In clinical trials of longitudinal continuous outcomes, reference based imputation (RBI) has commonly been applied to handle missing outcome data in settings where the estimand incorporates the effects of intercurrent events, e.g. treatment discontinuation. RBI was originally developed in the multiple imputation framework, however recently conditional mean imputation (CMI) combined with the jackknife estimator of the standard error was proposed as a way to obtain deterministic treatment effect estimates and correct frequentist inference. For both multiple and CMI, a mixed model for repeated measures (MMRM) is often used for the imputation model, but this can be computationally intensive to fit to multiple data sets (e.g. the jackknife samples) and lead to convergence issues with complex MMRM models with many parameters. Therefore, a step-wise approach based on sequential linear regression (SLR) of the outcomes at each visit was developed for the imputation model in the multiple imputation framework, but similar developments in the CMI framework are lacking. In this article, we fill this gap in the literature by proposing a SLR approach to implement RBI in the CMI framework, and justify its validity using theoretical results and simulations. We also illustrate our proposal on a real data application.
Personalized Imputation in metric spaces via conformal prediction: Applications in Predicting Diabetes Development with Continuous Glucose Monitoring Information
Objective: Researchers often use model-based multiple imputation to handle missing at random data to minimize bias while making the best use of all available data. However, there are sometimes constraints within the data that make model-based imputation difficult and may result in implausible values. In these contexts, we describe how to use random hot deck imputation to allow for plausible multiple imputation in longitudinal studies. Study Design and Setting: We illustrate random hot deck multiple imputation using The Childhood Health, Activity, and Motor Performance School Study Denmark (CHA…
Missing data on response variables are common in clinical studies. Corresponding to the uncertainty of missing mechanism, theoretical frameworks on controlled imputation have been developed. In practice, it is recommended to conduct a statistically valid analysis under the primary assumptions on missing data, followed by sensitivity analysis under alternative assumptions to assess the robustness of results. Due to the availability of software, controlled multiple imputation (MI) procedures, including delta-based and reference-based approaches, have become popular for analyzing continuous varia…
Biased sampling designs can be highly efficient when studying rare (binary) or low variability (continuous) endpoints. We consider longitudinal data settings in which the probability of being sampled depends on a repeatedly measured response through an outcome-related, auxiliary variable. Such auxiliary variable- or outcome-dependent sampling improves observed response and possibly exposure variability over random sampling, {even though} the auxiliary variable is not of scientific interest. {For analysis,} we propose a generalized linear model based approach using a sequence of two offsetted r…
An efficient monotone data augmentation (MDA) algorithm is proposed for missing data imputation for incomplete multivariate nonnormal data that may contain variables of different types, and are modeled by a sequence of regression models including the linear, binary logistic, multinomial logistic, proportional odds, Poisson, negative binomial, skew-normal, skew-t regressions or a mixture of these models. The MDA algorithm is applied to the sensitivity analyses of longitudinal trials with nonignorable dropout using the controlled pattern imputations that assume the treatment effect reduces or di…
Missing data is inevitable in longitudinal clinical trials. Conventionally, the missing at random assumption is assumed to handle missingness, which however is unverifiable empirically. Thus, sensitivity analysis is critically important to assess the robustness of the study conclusions against untestable assumptions. Toward this end, regulatory agencies often request using imputation models such as return-to-baseline, control-based, and washout imputation. Multiple imputation is popular in sensitivity analysis; however, it may be inefficient and result in an unsatisfying interval estimation by…
It is argued that the Calibrated Bayesian (CB) approach to statistical inference capitalizes on the strength of Bayesian and frequentist approaches to statistical inference. In the CB approach, inferences under a particular model are Bayesian, but frequentist methods are useful for model development and model checking. In this article the CB approach is outlined. Bayesian methods for missing data are then reviewed from a CB perspective. The basic theory of the Bayesian approach, and the closely related technique of multiple imputation, is described. Then applications of the Bayesian approach t…
Multiple imputation is a straightforward method for handling missing data in a principled fashion. This paper presents an overview of multiple imputation, including important theoretical results and their practical implications for generating and using multiple imputations. A review of strategies for generating imputations follows, including recent developments in flexible joint modeling and sequential regression/chained equations/fully conditional specification approaches. Finally, we compare and contrast different methods for generating imputations on a range of criteria before identifying p…
Missing data is unavoidable in longitudinal clinical trials, and outcomes are not always normally distributed. In the presence of outliers or heavy-tailed distributions, the conventional multiple imputation with the mixed model with repeated measures analysis of the average treatment effect (ATE) based on the multivariate normal assumption may produce bias and power loss. Control-based imputation (CBI) is an approach for evaluating the treatment effect under the assumption that participants in both the test and control groups with missing outcome data have a similar outcome profile as those wi…
Construction of just-in-time adaptive interventions, such as prompts delivered by mobile apps to promote and maintain behavioral change, requires knowledge about time-varying moderated effects to inform when and how we deliver intervention options. Micro-randomized trials (MRT) have emerged as a sequentially randomized design to gather requisite data for effect estimation. The existing literature (Qian et al., 2020; Boruvka et al., 2018; Dempsey et al., 2020) has defined a general class of causal estimands, referred to as "causal excursion effects", to assess the time-varying moderated effect.…
Generalized Estimation Equations (GEE) are a well-known method for the analysis of non-Gaussian longitudinal data. This method has computational simplicity and marginal parameter interpretation. However, in the presence of missing data, it is only valid under the strong assumption of missing completely at random (MCAR). Some corrections can be done when the missing data mechanism is missing at random (MAR): inverse probability weighting (WGEE) and multiple imputation (MIGEE). In order to obtain consistent estimates, it is necessary the correct specification of the weight model for WGEE or the …
A method using multiple imputation and bootstrap for dealing with missing data in mediation analysis is introduced and implemented in SAS. Through simulation studies, it is shown that the method performs well for both MCAR and MAR data without and with auxiliary variables. It is also shown that the method works equally well for MNAR data if auxiliary variables related to missingness are included. The application of the method is demonstrated through the analysis of a subset of data from the National Longitudinal Survey of Youth.
