Bayesian blinded sample size re-estimation

Information before unblinding regarding the success of confirmatory clinical trials is highly uncertain. Current techniques using point estimates of auxiliary parameters for estimating expected blinded sample size: (i) fail to describe the range of likely sample sizes obtained after the anticipated data are observed, and (ii) fail to adjust to the changing patient population. Sequential MCMC-based algorithms are implemented for purposes of sample size adjustments. The uncertainty arising from clinical trials is characterized by filtering later auxiliary parameters through their earlier counterparts and employing posterior distributions to estimate sample size and power. The use of approximate expected power estimates to determine the required additional sample size are closely related to techniques employing Simple Adjustments or the EM algorithm. By contrast with these, our proposed methodology provides intervals for the expected sample size using the posterior distribution of auxiliary parameters. Future decisions about additional subjects are better informed due to our ability to account for subject response heterogeneity over time. We apply the proposed methodologies to a depression trial. Our proposed blinded procedures should be considered for most studies due to ease of implementation.     

Sample size re‐estimation incorporating prior information on a nuisance parameter

Prior information is often incorporated informally when planning a clinical trial. Here, we present an approach on how to incorporate prior information, such as data from historical clinical trials, into the nuisance parameter–based sample size re‐estimation in a design with an internal pilot study. We focus on trials with continuous endpoints in which the outcome variance is the nuisance parameter. For planning and analyzing the trial, frequentist methods are considered. Moreover, the external information on the variance is summarized by the Bayesian meta‐analytic‐predictive approach. To incorporate external information into the sample size re‐estimation, we propose to update the meta‐analytic‐predictive prior based on the results of the internal pilot study and to re‐estimate the sample size using an estimator from the posterior. By means of a simulation study, we compare the operating characteristics such as power and sample size distribution of the proposed procedure with the traditional sample size re‐estimation approach that uses the pooled variance estimator. The simulation study shows that, if no prior‐data conflict is present, incorporating external information into the sample size re‐estimation improves the operating characteristics compared to the traditional approach. In the case of a prior‐data conflict, that is, when the variance of the ongoing clinical trial is unequal to the prior location, the performance of the traditional sample size re‐estimation procedure is in general superior, even when the prior information is robustified. When considering to include prior information in sample size re‐estimation, the potential gains should be balanced against the risks.     

Bootstrapping mean‐squared errors of robust small‐area estimators: Application to the method‐of‐payments surveys data

This paper proposes a new bootstrap procedure for mean‐squared errors of robust small‐area estimators. We formally prove the asymptotic validity of the proposed bootstrap method and examine its finite‐sample performance through Monte Carlo simulations. The results show that our procedure performs well and competes with existing ones. We also provide an application to the estimation of the total volume and value of cash, debit card, and credit card transactions in Canada as well as in its provinces and subgroups of households. In particular, we found that there is a significant average annual decline rate of 3.1% in the volume of cash transactions and that this decline is relatively higher among high‐income households living in heavily populated provinces. Our bootstrap estimator also provides indicators of quality useful in selecting the best small‐area predictor among several alternatives in practice.     

Practical procedures to deal with common support problems in matching estimation

This paper assesses the performance of common estimators adjusting for differences in covariates, such as matching and regression, when faced with the so-called common support problems. It also shows how different procedures suggested in the literature affect the properties of such estimators. Based on an empirical Monte Carlo simulation design, a lack of common support is found to increase the root-mean-squared error of all investigated parametric and semiparametric estimators. Dropping observations that are off support usually improves their performance, although the magnitude of the improvement depends on the particular method used.     

Blinded continuous monitoring in clinical trials with recurrent event endpoints

In studies with recurrent event endpoints, misspecified assumptions of event rates or dispersion can lead to underpowered trials or overexposure of patients. Specification of overdispersion is often a particular problem as it is usually not reported in clinical trial publications. Changing event rates over the years have been described for some diseases, adding to the uncertainty in planning. To mitigate the risks of inadequate sample sizes, internal pilot study designs have been proposed with a preference for blinded sample size reestimation procedures, as they generally do not affect the type I error rate and maintain trial integrity. Blinded sample size reestimation procedures are available for trials with recurrent events as endpoints. However, the variance in the reestimated sample size can be considerable in particular with early sample size reviews. Motivated by a randomized controlled trial in paediatric multiple sclerosis, a rare neurological condition in children, we apply the concept of blinded continuous monitoring of information, which is known to reduce the variance in the resulting sample size. Assuming negative binomial distributions for the counts of recurrent relapses, we derive information criteria and propose blinded continuous monitoring procedures. The operating characteristics of these are assessed in Monte Carlo trial simulations demonstrating favourable properties with regard to type I error rate, power, and stopping time, ie, sample size.     

