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.     

A copula-based Markov chain model for the analysis of binary longitudinal data

A fully parametric first-order autoregressive (AR(1)) model is proposed to analyse binary longitudinal data. By using a discretized version of a copula, the modelling approach allows one to construct separate models for the marginal response and for the dependence between adjacent responses. In particular, the transition model that is focused on discretizes the Gaussian copula in such a way that the marginal is a Bernoulli distribution. A probit link is used to take into account concomitant information in the behaviour of the underlying marginal distribution. Fixed and time-varying covariates can be included in the model. The method is simple and is a natural extension of the AR(1) model for Gaussian series. Since the approach put forward is likelihood-based, it allows interpretations and inferences to be made that are not possible with semi-parametric approaches such as those based on generalized estimating equations. Data from a study designed to reduce the exposure of children to the sun are used to illustrate the methods.     

Bayesian robustness of the compound Poisson distribution under bidimensional prior: an application to the collective risk model

The distribution of the aggregate claims in one year plays an important role in Actuarial Statistics for computing, for example, insurance premiums when both the number and size of the claims must be implemented into the model. When the number of claims follows a Poisson distribution the aggregated distribution is called the compound Poisson distribution. In this article we assume that the claim size follows an exponential distribution and later we make an extensive study of this model by assuming a bidimensional prior distribution for the parameters of the Poisson and exponential distribution with marginal gamma. This study carries us to obtain expressions for net premiums, marginal and posterior distributions in terms of some well-known special functions used in statistics. Later, a Bayesian robustness study of this model is made. Bayesian robustness on bidimensional models was deeply treated in the 1990s, producing numerous results, but few applications dealing with this problem can be found in the literature.     

A re-evaluation of random-effects meta-analysis

Summary.  Meta-analysis in the presence of unexplained heterogeneity is frequently undertaken by using a random-effects model, in which the effects underlying different studies are assumed to be drawn from a normal distribution. Here we discuss the justification and interpretation of such models, by addressing in turn the aims of estimation, prediction and hypothesis testing. A particular issue that we consider is the distinction between inference on the mean of the random-effects distribution and inference on the whole distribution. We suggest that random-effects meta-analyses as currently conducted often fail to provide the key results, and we investigate the extent to which distribution-free, classical and Bayesian approaches can provide satisfactory methods. We conclude that the Bayesian approach has the advantage of naturally allowing for full uncertainty, especially for prediction. However, it is not without problems, including computational intensity and sensitivity to a priori judgements. We propose a simple prediction interval for classical meta-analysis and offer extensions to standard practice of Bayesian meta-analysis, making use of an example of studies of 'set shifting' ability in people with eating disorders.     

A new alternative to the standard F test for clustered data

The data collection process and the inherent population structure are the main causes for clustered data. The observations in a given cluster are correlated, and the magnitude of such correlation is often measured by the intra-cluster correlation coefficient. The intra-cluster correlation can lead to an inflated size of the standard F test in a linear model. In this paper, we propose a solution to this problem. Unlike previous adjustments, our method does not require estimation of the intra-class correlation, which is problematic especially when the number of clusters is small. Our simulation results show that the new method outperforms the existing methods.     

A ‘nondecimated’ lifting transform

Classical nondecimated wavelet transforms are attractive for many applications. When the data comes from complex or irregular designs, the use of second generation wavelets in nonparametric regression has proved superior to that of classical wavelets. However, the construction of a nondecimated second generation wavelet transform is not obvious. In this paper we propose a new ‘nondecimated’ lifting transform, based on the lifting algorithm which removes one coefficient at a time, and explore its behavior. Our approach also allows for embedding adaptivity in the transform, i.e. wavelet functions can be constructed such that their smoothness adjusts to the local properties of the signal. We address the problem of nonparametric regression and propose an (averaged) estimator obtained by using our nondecimated lifting technique teamed with empirical Bayes shrinkage. Simulations show that our proposed method has higher performance than competing techniques able to work on irregular data. Our construction also opens avenues for generating a ‘best’ representation, which we shall explore.     

THE USE OF AGGREGATE DATA TO ESTIMATE GOMPERTZ‐TYPE OLD‐AGE MORTALITY IN HETEROGENEOUS POPULATIONS

We consider two related aspects of the study of old‐age mortality. One is the estimation of a parameterized hazard function from grouped data, and the other is its possible deceleration at extreme old age owing to heterogeneity described by a mixture of distinct sub‐populations. The first is treated by half of a logistic transform, which is known to be free of discretization bias at older ages, and also preserves the increasing slope of the log hazard in the Gompertz case. It is assumed that data are available in the form published by official statistical agencies, that is, as aggregated frequencies in discrete time. Local polynomial modelling and weighted least squares are applied to cause‐of‐death mortality counts. The second, related, problem is to discover what conditions are necessary for population mortality to exhibit deceleration for a mixture of Gompertz sub‐populations. The general problem remains open but, in the case of three groups, we demonstrate that heterogeneity may be such that it is possible for a population to show decelerating mortality and then return to a Gompertz‐like increase at a later age. This implies that there are situations, depending on the extent of heterogeneity, in which there is at least one age interval in which the hazard function decreases before increasing again.     

SEMIPARAMETRIC REGRESSION AND GRAPHICAL MODELS

Semiparametric regression models that use spline basis functions with penalization have graphical model representations. This link is more powerful than previously established mixed model representations of semiparametric regression, as a larger class of models can be accommodated. Complications such as missingness and measurement error are more naturally handled within the graphical model architecture. Directed acyclic graphs, also known as Bayesian networks, play a prominent role. Graphical model-based Bayesian 'inference engines', such as bugs and vibes , facilitate fitting and inference. Underlying these are Markov chain Monte Carlo schemes and recent developments in variational approximation theory and methodology.