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.     

Sample size estimation for comparing rates of change in K-group repeated count outcomes

Sample size estimation for comparing the rates of change in two-arm repeated measurements has been investigated by many investigators. In contrast, the literature has paid relatively less attention to sample size estimation for studies with multi-arm repeated measurements where the design and data analysis can be more complex than two-arm trials. For continuous outcomes, Jung and Ahn (2004 Jung, S., Ahn, C. (2004). K-sample test and sample size calculation for comparing slopes in data with repeated measurements. Biometrical J. 46(5):554–564.[Crossref], [Web of Science ®] , [Google Scholar]) and Zhang and Ahn (2013 Zhang, S., Ahn, C. (2013). Sample size calculation for comparing time-averaged responses in k-group repeated measurement studies. Comput. Stat. Data Anal. 58:283–291.[Crossref], [PubMed], [Web of Science ®] , [Google Scholar]) have presented sample size formulas to compare the rates of change and time-averaged responses in multi-arm trials, using the generalized estimating equation (GEE) approach. To our knowledge, there has been no corresponding development for multi-arm trials with count outcomes. We present a sample size formula for comparing the rates of change in multi-arm repeated count outcomes using the GEE approach that accommodates various correlation structures, missing data patterns, and unbalanced designs. We conduct simulation studies to assess the performance of the proposed sample size formula under a wide range of designing configurations. Simulation results suggest that empirical type I error and power are maintained close to their nominal levels. The proposed method is illustrated using an epileptic clinical trial example.     

Alone and adrift: The association between mass school shootings,school size,and student support

Background

School shootings have approached epidemic levels in recent years. While mental illness is undoubtedly involved in nearly all cases of mass school violence, we sought to determine how environmental context may exacerbate preexisting personal factors. The present study investigated the associations between mass school shootings, school enrollment size, student–teacher ratios, and student transitions.

A study of quadratic inference functions with alternative weighting matrices

Quadratic inference function (QIF) is an alternative methodology to the popular generalized estimating equations (GEE) approach, it does not involve direct estimation of the correlation parameter, and thus remains optimal even if the working correlation structure is misspecified. The idea is to represent the inverse of the working correlation matrix by a linear combination of some basis matrices. In this article, we present a modification of QIF with a robust variance estimator of the extended score function. Theoretical and numerical results show that the modified QIF attains better efficiency and achieves better small sample performance than the original QIF method.     

Computational approach test for inference about several correlation coefficients: Equality and common

In this article, we consider inference about the correlation coefficients of several bivariate normal distributions. We first propose computational approach tests for testing the equality of the correlation coefficients. In fact, these approaches are parametric bootstrap tests, and simulation studies show that they perform very satisfactory, and the actual sizes of these tests are better than other existing approaches. We also present a computational approach test and a parametric bootstrap confidence interval for inference about the parameter of common correlation coefficient. At the end, all the approaches are illustrated using two real examples.     

A direct procedure for monitoring the coefficient of variation using a variable sample size scheme

A variable sample size (VSS) scheme directly monitoring the coefficient of variation (CV), instead of monitoring the transformed statistics, is proposed. Optimal chart parameters are computed based on two criteria: (i) minimizing the out-of-control ARL (ARL₁) and (ii) minimizing the out-of-control ASS (ASS₁). Then the performances are compared between these two criteria. The advantages of the proposed chart over the VSS chart based on the transformed statistics in the existing literature are: the former (i) provides an easier alternative as no transformation is involved and (ii) requires less number of observations to detect a shift when ASS₁ is minimized.     

Monitoring the coefficient of variation using a variable sample size and sampling interval control chart

This article proposes a CV chart by using the variable sample size and sampling interval (VSSI) feature to improve the performance of the basic CV chart, for detecting small and moderate shifts in the CV. The proposed VSSI CV chart is designed by allowing the sample size and the sampling interval to vary. The VSSI CV chart's statistical performance is measured by using the average time to signal (ATS) and expected average time to signal (EATS) criteria and is compared with that of existing CV charts. The Markov chain approach is employed in the design of the chart.     

Bayesian prediction of order statistics with fixed and random sample sizes based on k-record values from Pareto distribution

In this paper, the two-parameter Pareto distribution is considered and the problem of prediction of order statistics from a future sample and that of its geometric mean are discussed. The Bayesian approach is applied to construct predictors based on observed k-record values for the cases when the future sample size is fixed and when it is random. Several Bayesian prediction intervals are derived. Finally, the results of a simulation study and a numerical example are presented for illustrating all the inferential procedures developed here.     

The effect of number of siblings on adult mortality: Evidence from Swedish registers for cohorts born between 1938 and 1972

Demographic research has paid much attention to the impact of childhood conditions on adult mortality. We focus on one of the key aspects of early life conditions, sibling group size, and examine the causal effect of growing up in a large family on mortality. While previous studies have focused on low- or middle-income countries, we examine whether growing up in a large family is a disadvantage in Sweden, a context where most parents have adequate resources, which are complemented by a generous welfare state. We used Swedish register data and frailty models, examining all-cause and cause-specific mortality between the ages of 40 and 74 for the 1938–72 cohorts, and also a quasi-experimental approach that exploited multiple births as a source of exogenous variation in the number of siblings. Overall our results do not indicate that growing up in a large family has a detrimental effect on longevity in Sweden.     

Considerations on jury size and composition using lower probabilities

The use of lower probabilities is considered for inferences in basic jury scenarios to study aspects of the size of juries and their composition if society consists of subpopulations. The use of lower probability seems natural in law, as it leads to robust inference in the sense of providing a defendant with the benefit of the doubt. The method presented in this paper focusses on how representative a jury is for the whole population, using a novel concept of a second ’imaginary’ jury together with exchangeability assumptions. It has the advantage that there is an explicit absence of any assumption with regard to guilt of a defendant. Although the concept of a jury in law is central in the presentation, the novel approach and the conclusions of this paper hold for representative decision making processes in many fields, and it also provides a new perspective to stratified sampling.