Missing data occur in many types of studies and typically complicate the analysis. Multiple imputation, either using joint modelling or the more flexible fully conditional specification approach, are popular and work well in standard settings. In settings involving non-linear associations or interactions, however, incompatibility of the imputation model with the analysis model is an issue often resulting in bias. Similarly, complex outcomes such as longitudinal or survival outcomes cannot be adequately handled by standard implementations. In this paper, we introduce the R package JointAI, whic…
Although approaches for handling missing data from longitudinal studies are well-developed when the patterns of missingness are monotone, fewer methods are available for non-monotone missingness. Moreover, the conventional missing at random (MAR) assumption -- a natural benchmark for monotone missingness -- does not model realistic beliefs about non-monotone missingness processes (Robins and Gill, 1997). This has provided the impetus for alternative non-monotone missing not at random (MNAR) mechanisms. The "no self-censoring" (NSC) model is such a mechanism and assumes the probability an outco…
Clinical trials with longitudinal outcomes typically include missing data due to missed assessments or structural missingness of outcomes after intercurrent events handled with a hypothetical strategy. Approaches based on Bayesian random multiple imputation and Rubin's rule for pooling results across multiple imputed datasets are increasingly used in order to align the analysis of these trials with the targeted estimand. We propose and justify deterministic conditional mean imputation combined with the jackknife for inference as an alternative approach. The method is applicable to imputations …
In clinical trials, mixed effects models for repeated measures (MMRM) and pattern mixture models (PMM) are often used to analyze longitudinal continuous outcomes. We describe a simple missing data imputation algorithm for the MMRM that can be easily implemented in standard statistical software packages such as SAS PROC MI. We explore the relationship of the missing data distribution in the control-based and delta-adjusted PMMs with that in the MMRM, and suggest an efficient imputation algorithm for these PMMs. The unobserved values in PMMs can be imputed by subtracting the mean difference in t…
Electronic health records (EHRs) are increasingly used for clinical and comparative effectiveness research, but suffer from missing data. Motivated by health services research on diabetes care, we seek to increase the quality of EHRs by focusing on missing values of longitudinal glycosylated hemoglobin (A1c), a key risk factor for diabetes complications and adverse events. Under the framework of multiple imputation (MI), we propose an individualized Bayesian latent profiling approach to capture A1c measurement trajectories subject to missingness. The proposed method is applied to EHRs of adult…
\Multiple imputation (MI) is a popular and well-established method for handling missing data in multivariate data sets, but its practicality for use in massive and complex data sets has been questioned. One such data set is the Panel Study of Income Dynamics (PSID), a longstanding and extensive survey of household income and wealth in the U.S. Missing data for this survey are currently handled using traditional hot deck methods because of the simple implementation; however, the univariate hot deck results in large random wealth fluctuations. MI is effective but faced with operational challenge…
We consider estimating the "de facto" or effectiveness estimand in a randomised placebo-controlled or standard-of-care-controlled drug trial with quantitative outcome, where participants who discontinue an investigational treatment are not followed up thereafter. Carpenter et al (2013) proposed reference-based imputation methods which use a reference arm to inform the distribution of post-discontinuation outcomes and hence to inform an imputation model. However, the reference-based imputation methods were not formally justified. We present a causal model which makes an explicit assumption in a…
Multiple imputation is a well-established general technique for analyzing data with missing values. A convenient way to implement multiple imputation is sequential regression multiple imputation (SRMI), also called chained equations multiple imputation. In this approach, we impute missing values using regression models for each variable, conditional on the other variables in the data. This approach, however, assumes that the missingness mechanism is missing at random, and it is not well-justified under not-at-random missingness without additional modification. In this paper, we describe how we…
Panel studies typically suffer from attrition, which reduces sample size and can result in biased inferences. It is impossible to know whether or not the attrition causes bias from the observed panel data alone. Refreshment samples - new, randomly sampled respondents given the questionnaire at the same time as a subsequent wave of the panel - offer information that can be used to diagnose and adjust for bias due to attrition. We review and bolster the case for the use of refreshment samples in panel studies. We include examples of both a fully Bayesian approach for analyzing the concatenated p…
