Statistical modeling for Bayesian extrapolation of adult clinical trial information in pediatric drug evaluation

Children represent a large underserved population of “therapeutic orphans,” as an estimated 80% of children are treated off‐label. However, pediatric drug development often faces substantial challenges, including economic, logistical, technical, and ethical barriers, among others. Among many efforts trying to remove these barriers, increased recent attention has been paid to extrapolation; that is, the leveraging of available data from adults or older age groups to draw conclusions for the pediatric population. The Bayesian statistical paradigm is natural in this setting, as it permits the combining (or “borrowing”) of information across disparate sources, such as the adult and pediatric data. In this paper, authored by the pediatric subteam of the Drug Information Association Bayesian Scientific Working Group and Adaptive Design Working Group, we develop, illustrate, and provide suggestions on Bayesian statistical methods that could be used to design improved pediatric development programs that use all available information in the most efficient manner. A variety of relevant Bayesian approaches are described, several of which are illustrated through 2 case studies: extrapolating adult efficacy data to expand the labeling for Remicade to include pediatric ulcerative colitis and extrapolating adult exposure‐response information for antiepileptic drugs to pediatrics.     

Measuring the complexity of generalized linear hierarchical models

Measuring a statistical model's complexity is important for model criticism and comparison. However, it is unclear how to do this for hierarchical models due to uncertainty about how to count the random effects. The authors develop a complexity measure for generalized linear hierarchical models based on linear model theory. They demonstrate the new measure for binomial and Poisson observables modeled using various hierarchical structures, including a longitudinal model and an areal‐data model having both spatial clustering and pure heterogeneity random effects. They compare their new measure to a Bayesian index of model complexity, the effective number p_D of parameters (Spiegelhalter, Best, Carlin & van der Linde 2002); the comparisons are made in the binomial and Poisson cases via simulation and two real data examples. The two measures are usually close, but differ markedly in some instances where p_D is arguably inappropriate. Finally, the authors show how the new measure can be used to approach the difficult task of specifying prior distributions for variance components, and in the process cast further doubt on the commonly‐used vague inverse gamma prior.     

AN ALGORITHMIC APPROACH TO BAYESIAN LINEAR MODEL CALCULATIONS

A framework is described for organizing and understanding the computations necessary to obtain the posterior mean of a vector of linear effects in a normal linear model, conditional on the parameters that determine covariance structure. The approach has two major uses; firstly, as a pedagogical tool in the derivation of formulae, and secondly, as a practical tool for developing computational strategies without needing complicated matrix formulae that are often unwieldy in complex hierarchical models. The proposed technique is based upon symbolic application of the sweep operator SWP to an appropriate tableau of means and covariances. The method is illustrated with standard linear model specifications, including the so-called mixed model, with both fixed and random effects.     

An iterative Monte Carlo method for nonconjugate Bayesian analysis

The Gibbs sampler has been proposed as a general method for Bayesian calculation in Gelfand and Smith (1990). However, the predominance of experience to date resides in applications assuming conjugacy where implementation is reasonably straightforward. This paper describes a tailored approximate rejection method approach for implementation of the Gibbs sampler when nonconjugate structure is present. Several challenging applications are presented for illustration.     

Bias and precision of measures of survival gain from right‐censored data

In cost‐effectiveness analyses of drugs or health technologies, estimates of life years saved or quality‐adjusted life years saved are required. Randomised controlled trials can provide an estimate of the average treatment effect; for survival data, the treatment effect is the difference in mean survival. However, typically not all patients will have reached the endpoint of interest at the close‐out of a trial, making it difficult to estimate the difference in mean survival. In this situation, it is common to report the more readily estimable difference in median survival. Alternative approaches to estimating the mean have also been proposed. We conducted a simulation study to investigate the bias and precision of the three most commonly used sample measures of absolute survival gain – difference in median, restricted mean and extended mean survival – when used as estimates of the true mean difference, under different censoring proportions, while assuming a range of survival patterns, represented by Weibull survival distributions with constant, increasing and decreasing hazards. Our study showed that the three commonly used methods tended to underestimate the true treatment effect; consequently, the incremental cost‐effectiveness ratio (ICER) would be overestimated. Of the three methods, the least biased is the extended mean survival, which perhaps should be used as the point estimate of the treatment effect to be inputted into the ICER, while the other two approaches could be used in sensitivity analyses. More work on the trade‐offs between simple extrapolation using the exponential distribution and more complicated extrapolation using other methods would be valuable. Copyright © 2015 John Wiley & Sons, Ltd.     

Operational research at the National Defence Research Institute of Sweden (FOA)

This paper gives an account of an institute for applied research so as to enable comparisons to be made with other institutes: such comparisons need not be limited to defence establishments. In elaborating the methodology of the institute its local concepts are applied, a conceptualisation which has proven useful outside defence [I]. Defence methodology still creates civilian spin-off.     

Inferring an Augmented Bayesian Network to Confront a Complex Quantitative Microbial Risk Assessment Model with Durability Studies: Application to Bacillus Cereus on a Courgette Purée Production Chain

The Monte Carlo (MC) simulation approach is traditionally used in food safety risk assessment to study quantitative microbial risk assessment (QMRA) models. When experimental data are available, performing Bayesian inference is a good alternative approach that allows backward calculation in a stochastic QMRA model to update the experts’ knowledge about the microbial dynamics of a given food‐borne pathogen. In this article, we propose a complex example where Bayesian inference is applied to a high‐dimensional second‐order QMRA model. The case study is a farm‐to‐fork QMRA model considering genetic diversity of Bacillus cereus in a cooked, pasteurized, and chilled courgette purée. Experimental data are Bacillus cereus concentrations measured in packages of courgette purées stored at different time‐temperature profiles after pasteurization. To perform a Bayesian inference, we first built an augmented Bayesian network by linking a second‐order QMRA model to the available contamination data. We then ran a Markov chain Monte Carlo (MCMC) algorithm to update all the unknown concentrations and unknown quantities of the augmented model. About 25% of the prior beliefs are strongly updated, leading to a reduction in uncertainty. Some updates interestingly question the QMRA model.