Rate/Mean Regression for Multiple-Sequence Recurrent Event Data with Missing Event Category

Abstract.  Censored recurrent event data frequently arise in biomedical studies. Often, the events are not homogenous, and may be categorized. We propose semiparametric regression methods for analysing multiple-category recurrent event data and consider the setting where event times are always known, but the information used to categorize events may be missing. Application of existing methods after censoring events of unknown category (i.e. 'complete-case' methods) produces consistent estimators only when event types are missing completely at random, an assumption which will frequently fail in practice. We propose methods, based on weighted estimating equations, which are applicable when event category missingness is missing at random. Parameter estimators are shown to be consistent and asymptotically normal. Finite sample properties are examined through simulations and the proposed methods are applied to an end-stage renal disease data set obtained from a national organ failure registry.     

Control‐based imputation for sensitivity analyses in informative censoring for recurrent event data

In clinical trials, missing data commonly arise through nonadherence to the randomized treatment or to study procedure. For trials in which recurrent event endpoints are of interests, conventional analyses using the proportional intensity model or the count model assume that the data are missing at random, which cannot be tested using the observed data alone. Thus, sensitivity analyses are recommended. We implement the control‐based multiple imputation as sensitivity analyses for the recurrent event data. We model the recurrent event using a piecewise exponential proportional intensity model with frailty and sample the parameters from the posterior distribution. We impute the number of events after dropped out and correct the variance estimation using a bootstrap procedure. We apply the method to an application of sitagliptin study.     

Treatment policy estimands for recurrent event data using data collected after cessation of randomised treatment

In the past, many clinical trials have withdrawn subjects from the study when they prematurely stopped their randomised treatment and have therefore only collected ‘on‐treatment’ data. Thus, analyses addressing a treatment policy estimand have been restricted to imputing missing data under assumptions drawn from these data only. Many confirmatory trials are now continuing to collect data from subjects in a study even after they have prematurely discontinued study treatment as this event is irrelevant for the purposes of a treatment policy estimand. However, despite efforts to keep subjects in a trial, some will still choose to withdraw. Recent publications for sensitivity analyses of recurrent event data have focused on the reference‐based imputation methods commonly applied to continuous outcomes, where imputation for the missing data for one treatment arm is based on the observed outcomes in another arm. However, the existence of data from subjects who have prematurely discontinued treatment but remained in the study has now raised the opportunity to use this ‘off‐treatment’ data to impute the missing data for subjects who withdraw, potentially allowing more plausible assumptions for the missing post‐study‐withdrawal data than reference‐based approaches. In this paper, we introduce a new imputation method for recurrent event data in which the missing post‐study‐withdrawal event rate for a particular subject is assumed to reflect that observed from subjects during the off‐treatment period. The method is illustrated in a trial in chronic obstructive pulmonary disease (COPD) where the primary endpoint was the rate of exacerbations, analysed using a negative binomial model.     

Missing data sensitivity analysis for recurrent event data using controlled imputation

Statistical analyses of recurrent event data have typically been based on the missing at random assumption. One implication of this is that, if data are collected only when patients are on their randomized treatment, the resulting de jure estimator of treatment effect corresponds to the situation in which the patients adhere to this regime throughout the study. For confirmatory analysis of clinical trials, sensitivity analyses are required to investigate alternative de facto estimands that depart from this assumption. Recent publications have described the use of multiple imputation methods based on pattern mixture models for continuous outcomes, where imputation for the missing data for one treatment arm (e.g. the active arm) is based on the statistical behaviour of outcomes in another arm (e.g. the placebo arm). This has been referred to as controlled imputation or reference‐based imputation. In this paper, we use the negative multinomial distribution to apply this approach to analyses of recurrent events and other similar outcomes. The methods are illustrated by a trial in severe asthma where the primary endpoint was rate of exacerbations and the primary analysis was based on the negative binomial model. Copyright © 2014 John Wiley & Sons, Ltd.     

Sensitivity analyses for partially observed recurrent event data

Recurrent events involve the occurrences of the same type of event repeatedly over time and are commonly encountered in longitudinal studies. Examples include seizures in epileptic studies or occurrence of cancer tumors. In such studies, interest lies in the number of events that occur over a fixed period of time. One considerable challenge in analyzing such data arises when a large proportion of patients discontinues before the end of the study, for example, because of adverse events, leading to partially observed data. In this situation, data are often modeled using a negative binomial distribution with time‐in‐study as offset. Such an analysis assumes that data are missing at random (MAR). As we cannot test the adequacy of MAR, sensitivity analyses that assess the robustness of conclusions across a range of different assumptions need to be performed. Sophisticated sensitivity analyses for continuous data are being frequently performed. However, this is less the case for recurrent event or count data. We will present a flexible approach to perform clinically interpretable sensitivity analyses for recurrent event data. Our approach fits into the framework of reference‐based imputations, where information from reference arms can be borrowed to impute post‐discontinuation data. Different assumptions about the future behavior of dropouts dependent on reasons for dropout and received treatment can be made. The imputation model is based on a flexible model that allows for time‐varying baseline intensities. We assess the performance in a simulation study and provide an illustration with a clinical trial in patients who suffer from bladder cancer. Copyright © 2015 John Wiley & Sons, Ltd.     