Censored survival data are common in clinical trial studies. We propose a unified framework for sensitivity analysis to censoring at random in survival data using multiple imputation and martingale, called SMIM. The proposed framework adopts the δ-adjusted and control-based models, indexed by the sensitivity parameter, entailing censoring at random and a wide collection of censoring not at random assumptions. Also, it targets for a broad class of treatment effect estimands defined as functionals of treatment-specific survival functions, taking into account of missing data due to censoring. Mul…
A dynamic treatment regimen (DTR) is a pre-specified sequence of decision rules which maps baseline or time-varying measurements on an individual to a recommended intervention or set of interventions. Sequential multiple assignment randomized trials (SMARTs) represent an important data collection tool for informing the construction of effective DTRs. A common primary aim in a SMART is the marginal mean comparison between two or more of the DTRs embedded in the trial. This manuscript develops a mixed effects modeling and estimation approach for these primary aim comparisons based on a continuou…
Consider estimating the G-formula for the counterfactual mean outcome under a given treatment regime in a longitudinal study. Bang and Robins provided an estimator for this quantity that relies on a sequential regression formulation of this parameter. This approach is doubly robust in that it is consistent if either the outcome regressions or the treatment mechanisms are consistently estimated. We define a stronger notion of double robustness, termed sequential double robustness, for estimators of the longitudinal G-formula. The definition emerges naturally from a more general definition of se…
The mixed effects model for repeated measures (MMRM) has been widely used for the analysis of longitudinal clinical data collected at a number of fixed time points. We propose a robust extension of the MMRM for skewed and heavy-tailed data on basis of the multivariate skew-t distribution, and it includes the multivariate normal, t, and skew-normal distributions as special cases. An efficient Markov chain Monte Carlo algorithm is developed using the monotone data augmentation and parameter expansion techniques. We employ the algorithm to perform controlled pattern imputations for sensitivity an…
Data collected in clinical trials are often composed of multiple types of variables. For example, laboratory measurements and vital signs are longitudinal data of continuous or categorical variables, adverse events may be recurrent events, and death is a time-to-event variable. Missing data due to patients' discontinuation from the study or as a result of handling intercurrent events using a hypothetical strategy almost always occur during any clinical trial. Imputing these data with mixed types of variables simultaneously is a challenge that has not been studied extensively. In this article, …
Standard approaches for variable selection in linear models are not tailored to deal properly with high-dimensional and incomplete data. Currently, methods dedicated to high-dimensional data handle missing values by ad-hoc strategies, like complete case analysis or single imputation, while methods dedicated to missing values, mainly based on multiple imputation, do not discuss the imputation method to use with high-dimensional data. Consequently, both approaches appear to be limited for many modern applications. With inspiration from ensemble methods, a new variable selection method is propose…
Personalized longitudinal disease assessment is central to quickly diagnosing, appropriately managing, and optimally adapting the therapeutic strategy of multiple sclerosis (MS). It is also important for identifying the idiosyncratic subject-specific disease profiles. Here, we design a novel longitudinal model to map individual disease trajectories in an automated way using sensor data that may contain missing values. First, we collect digital measurements related to gait and balance, and upper extremity functions using sensor-based assessments administered on a smartphone. Next, we treat miss…
Often in Phase 3 clinical trials measuring a long-term time-to-event endpoint, such as overall survival or progression-free survival, investigators also collect repeated measures on biomarkers which may be predictive of the primary endpoint. Although these data may not be leveraged directly to support early stopping decisions, can we make greater use of these data to increase efficiency and improve interim decision making? We present a joint model for longitudinal and time-to-event data and a method which establishes the distribution of successive estimates of parameters in the joint model acr…
Longitudinal observational patient data can be used to investigate the causal effects of time-varying treatments on time-to-event outcomes. Several methods have been developed for controlling for the time-dependent confounding that typically occurs. The most commonly used is inverse probability weighted estimation of marginal structural models (MSM-IPTW). An alternative, the sequential trials approach, is increasingly popular, in particular in combination with the target trial emulation framework. This approach involves creating a sequence of `trials' from new time origins, restricting to indi…
