Clinical Trials with Exponential Survival Times

We consider a bandit process with delayed responses which are exponentially distributed survival times. The objective is to maximize the expected value of the total response from all selections. We formulate the problem and show that the optimal strategy is characterized by a sequence of break-even values. A monotonicity property of this sequence is derived, which implies the non-optimality of the myopic strategy and a special optimal stopping solution. An example is included to illustrate a possible application of the main results.     

Marginal Regression for Binary Longitudinal Data in Adaptive Clinical Trials

Abstract.  In an adaptive clinical trial research, it is common to use certain data-dependent design weights to assign individuals to treatments so that more study subjects are assigned to the better treatment. These design weights must also be used for consistent estimation of the treatment effects as well as the effects of the other prognostic factors. In practice, there are however situations where it may be necessary to collect binary responses repeatedly from an individual over a period of time and to obtain consistent estimates for the treatment effect as well as the effects of the other covariates in such a binary longitudinal set up. In this paper, we introduce a binary response-based longitudinal adaptive design for the allocation of individuals to a better treatment and propose a weighted generalized quasi-likelihood approach for the consistent and efficient estimation of the regression parameters including the treatment effects.     

Application of Multiple Imputation in Analysis of Data from Clinical Trials with Treatment Related Dropouts

This article develops a functional form of the generalized Poisson regression model that parametrically nests the Poisson and the two well known generalized Poisson regression models (GP-1 and GP-2). The proposed model is applied on the Malaysian motor insurance claim count data.     

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.     

Assessing Effects on Long-term Survival after Early Termination of Randomized Trials

In this paper we present an approach to using historical control data to augment information from a randomized controlled clinical trial, when it is not possible to continue the control regimen to obtain the most reliable and valid assessment of long term treatment effects. Using an adjustment procedure to the historical control data, we investigate a method of estimating the long term survival function for the clinical trial control group and for evaluating the long term treatment effect. The suggested method is simple to interpret, and particularly motivated in clinical trial settings when ethical considerations preclude the long term follow-up of placebo controls. A simulation study reveals that the bias in parameter estimates that arises in the setting of group sequential monitoring will be attenuated when long term historical control information is used in the proposed manner. Data from the first and second National Wilms' Tumor studies are used to illustrate the method.     

Missing Data Mechanisms for Analysing Longitudinal Data with Incomplete Observations in Both Responses and Covariates

Missing observations in both responses and covariates arise frequently in longitudinal studies. When missing data are missing not at random, inferences under the likelihood framework often require joint modelling of response and covariate processes, as well as missing data processes associated with incompleteness of responses and covariates. Specification of these four joint distributions is a nontrivial issue from the perspectives of both modelling and computation. To get around this problem, we employ pairwise likelihood formulations, which avoid the specification of third or higher order association structures. In this paper, we consider three specific missing data mechanisms which lead to further simplified pairwise likelihood (SPL) formulations. Under these missing data mechanisms, inference methods based on SPL formulations are developed. The resultant estimators are consistent, and enjoy better robustness and computation convenience. The performance is evaluated empirically though simulation studies. Longitudinal data from the National Population Health Survey and Waterloo Smoking Prevention Project are analysed to illustrate the usage of our methods.     

Rank Tests for Matched Survival Data

In a clinical trial with the time to an event as the outcome of interest, we may randomize a number of matched subjects, such as litters, to different treatments. The number of treatments equals the number of subjects per litter, two in the case of twins. In this case, the survival times of matched subjects could be dependent. Although the standard rank tests, such as the logrank and Wilcoxon tests, for independent samples may be used to test the equality of marginal survival distributions, their standard error should be modified to accommodate the possible dependence of survival times between matched subjects. In this paper we propose a method of calculating the standard error of the rank tests for paired two-sample survival data. The method is naturally extended to that for K-sample tests under dependence.     

Comparisons of Test Statistics Arising from Marginal Analyses of Multivariate Survival Data

We investigate the properties of several statistical tests for comparing treatment groups with respect to multivariate survival data, based on the marginal analysis approach introduced by Wei, Lin and Weissfeld [Regression Analysis of multivariate incomplete failure time data by modelling marginal distributians, JASA vol. 84 pp. 1065–1073]. We consider two types of directional tests, based on a constrained maximization and on linear combinations of the unconstrained maximizer of the working likelihood function, and the omnibus test arising from the same working likelihood. The directional tests are members of a larger class of tests, from which an asymptotically optimal test can be found. We compare the asymptotic powers of the tests under general contiguous alternatives for a variety of settings, and also consider the choice of the number of survival times to include in the multivariate outcome. We illustrate the results with simulations and with the results from a clinical trial examining recurring opportunistic infections in persons with HIV.     