Multiple imputation for ordinal longitudinal data with monotone missing data patterns

Missing data often complicate the analysis of scientific data. Multiple imputation is a general purpose technique for analysis of datasets with missing values. The approach is applicable to a variety of missing data patterns but often complicated by some restrictions like the type of variables to be imputed and the mechanism underlying the missing data. In this paper, the authors compare the performance of two multiple imputation methods, namely fully conditional specification and multivariate normal imputation in the presence of ordinal outcomes with monotone missing data patterns. Through a simulation study and an empirical example, the authors show that the two methods are indeed comparable meaning any of the two may be used when faced with scenarios, at least, as the ones presented here.     

Reference‐based sensitivity analysis for time‐to‐event data

The analysis of time‐to‐event data typically makes the censoring at random assumption, ie, that—conditional on covariates in the model—the distribution of event times is the same, whether they are observed or unobserved (ie, right censored). When patients who remain in follow‐up stay on their assigned treatment, then analysis under this assumption broadly addresses the de jure, or “while on treatment strategy” estimand. In such cases, we may well wish to explore the robustness of our inference to more pragmatic, de facto or “treatment policy strategy,” assumptions about the behaviour of patients post‐censoring. This is particularly the case when censoring occurs because patients change, or revert, to the usual (ie, reference) standard of care. Recent work has shown how such questions can be addressed for trials with continuous outcome data and longitudinal follow‐up, using reference‐based multiple imputation. For example, patients in the active arm may have their missing data imputed assuming they reverted to the control (ie, reference) intervention on withdrawal. Reference‐based imputation has two advantages: (a) it avoids the user specifying numerous parameters describing the distribution of patients' postwithdrawal data and (b) it is, to a good approximation, information anchored, so that the proportion of information lost due to missing data under the primary analysis is held constant across the sensitivity analyses. In this article, we build on recent work in the survival context, proposing a class of reference‐based assumptions appropriate for time‐to‐event data. We report a simulation study exploring the extent to which the multiple imputation estimator (using Rubin's variance formula) is information anchored in this setting and then illustrate the approach by reanalysing data from a randomized trial, which compared medical therapy with angioplasty for patients presenting with angina.     

Estimating treatment effects on the marginal recurrent event mean in the presence of a terminating event

In biomedical studies where the event of interest is recurrent (e.g., hospitalization), it is often the case that the recurrent event sequence is subject to being stopped by a terminating event (e.g., death). In comparing treatment options, the marginal recurrent event mean is frequently of interest. One major complication in the recurrent/terminal event setting is that censoring times are not known for subjects observed to die, which renders standard risk set based methods of estimation inapplicable. We propose two semiparametric methods for estimating the difference or ratio of treatment-specific marginal mean numbers of events. The first method involves imputing unobserved censoring times, while the second methods uses inverse probability of censoring weighting. In each case, imbalances in the treatment-specific covariate distributions are adjusted out through inverse probability of treatment weighting. After the imputation and/or weighting, the treatment-specific means (then their difference or ratio) are estimated nonparametrically. Large-sample properties are derived for each of the proposed estimators, with finite sample properties assessed through simulation. The proposed methods are applied to kidney transplant data.     

Latent class based multiple imputation approach for missing categorical data

In this paper we propose a latent class based multiple imputation approach for analyzing missing categorical covariate data in a highly stratified data model. In this approach, we impute the missing data assuming a latent class imputation model and we use likelihood methods to analyze the imputed data. Via extensive simulations, we study its statistical properties and make comparisons with complete case analysis, multiple imputation, saturated log-linear multiple imputation and the Expectation–Maximization approach under seven missing data mechanisms (including missing completely at random, missing at random and not missing at random). These methods are compared with respect to bias, asymptotic standard error, type I error, and 95% coverage probabilities of parameter estimates. Simulations show that, under many missingness scenarios, latent class multiple imputation performs favorably when jointly considering these criteria. A data example from a matched case–control study of the association between multiple myeloma and polymorphisms of the Inter-Leukin 6 genes is considered.     

