Meta‐analysis of QTc interval – pooling data from heterogeneous trials

A diverse range of non‐cardiovascular drugs are associated with QT interval prolongation, which may be associated with a potentially fatal ventricular arrhythmia known as torsade de pointes. QT interval has been assessed for two recent submissions at GlaxoSmithKline. Meta‐analyses of ECG data from several clinical pharmacology studies were conducted for the two submissions. A general fixed effects meta‐analysis approach using summaries of the individual studies was used to calculate a pooled estimate and 90% confidence interval for the difference between each active dose and placebo following both single and repeat dosing separately. The meta‐analysis approach described provided a pragmatic solution to pooling complex and varied studies, and is a good way of addressing regulatory questions on QTc prolongation. Copyright © 2002 John Wiley & Sons, Ltd.     

Statistical analysis of data from dilution assays with censored correlated counts

Frequently, count data obtained from dilution assays are subject to an upper detection limit, and as such, data obtained from these assays are usually censored. Also, counts from the same subject at different dilution levels are correlated. Ignoring the censoring and the correlation may provide unreliable and misleading results. Therefore, any meaningful data modeling requires that the censoring and the correlation be simultaneously addressed. Such comprehensive approaches of modeling censoring and correlation are not widely used in the analysis of dilution assays data. Traditionally, these data are analyzed using a general linear model on a logarithmic-transformed average count per subject. However, this traditional approach ignores the between-subject variability and risks, providing inconsistent results and unreliable conclusions. In this paper, we propose the use of a censored negative binomial model with normal random effects to analyze such data. This model addresses, in addition to the censoring and the correlation, any overdispersion that may be present in count data. The model is shown to be widely accessible through the use of several modern statistical software.     

The estimation of multidimensional fixed effects panel data models

This article introduces the appropriate within estimators for the most frequently used three-dimensional fixed effects panel data models. It analyzes the behavior of these estimators in the cases of no self-flow data, unbalanced data, and dynamic autoregressive models. The main results are then generalized for higher dimensional panel data sets as well.     

Bayesian analysis of the Box-Cox transformation model based on left-truncated and right-censored data

In this paper, we discuss the inference problem about the Box-Cox transformation model when one faces left-truncated and right-censored data, which often occur in studies, for example, involving the cross-sectional sampling scheme. It is well-known that the Box-Cox transformation model includes many commonly used models as special cases such as the proportional hazards model and the additive hazards model. For inference, a Bayesian estimation approach is proposed and in the method, the piecewise function is used to approximate the baseline hazards function. Also the conditional marginal prior, whose marginal part is free of any constraints, is employed to deal with many computational challenges caused by the constraints on the parameters, and a MCMC sampling procedure is developed. A simulation study is conducted to assess the finite sample performance of the proposed method and indicates that it works well for practical situations. We apply the approach to a set of data arising from a retirement center.     

Double filter instrumental variable estimation of panel data models with weakly exogenous variables

In this article, we propose instrumental variables (IV) and generalized method of moments (GMM) estimators for panel data models with weakly exogenous variables. The model is allowed to include heterogeneous time trends besides the standard fixed effects (FE). The proposed IV and GMM estimators are obtained by applying a forward filter to the model and a backward filter to the instruments in order to remove FE, thereby called the double filter IV and GMM estimators. We derive the asymptotic properties of the proposed estimators under fixed T and large N, and large T and large N asymptotics where N and T denote the dimensions of cross section and time series, respectively. It is shown that the proposed IV estimator has the same asymptotic distribution as the bias corrected FE estimator when both N and T are large. Monte Carlo simulation results reveal that the proposed estimator performs well in finite samples and outperforms the conventional IV/GMM estimators using instruments in levels in many cases.     

The impact of dichotomization in longitudinal data analysis: a simulation study

In this paper, a simulation study is conducted to systematically investigate the impact of dichotomizing longitudinal continuous outcome variables under various types of missing data mechanisms. Generalized linear models (GLM) with standard generalized estimating equations (GEE) are widely used for longitudinal outcome analysis, but these semi‐parametric approaches are only valid under missing data completely at random (MCAR). Alternatively, weighted GEE (WGEE) and multiple imputation GEE (MI‐GEE) were developed to ensure validity under missing at random (MAR). Using a simulation study, the performance of standard GEE, WGEE and MI‐GEE on incomplete longitudinal dichotomized outcome analysis is evaluated. For comparisons, likelihood‐based linear mixed effects models (LMM) are used for incomplete longitudinal original continuous outcome analysis. Focusing on dichotomized outcome analysis, MI‐GEE with original continuous missing data imputation procedure provides well controlled test sizes and more stable power estimates compared with any other GEE‐based approaches. It is also shown that dichotomizing longitudinal continuous outcome will result in substantial loss of power compared with LMM. Copyright © 2009 John Wiley & Sons, Ltd.     

