage and weighted least squares in the second. We indicate how computational subroutines written in R may be used to fit the proposed models and illustrate the different analysis strategies with observational data collected to compare the accuracy of three distinct non-invasive diagnostic methods for endometriosis. The results indicate that even when the MCAR assumption is plausible, the naive partial analyses should be avoided.     

High breakdown point robust estimators with missing data

In this paper, we propose a new procedure to estimate the distribution of a variable y when there are missing data. To compensate the presence of missing responses, it is assumed that a covariate vector x is observed and that y and x are related by means of a semi-parametric regression model. Observed residuals are combined with predicted values to estimate the missing response distribution. Once the responses distribution is consistently estimated, we can estimate any parameter defined through a continuous functional T using a plug in procedure. We prove that the proposed estimators have high breakdown point.     

A calibrated imputation method for secondary data analysis of survey data

In practical survey sampling, missing data are unavoidable due to nonresponse, rejected observations by editing, disclosure control, or outlier suppression. We propose a calibrated imputation approach so that valid point and variance estimates of the population (or domain) totals can be computed by the secondary users using simple complete‐sample formulae. This is especially helpful for variance estimation, which generally require additional information and tools that are unavailable to the secondary users. Our approach is natural for continuous variables, where the estimation may be either based on reweighting or imputation, including possibly their outlier‐robust extensions. We also propose a multivariate procedure to accommodate the estimation of the covariance matrix between estimated population totals, which facilitates variance estimation of the ratios or differences among the estimated totals. We illustrate the proposed approach using simulation data in supplementary materials that are available online.