Using multiple imputation to estimate cumulative distribution functions in longitudinal data analysis with data missing at random

In longitudinal clinical studies, after randomization at baseline, subjects are followed for a period of time for development of symptoms. The interested inference could be the mean change from baseline to a particular visit in some lab values, the proportion of responders to some threshold category at a particular visit post baseline, or the time to some important event. However, in some applications, the interest may be in estimating the cumulative distribution function (CDF) at a fixed time point post baseline. When the data are fully observed, the CDF can be estimated by the empirical CDF. When patients discontinue prematurely during the course of the study, the empirical CDF cannot be directly used. In this paper, we use multiple imputation as a way to estimate the CDF in longitudinal studies when data are missing at random. The validity of the method is assessed on the basis of the bias and the Kolmogorov–Smirnov distance. The results suggest that multiple imputation yields less bias and less variability than the often used last observation carried forward method. Copyright © 2013 John Wiley & Sons, Ltd.     

Joint model for bivariate zero-inflated recurrent event data with terminal events

Bivariate recurrent event data are observed when subjects are at risk of experiencing two different type of recurrent events. In this paper, our interest is to suggest statistical model when there is a substantial portion of subjects not experiencing recurrent events but having a terminal event. In a context of recurrent event data, zero events can be related with either the risk free group or a terminal event. For simultaneously reflecting both a zero inflation and a terminal event in a context of bivariate recurrent event data, a joint model is implemented with bivariate frailty effects. Simulation studies are performed to evaluate the suggested models. Infection data from AML (acute myeloid leukemia) patients are analyzed as an application.     

A semiparametric method of multiple imputation

In this paper, we describe how to use multiple imputation semiparametrically to obtain estimates of parameters and their standard errors when some individuals have missing data. The methods given require the investigator to know or be able to estimate the process generating the missing data but requires no full distributional form for the data. The method is especially useful for non-standard problems, such as estimating the median when data are missing.     

Evaluation of multiple-imputation procedures for three-mode component models

Three-mode analysis is a generalization of principal component analysis to three-mode data. While two-mode data consist of cases that are measured on several variables, three-mode data consist of cases that are measured on several variables at several occasions. As any other statistical technique, the results of three-mode analysis may be influenced by missing data. Three-mode software packages generally use the expectation–maximization (EM) algorithm for dealing with missing data. However, there are situations in which the EM algorithm is expected to break down. Alternatively, multiple imputation may be used for dealing with missing data. In this study we investigated the influence of eight different multiple-imputation methods on the results of three-mode analysis, more specifically, a Tucker2 analysis, and compared the results with those of the EM algorithm. Results of the simulations show that multilevel imputation with the mode with the most levels nested within cases and the mode with the least levels represented as variables gives the best results for a Tucker2 analysis. Thus, this may be a good alternative for the EM algorithm in handling missing data in a Tucker2 analysis.     

Sensitivity to censored‐at‐random assumption in the analysis of time‐to‐event endpoints

Over the past years, significant progress has been made in developing statistically rigorous methods to implement clinically interpretable sensitivity analyses for assumptions about the missingness mechanism in clinical trials for continuous and (to a lesser extent) for binary or categorical endpoints. Studies with time‐to‐event outcomes have received much less attention. However, such studies can be similarly challenged with respect to the robustness and integrity of primary analysis conclusions when a substantial number of subjects withdraw from treatment prematurely prior to experiencing an event of interest. We discuss how the methods that are widely used for primary analyses of time‐to‐event outcomes could be extended in a clinically meaningful and interpretable way to stress‐test the assumption of ignorable censoring. We focus on a ‘tipping point’ approach, the objective of which is to postulate sensitivity parameters with a clear clinical interpretation and to identify a setting of these parameters unfavorable enough towards the experimental treatment to nullify a conclusion that was favorable to that treatment. Robustness of primary analysis results can then be assessed based on clinical plausibility of the scenario represented by the tipping point. We study several approaches for conducting such analyses based on multiple imputation using parametric, semi‐parametric, and non‐parametric imputation models and evaluate their operating characteristics via simulation. We argue that these methods are valuable tools for sensitivity analyses of time‐to‐event data and conclude that the method based on piecewise exponential imputation model of survival has some advantages over other methods studied here. Copyright © 2016 John Wiley & Sons, Ltd.     

A multiple imputation approach to nonlinear mixed-effects models with covariate measurement errors and missing values

In longitudinal studies, nonlinear mixed-effects models have been widely applied to describe the intra- and the inter-subject variations in data. The inter-subject variation usually receives great attention and it may be partially explained by time-dependent covariates. However, some covariates may be measured with substantial errors and may contain missing values. We proposed a multiple imputation method, implemented by a Markov Chain Monte-Carlo method along with Gibbs sampler, to address the covariate measurement errors and missing data in nonlinear mixed-effects models. The multiple imputation method is illustrated in a real data example. Simulation studies show that the multiple imputation method outperforms the commonly used naive methods.     

