Operational challenges in adaptive design implementation

Implementation of adaptive clinical trial designs raises challenges with regard to the processes by which accruing trial data is analyzed, reviewed, and acted upon. In line with current monitoring conventions, it should be viewed that inappropriate knowledge of interim results can raise concerns regarding maintaining trial integrity and interpretability of results. Here we discuss issues related to these processes in adaptive trials, and point out distinctions versus other more familiar monitoring situations. One topic involves the composition of the group of individuals who will have access to interim results in order to recommend adaptations. We discuss operational models for data review by this group; one question addressed is whether in adaptive trials a role in this process for a representative of the study sponsor could at times be warranted, and might be justified if adequate protections are in place. Another issue involves whether adaptations made based upon interim data can convey to observers an amount of information about the results, which could rise to a level of concern. We consider whether different types of adaptations might be more or less problematic with regard to this issue, and recommend steps that might be considered to mitigate this concern.     

A two phases queueing system with Bernoulli vacation schedule under multiple vacation policy

This paper deals with a single server Poisson arrival queue with two phases of heterogeneous service along with a Bernoulli schedule vacation model, where after two successive phases service the server either goes for a vacation with probability p (0≤p≤1) or may continue to serve the next unit, if any, with probability q(=1−p). Further the concept of multiple vacation policy is also introduced here. We obtained the queue size distributions at a departure epoch and at a random epoch, Laplace Stieltjes Transform of the waiting time distribution and busy period distribution along with some mean performance measures. Finally we discuss some statistical inference related issues.     

Precedence tests and Lehmann alternatives

G = F ^k (k > 1); G = 1 − (1−F) ^k (k < 1); G = F ^k (k < 1); and G = 1 − (1−F) ^k (k > 1), where F and G are two continuous cumulative distribution functions. If an optimal precedence test (one with the maximal power) is determined for one of these four classes, the optimal tests for the other classes of alternatives can be derived. Application of this is given using the results of Lin and Sukhatme (1992) who derived the best precedence test for testing the null hypothesis that the lifetimes of two types of items on test have the same distibution. The test has maximum power for fixed κ in the class of alternatives G = 1 − (1−F) ^k , with k < 1. Best precedence tests for the other three classes of Lehmann-type alternatives are derived using their results. Finally, a comparison of precedence tests with Wilcoxon's two-sample test is presented. Received: February 22, 1999; revised version: June 7, 2000     

On Non-parametric Estimation of the Survival Function with Competing Risks

The non-parametric maximum likelihood estimators (MLEs) are derived for survival functions associated with individual risks or system components in a reliability framework. Lifetimes are observed for systems that contain one or more of those components. Analogous to a competing risks model, the system is assumed to fail upon the first instance of any component failure; i.e. the system is configured in series. For any given risk or component type, the asymptotic distribution is shown to depend explicitly on the unknown survival function of the other risks, as well as the censoring distribution. Survival functions with increasing failure rate are investigated as a special case. The order restricted MLE is shown to be consistent under mild assumptions of the underlying component lifetime distributions.     

Markov Chain Monte Carlo in small worlds

As the number of applications for Markov Chain Monte Carlo (MCMC) grows, the power of these methods as well as their shortcomings become more apparent. While MCMC yields an almost automatic way to sample a space according to some distribution, its implementations often fall short of this task as they may lead to chains which converge too slowly or get trapped within one mode of a multi-modal space. Moreover, it may be difficult to determine if a chain is only sampling a certain area of the space or if it has indeed reached stationarity. In this paper, we show how a simple modification of the proposal mechanism results in faster convergence of the chain and helps to circumvent the problems described above. This mechanism, which is based on an idea from the field of “small-world” networks, amounts to adding occasional “wild” proposals to any local proposal scheme. We demonstrate through both theory and extensive simulations, that these new proposal distributions can greatly outperform the traditional local proposals when it comes to exploring complex heterogenous spaces and multi-modal distributions. Our method can easily be applied to most, if not all, problems involving MCMC and unlike many other remedies which improve the performance of MCMC it preserves the simplicity of the underlying algorithm.     

Profile upper Confidence Limits from Discrete Data

When the data are discrete, standard approximate confidence limits often have coverage well below nominal for some parameter values. While ad hoc adjustments may largely solve this problem for particular cases, Kabaila & Lloyd (1997) gave a more systematic method of adjustment which leads to tight upper limits, which have coverage which is never below nominal and are as small as possible within a particular class. However, their computation for all but the simplest models is infeasible. This paper suggests modifying tight upper limits by an initial replacement of the unknown nuisance parameter vector by its profile maximum likelihood estimator. While the resulting limits no longer possess the optimal properties of tight limits exactly, the paper presents both numerical and theoretical evidence that the resulting coverage function is close to optimal. Moreover these profile upper limits are much (possibly many orders of magnitude) easier to compute than tight upper limits.     

Amplification of Sensitivity Analysis in Matched Observational Studies

A sensitivity analysis displays the increase in uncertainty that attends an inference when a key assumption is relaxed. In matched observational studies of treatment effects, a key assumption in some analyses is that subjects matched for observed covariates are comparable, and this assumption is relaxed by positing a relevant covariate that was not observed and not controlled by matching. What properties would such an unobserved covariate need to have to materially alter the inference about treatment effects? For ease of calculation and reporting, it is convenient that the sensitivity analysis be of low dimension, perhaps indexed by a scalar sensitivity parameter, but for interpretation in specific contexts, a higher dimensional analysis may be of greater relevance. An amplification of a sensitivity analysis is defined as a map from each point in a low dimensional sensitivity analysis to a set of points, perhaps a 'curve,' in a higher dimensional sensitivity analysis such that the possible inferences are the same for all points in the set. Possessing an amplification, an investigator may calculate and report the low dimensional analysis, yet have available the interpretations of the higher dimensional analysis.     

Estimation in capture–recapture models when covariates are subject to measurement errors and missing data

For capture–recapture models when covariates are subject to measurement errors and missing data, a set of estimating equations is constructed to estimate population size and relevant parameters. These estimating equations can be solved by an algorithm similar to the EM algorithm. The proposed method is also applicable to the situation when covariates with no measurement errors have missing data. Simulation studies are used to assess the performance of the proposed estimator. The estimator is also applied to a capture–recapture experiment on the bird species Prinia flaviventris in Hong Kong. The Canadian Journal of Statistics 37: 645–658; 2009 © 2009 Statistical Society of Canada