Two-way analysis of variance for data from a concentrated bipolar Watson distribution

The bipolar Watson distribution is frequently used for modeling axial data. We extend the one-way analysis of variance based on this distribution to a two-way layout. We illustrate the method with directional data in three dimensions     

A Bayesian hierarchical model for categorical longitudinal data from a social survey of immigrants

Summary.  The paper investigates a Bayesian hierarchical model for the analysis of categorical longitudinal data from a large social survey of immigrants to Australia. Data for each subject are observed on three separate occasions, or waves, of the survey. One of the features of the data set is that observations for some variables are missing for at least one wave. A model for the employment status of immigrants is developed by introducing, at the first stage of a hierarchical model, a multinomial model for the response and then subsequent terms are introduced to explain wave and subject effects. To estimate the model, we use the Gibbs sampler, which allows missing data for both the response and the explanatory variables to be imputed at each iteration of the algorithm, given some appropriate prior distributions. After accounting for significant covariate effects in the model, results show that the relative probability of remaining unemployed diminished with time following arrival in Australia.     

Bayesian local influence analysis of skew-normal spatial dynamic panel data models

The existing studies on spatial dynamic panel data model (SDPDM) mainly focus on the normality assumption of response variables and random effects. This assumption may be inappropriate in some applications. This paper proposes a new SDPDM by assuming that response variables and random effects follow the multivariate skew-normal distribution. A Markov chain Monte Carlo algorithm is developed to evaluate Bayesian estimates of unknown parameters and random effects in skew-normal SDPDM by combining the Gibbs sampler and the Metropolis–Hastings algorithm. A Bayesian local influence analysis method is developed to simultaneously assess the effect of minor perturbations to the data, priors and sampling distributions. Simulation studies are conducted to investigate the finite-sample performance of the proposed methodologies. An example is illustrated by the proposed methodologies.     

Regression analysis of multivariate current status data under a varying coefficients additive hazards frailty model

This article discusses regression analysis of multivariate current status failure time data for which the observation time may be related to the underlying survival time. A local partial likelihood technique is used to estimate the varying coefficient covariate effect functions under the additive hazards frailty model. The asymptotic properties of the proposed estimators are established. An extensive simulation study is conducted for the evaluation of the proposed procedure, the results of which indicate that the proposed method works well in practice. Also, a real data study is provided to illustrate the performance of the proposed method.     

A comparison of procedures to correct for base-line differences in the analysis of continuous longitudinal data: a case-study

Summary.  The main advantage of longitudinal studies is that they can distinguish changes over time within individuals (longitudinal effects) from differences between subjects at the start of the study (base-line characteristics; cross-sectional effects). Often, especially in observational studies, subjects are very heterogeneous at base-line, and one may want to correct for this, when doing inferences for the longitudinal trends. Three procedures for base-line correction are compared in the context of linear mixed models for continuous longitudinal data. All procedures are illustrated extensively by using data from an experiment which aimed at studying the relationship between the post-operative evolution of the functional status of elderly hip fracture patients and their preoperative neurocognitive status.     

Review of guidelines and literature for handling missing data in longitudinal clinical trials with a case study

Missing data in clinical trials are inevitable. We highlight the ICH guidelines and CPMP points to consider on missing data. Specifically, we outline how we should consider missing data issues when designing, planning and conducting studies to minimize missing data impact. We also go beyond the coverage of the above two documents, provide a more detailed review of the basic concepts of missing data and frequently used terminologies, and examples of the typical missing data mechanism, and discuss technical details and literature for several frequently used statistical methods and associated software. Finally, we provide a case study where the principles outlined in this paper are applied to one clinical program at protocol design, data analysis plan and other stages of a clinical trial.     

Reliability analysis for stress-strength model from a general family of truncated distributions under censored data

Abstract

Under progressive Type-II censoring, inference of stress-strength reliability (SSR) is studied for a general family of lower truncated distributions. When the lifetime models of the strength and stress variables have arbitrary and common parameters, maximum likelihood and pivotal quantities based generalized estimators of SSR are established, respectively. Confidence intervals are constructed based on generalized pivotal quantities and bootstrap technique under different parameter cases as well. In addition, to compare the equivalence of the strength and stress parameters, likelihood ratio testing of interested parameters is provided as a complementary. Simulation studies and two real-life data examples are provided to investigate the performance of proposed methods.     

Performance of standard imputation methods for missing quality of life data as covariate in survival analysis based on simulations from the International Breast Cancer Study Group Trials VI and VII*

Abstract

Imputation methods for missing data on a time-dependent variable within time-dependent Cox models are investigated in a simulation study. Quality of life (QoL) assessments were removed from the complete simulated datasets, which have a positive relationship between QoL and disease-free survival (DFS) and delayed chemotherapy and DFS, by missing at random and missing not at random (MNAR) mechanisms. Standard imputation methods were applied before analysis. Method performance was influenced by missing data mechanism, with one exception for simple imputation. The greatest bias occurred under MNAR and large effect sizes. It is important to carefully investigate the missing data mechanism.