Statistical testing strategies for assessing treatment efficacy and marker accuracy in phase III trials

When a candidate predictive marker is available, but evidence on its predictive ability is not sufficiently reliable, all‐comers trials with marker stratification are frequently conducted. We propose a framework for planning and evaluating prospective testing strategies in confirmatory, phase III marker‐stratified clinical trials based on a natural assumption on heterogeneity of treatment effects across marker‐defined subpopulations, where weak rather than strong control is permitted for multiple population tests. For phase III marker‐stratified trials, it is expected that treatment efficacy is established in a particular patient population, possibly in a marker‐defined subpopulation, and that the marker accuracy is assessed when the marker is used to restrict the indication or labelling of the treatment to a marker‐based subpopulation, ie, assessment of the clinical validity of the marker. In this paper, we develop statistical testing strategies based on criteria that are explicitly designated to the marker assessment, including those examining treatment effects in marker‐negative patients. As existing and developed statistical testing strategies can assert treatment efficacy for either the overall patient population or the marker‐positive subpopulation, we also develop criteria for evaluating the operating characteristics of the statistical testing strategies based on the probabilities of asserting treatment efficacy across marker subpopulations. Numerical evaluations to compare the statistical testing strategies based on the developed criteria are provided.     

Bootstrapping Periodic State-Space Models

This article is concerned with how the bootstrap can be applied to study conditional forecast error distributions and construct prediction regions for future observations in periodic time-varying state-space models. We derive, first, an algorithm for assessing the precision of quasi-maximum likelihood estimates of the parameters. As a result, the derived algorithm is exploited for numerically evaluating the conditional forecast accuracy of a periodic time series model expressed in state space form. We propose a method which requires the backward, or reverse-time, representation of the model for assessing conditional forecast errors. Finally, the small sample properties of the proposed procedures will be investigated by some simulation studies. Furthermore, we illustrate the results by applying the proposed method to a real time series.     

Generating synthetic data to produce public-use microdata for small geographic areas based on complex sample survey data with application to the National Health Interview Survey

Small area statistics obtained from sample survey data provide a critical source of information used to study health, economic, and sociological trends. However, most large-scale sample surveys are not designed for the purpose of producing small area statistics. Moreover, data disseminators are prevented from releasing public-use microdata for small geographic areas for disclosure reasons; thus, limiting the utility of the data they collect. This research evaluates a synthetic data method, intended for data disseminators, for releasing public-use microdata for small geographic areas based on complex sample survey data. The method replaces all observed survey values with synthetic (or imputed) values generated from a hierarchical Bayesian model that explicitly accounts for complex sample design features, including stratification, clustering, and sampling weights. The method is applied to restricted microdata from the National Health Interview Survey and synthetic data are generated for both sampled and non-sampled small areas. The analytic validity of the resulting small area inferences is assessed by direct comparison with the actual data, a simulation study, and a cross-validation study.     

Computation of the percentage points and the power for the two-sided Kolmogorov-Smirnov one sample test

Two recursive schemes are presented for the calculation of the probabilityP(g(x)≤S _n (x)≤h(x) for allx∈®), whereS _n is the empirical distribution function of a sample from a continuous distribution andh, g are continuous and isotone functions. The results are specialized for the calculation of the distribution and the corresponding percentage points of the test statistic of the two-sided Kolmogorov-Smirnov one sample test. The schemes allow the calculation of the power of the test too. Finally an extensive tabulation of percentage points for the Kolmogorov-Smirnov test is given.     

Saddlepoint Approximation for Sample and Bootstrap Quantiles

The paper gives the saddlepoint approximation for the distribution function of the sample quantile. A comparison of the saddlepoint approximations for the distribution functions of the sample quantile and the bootstrap quantile shows that the error of the bootstrap approximation to the distribution of the sample quantile obtained by Singh (1981) as an absolute error is actually a relative error.