Accommodating stochastic departures from percentile invariance in causal models

Summary.  Consider a clinical trial in which participants are randomized to a single-dose treatment or a placebo control and assume that the adherence level is accurately recorded. If the treatment is effective, then good adherers in the treatment group should do better than poor ad- herers because they received more drug; the treatment group data follow a dose–response curve. But, good adherers to the placebo often do better than poor adherers, so the observed adherence–response in the treatment group cannot be completely attributed to the treatment. Efron and Feldman proposed an adjustment to the observed adherence–response in the treatment group by using the adherence–response in the control group. It relies on a percentile invariance assumption under which each participant's adherence percentile within their assigned treatment group does not depend on the assigned group (active drug or placebo). The Efron and Feldman approach is valid under percentile invariance, but not necessarily under departures from it. We propose an analysis based on a generalization of percentile invariance that allows adherence percentiles to be stochastically permuted across treatment groups, using a broad class of stochastic permutation models. We show that approximate maximum likelihood estimates of the underlying dose–response curve perform well when the stochastic permutation process is correctly specified and are quite robust to model misspecification.     

Using statistical techniques to detect fraud: a test case

In an experiment to test the effectiveness of statistical measures in detecting fraud, three physicians fabricated scores on the Montgomery–Åsberg Depression Rating Scale (MADRS) for a number of subjects in three sites. The fabricated data were then planted among MADRS data from 18 genuine sites. A statistician blinded as to the identity and quantity of the fabricated data attempted to detect the ‘fraudulent’ data by searching for unusual means and correlations. One of the three fabricated sites was correctly identified, and one genuine site was incorrectly identified as a potential fabrication. In addition, inlying and/or outlying means and correlations found in the genuine data suggested the possibility of using statistical checks for unusual data early in a study so that sites with unusual patterns could be prioritized for monitoring, training and, if necessary, auditing. Copyright © 2004 John Wiley & Sons Ltd.     

Minimax estimation of a probability of success under LINEX loss

Minimax estimation of a binomial probability under LINEX loss function is considered. It is shown that no equalizer estimator is available in the statistical decision problem under consideration. It is pointed out that the problem can be solved by determining the Bayes estimator with respect to a least favorable distribution having finite support. In this situation, the optimal estimator and the least favorable distribution can be determined only by using numerical methods. Some properties of the minimax estimators and the corresponding least favorable prior distributions are provided depending on the parameters of the loss function. The properties presented are exploited in computing the minimax estimators and the least favorable distributions. The results obtained can be applied to determine minimax estimators of a cumulative distribution function and minimax estimators of a survival function.     

Testing for ordered failure rates under general progressive censoring

For exponentially distributed failure times under general progressive censoring schemes, testing procedures for ordered failure rates are proposed using the likelihood ratio principle. Constrained maximum likelihood estimators of the failure rates are found. The asymptotic distributions of the test statistics are shown to be mixtures of chi-square distributions. When testing the equality of the failure rates, a simulation study shows that the proposed test with restricted alternative has improved power over the usual chi-square statistic with an unrestricted alternative. The proposed methods are illustrated using data of survival times of patients with squamous carcinoma of the oropharynx.     

Dynamic allocation as a balancing act

The CPMP Points to Consider on Adjustment for Baseline Covariates recently came into operation. As well as providing sound guidance, this document states a strong position against dynamic allocation. This paper reviews the most important issues involved and aims to stimulate interest in further investigating alternative allocation methods in clinical trials. Copyright © 2004 John Wiley & Sons, Ltd.     

A Bayesian method of sample size determination with practical applications

Summary.  The problem motivating the paper is the determination of sample size in clinical trials under normal likelihoods and at the substantive testing stage of a financial audit where normality is not an appropriate assumption. A combination of analytical and simulation-based techniques within the Bayesian framework is proposed. The framework accommodates two different prior distributions: one is the general purpose fitting prior distribution that is used in Bayesian analysis and the other is the expert subjective prior distribution, the sampling prior which is believed to generate the parameter values which in turn generate the data. We obtain many theoretical results and one key result is that typical non-informative prior distributions lead to very small sample sizes. In contrast, a very informative prior distribution may either lead to a very small or a very large sample size depending on the location of the centre of the prior distribution and the hypothesized value of the parameter. The methods that are developed are quite general and can be applied to other sample size determination problems. Some numerical illustrations which bring out many other aspects of the optimum sample size are given.     

NEAREST NEIGHBOUR ANALYSIS OF UNEQUALLY REPLICATED TRIALS

There has been much work on the use of neighbouring plots to control environmental variation in the analysis of agricultural field experiments. In particular, the Residual Maximum Likelihood Neighbour (REMLN) analysis of Gleeson&Cullis (1987) appears very promising. The application of the REMLN analysis to an unequally replicated field trial augmented with an additional variety planted every six plots in a grid system is here compared with a covariance (COV) analysis using the neighbouring grid or check plot values as the covariate. The results indicate that the REMLN analysis gives more accurate estimates of treatment contrasts than the COV analyses, but that the estimate of treatment means can be biased. The bias depends on the mean of the check plot. This bias can be removed by adjusting the estimates of the treatment means such that their average equals the average of the raw means rather than that of the raw data.     

Some large trial properties of minimum likelihood allocation

The method of minimum likelihood allocation (MLA) for allocating subjects to treatments in a clinical trial amounts to checking at each stage which allocation would lead an outside observer to find the least evidence of a relationship between treatment and factors of prognostic significance, assuming that the observer would use a linear exponential model. One advantage of MLA is that results from game theory and likelihood theory can be used to prove it has desirable long run properties. Two of these demonstrated here are (1) ‘consistency’, in the sense that the average likelihood ratio which measures design imbalance tends to zero, and (2) ‘efficiency’ in the sense that the variance estimates of treatment effects will tend to be minimized in the long run.     

Some computational problems related to multinomial trials

Efficient numerical algorithms are developed to evaluate several probabilities related to multinomial trials.In the first part of the paper, the probability distribution of the number of trials until the alternatives j, j = 1,… m, have occurred at least i_j times is computed. The multinomial trials involve the m alternatives l,…, m, with positive probabilities P_l-P_m of occurrence. In the second part, several aspects of a multinomial subset selection problem, discussed by S. S. Gupta and K. Nagel, are investigated.