Comparisons of imputation methods with application to assess factors associated with self efficacy of physical activity in breast cancer survivors

ABSTRACT

Missing data are commonly encountered in self-reported measurements and questionnaires. It is crucial to treat missing values using appropriate method to avoid bias and reduction of power. Various types of imputation methods exist, but it is not always clear which method is preferred for imputation of data with non-normal variables. In this paper, we compared four imputation methods: mean imputation, quantile imputation, multiple imputation, and quantile regression multiple imputation (QRMI), using both simulated and real data investigating factors affecting self-efficacy in breast cancer survivors. The results displayed an advantage of using multiple imputation, especially QRMI when data are not normal.     

Simulated maximum likelihood estimation in joint models for multiple longitudinal markers and recurrent events of multiple types,in the presence of a terminal event

In medical studies we are often confronted with complex longitudinal data. During the follow-up period, which can be ended prematurely by a terminal event (e.g. death), a subject can experience recurrent events of multiple types. In addition, we collect repeated measurements from multiple markers. An adverse health status, represented by ‘bad’ marker values and an abnormal number of recurrent events, is often associated with the risk of experiencing the terminal event. In this situation, the missingness of the data is not at random and, to avoid bias, it is necessary to model all data simultaneously using a joint model. The correlations between the repeated observations of a marker or an event type within an individual are captured by normally distributed random effects. Because the joint likelihood contains an analytically intractable integral, Bayesian approaches or quadrature approximation techniques are necessary to evaluate the likelihood. However, when the number of recurrent event types and markers is large, the dimensionality of the integral is high and these methods are too computationally expensive. As an alternative, we propose a simulated maximum-likelihood approach based on quasi-Monte Carlo integration to evaluate the likelihood of joint models with multiple recurrent event types and markers.     

A multiple imputation method for incomplete correlated ordinal data using multivariate probit models

The multiple imputation technique has proven to be a useful tool in missing data analysis. We propose a Markov chain Monte Carlo method to conduct multiple imputation for incomplete correlated ordinal data using the multivariate probit model. We conduct a thorough simulation study to compare the performance of our proposed method with two available imputation methods – multivariate normal-based and chain equation methods for various missing data scenarios. For illustration, we present an application using the data from the smoking cessation treatment study for low-income community corrections smokers.     

Missing data methods for arbitrary missingness with small samples

Missing data are a prevalent and widespread data analytic issue and previous studies have performed simulations to compare the performance of missing data methods in various contexts and for various models; however, one such context that has yet to receive much attention in the literature is the handling of missing data with small samples, particularly when the missingness is arbitrary. Prior studies have either compared methods for small samples with monotone missingness commonly found in longitudinal studies or have investigated the performance of a single method to handle arbitrary missingness with small samples but studies have yet to compare the relative performance of commonly implemented missing data methods for small samples with arbitrary missingness. This study conducts a simulation study to compare and assess the small sample performance of maximum likelihood, listwise deletion, joint multiple imputation, and fully conditional specification multiple imputation for a single-level regression model with a continuous outcome. Results showed that, provided assumptions are met, joint multiple imputation unanimously performed best of the methods examined in the conditions under study.     

Nonparametric methods for the estimation of imputation uncertainty

It is cleared in recent researches that the raising of missing values in datasets is inevitable. Imputation of missing data is one of the several methods which have been introduced to overcome this issue. Imputation techniques are trying to answer the case of missing data by covering missing values with reasonable estimates permanently. There are a lot of benefits for these procedures rather than their drawbacks. The operation of these methods has not been clarified, which means that they provide mistrust among analytical results. One approach to evaluate the outcomes of the imputation process is estimating uncertainty in the imputed data. Nonparametric methods are appropriate to estimating the uncertainty when data are not followed by any particular distribution. This paper deals with a nonparametric method for estimation and testing the significance of the imputation uncertainty, which is based on Wilcoxon test statistic, and which could be employed for estimating the precision of the imputed values created by imputation methods. This proposed procedure could be employed to judge the possibility of the imputation process for datasets, and to evaluate the influence of proper imputation methods when they are utilized to the same dataset. This proposed approach has been compared with other nonparametric resampling methods, including bootstrap and jackknife to estimate uncertainty in the imputed data under the Bayesian bootstrap imputation method. The ideas supporting the proposed method are clarified in detail, and a simulation study, which indicates how the approach has been employed in practical situations, is illustrated.