Flexible Bayesian Modelling for Survival Data

The analysis of failure time data often involves two strong assumptions. The proportional hazards assumption postulates that hazard rates corresponding to different levels of explanatory variables are proportional. The additive effects assumption specifies that the effect associated with a particular explanatory variable does not depend on the levels of other explanatory variables. A hierarchical Bayes model is presented, under which both assumptions are relaxed. In particular, time-dependent covariate effects are explicitly modelled, and the additivity of effects is relaxed through the use of a modified neural network structure. The hierarchical nature of the model is useful in that it parsimoniously penalizes violations of the two assumptions, with the strength of the penalty being determined by the data.     

Rank Tests for Clustered Survival Data

In a clinical trial, we may randomize subjects (called clusters) to different treatments (called groups), and make observations from multiple sites (called units) of each subject. In this case, the observations within each subject could be dependent, whereas those from different subjects are independent. If the outcome of interest is the time to an event, we may use the standard rank tests proposed for independent survival data, such as the logrank and Wilcoxon tests, to test the equality of marginal survival distributions, but their standard error should be modified to accommodate the possible intracluster correlation. In this paper we propose a method of calculating the standard error of the rank tests for two-sample clustered survival data. The method is naturally extended to that for K-sample tests under dependence.     

Self-Consistency Estimation of Distributions Based on Truncated and Doubly Censored Survival Data with Applications to AIDS Cohort Studies

Gomez and Lagakos (1994) propose a nonparametric method for estimating the distribution of a survival time when the origin and end points defining the survival time suffer interval-censoring and right-censoring, respectively. In some situations, the end point also suffers interval-censoring as well as truncation. In this paper, we consider this general situation and propose a two-step estimation procedure for the estimation of the distribution of a survival time based on doubly interval-censored and truncated data. The proposed method generalizes the methods proposed by DeGruttola and Lagakos (1989) and Sun (1995) and is more efficient than that given in Gomez and Lagakos (1994). The approach is based on self-consistency equations. The method is illustrated by an analysis of an AIDS cohort study.     

Duration of Accrual and Follow-up for Two-Stage Clinical Trials

Group sequential trialswith time to event end points can be complicated to design. Notonly are there unlimited choices for the number of events requiredat each stage, but for each of these choices, there are unlimitedcombinations of accrual and follow-up at each stage that providethe required events. Methods are presented for determining optimalcombinations of accrual and follow-up for two-stage clinicaltrials with time to event end points. Optimization is based onminimizing the expected total study length as a function of theexpected accrual duration or sample size while providing an appropriateoverall size and power. Optimal values of expected accrual durationand minimum expected total study length are given assuming anexponential proportional hazards model comparing two treatmentgroups. The expected total study length can be substantiallydecreased by including a follow-up period during which accrualis suspended. Conditions that warrant an interim follow-up periodare considered, and the gain in efficiency achieved by includingan interim follow-up period is quantified. The gain in efficiencyshould be weighed against the practical difficulties in implementingsuch designs. An example is given to illustrate the use of thesetechniques in designing a clinical trial to compare two chemotherapyregimens for lung cancer. Practical considerations of includingan interim follow-up period are discussed.     

A Quantile Survival Model for Censored Data

In this paper we propose a quantile survival model to analyze censored data. This approach provides a very effective way to construct a proper model for the survival time conditional on some covariates. Once a quantile survival model for the censored data is established, the survival density, survival or hazard functions of the survival time can be obtained easily. For illustration purposes, we focus on a model that is based on the generalized lambda distribution (GLD). The GLD and many other quantile function models are defined only through their quantile functions, no closed‐form expressions are available for other equivalent functions. We also develop a Bayesian Markov Chain Monte Carlo (MCMC) method for parameter estimation. Extensive simulation studies have been conducted. Both simulation study and application results show that the proposed quantile survival models can be very useful in practice.     

Multilevel Mixed Linear Models for Survival Data

For the analysis of correlated survival data mixed linear models are useful alternatives to frailty models. By their use the survival times can be directly modelled, so that the interpretation of the fixed and random effects is straightforward. However, because of intractable integration involved with the use of marginal likelihood the class of models in use has been severely restricted. Such a difficulty can be avoided by using hierarchical-likelihood, which provides a statistically efficient and fast fitting algorithm for multilevel models. The proposed method is illustrated using the chronic granulomatous disease data. A simulation study is carried out to evaluate the performance.     

Bayesian Transformation Models for Multivariate Survival Data

In this paper, we propose a general class of Gamma frailty transformation models for multivariate survival data. The transformation class includes the commonly used proportional hazards and proportional odds models. The proposed class also includes a family of cure rate models. Under an improper prior for the parameters, we establish propriety of the posterior distribution. A novel Gibbs sampling algorithm is developed for sampling from the observed data posterior distribution. A simulation study is conducted to examine the properties of the proposed methodology. An application to a data set from a cord blood transplantation study is also reported.