Issues in the design and analysis of therapeutic trials in human immunodeficiency virus infection

The first randomized trial of antiviral therapy in human immunodeficiency virus (HIV) disease included 282 patients with acquired immune deficiency syndrome (AIDS) or AIDS-related complex and was stopped in 1986 after an average follow-up of 4 months because of a substantial reduction in mortality in the group who received zidovudine (AZT). The era of anti-HIV treatment had begun. This paper discusses some of the difficulties which have emerged over the subsequent 10 years as new anti-HIV drugs have been developed requiring evaluation in clinical trials. The trials in which the British Medical Research Council has played a major role (the Concorde, Alpha and Delta trials) and some of the key trials conducted by the AIDS Clinical Trials Group (ACTG) (the ACTG 019 and ACTG 175 trials) and the Community Programs for Clinical Research on AIDS (CPCRA) (the CPCRA 007 trial) in the US will be used to illustrate some of the issues faced by clinical trialists and governmental regulatory agencies in the evaluation of therapies for a disease which, in spite of advances in therapy, still has a high mortality.     

Simultaneous Confidence Intervals for the Mean of Multivariate Poisson Distribution: A Comparison

Haibing (2009) proposed a procedure for successive comparisons between ordered treatment effects in one-way layout and showed that the proposed procedure has greater power than the procedure proposed by Lee and Spurrier (1995). Critical constants required for the proposed procedure were estimated using Monte Carlo simulation and few values of the constants were tabulated which limit the applications of the proposed procedure. In this article, a numerical method, using recursive integration methodology, is discussed to compute the critical constants which work efficiently for a large number of treatments and extensive values of critical constants are tabulated for the use of practitioners. Power comparisons of Haibing's and Lee and Spurrier's procedure is also discussed.     

On the effect of the number of quadrature points in a logistic random effects model: an example

Although generalized linear mixed models are recognized to be of major practical importance, it is also known that they can be computationally demanding. The problem is the evaluation of the integral in calculating the marginalized likelihood. The straightforward method is based on the Gauss–Hermite technique, based on Gaussian quadrature points. Another approach is provided by the class of penalized quasi-likelihood methods. It is commonly believed that the Gauss–Hermite method works relatively well in simple situations but fails in more complicated structures. However, we present here a strikingly simple example of a logistic random-intercepts model in the context of a longitudinal clinical trial where the method gives valid results only for a high number of quadrature points ( Q ). As a consequence, this result warns the practitioner to examine routinely the dependence of the results on Q . The adaptive Gaussian quadrature, as implemented in the new SAS procedure NLMIXED, offered the solution to our problem. However, even the adaptive version of Gaussian quadrature needs careful handling to ensure convergence.     

Robustness of the Multiple Correlation Coefficient When Sampling From a Mixture of Two Multivariate Normal Populations

The density of the multiple correlation coefficient is derived by direct integration when the sample covariance matrix has a linear non-central distribution. Using the density, we deduce the null and non-null distribution of the multiple correlation coefficient when sampling from a mixture of two multivariate normal populations with the same covariance matrix. We also compute actual significance levels of the test of the hypothesis H_o : ρ_1·2…p = 0 versus H_a:ρ_1·2…p > 0, given the mixture model.     

Estimators of the multiple correlation coefficient: Local robustness and confidence intervals

Many robust regression estimators are defined by minimizing a measure of spread of the residuals. An accompanying R ²-measure, or multiple correlation coefficient, is then easily obtained. In this paper, local robustness properties of these robust R ²-coefficients are investigated. It is also shown how confidence intervals for the population multiple correlation coefficient can be constructed in the case of multivariate normality.     

Nonparametric estimation of the sojourn time distributions for a multipath model

Summary. We use a multipath (multistate) model to describe data with multiple end points. Statistical inference based on the intermediate end point is challenging because of the problems of nonidentifiability and dependent censoring. We study nonparametric estimation for the path probability and the sojourn time distributions between the states. The methodology proposed can be applied to analyse cure models which account for the competing risk of death. Asymptotic properties of the estimators proposed are derived. Simulation shows that the methods proposed have good finite sample performance. The methodology is applied to two data sets.     

Bayes methods in the ecological fallacy cntext:estimation of individual correlation from aggregate data

The ecological fallacy is related to Simpson's paradox (1951) where relationships among group means may be counterintuitive and substantially different from relationships within groups, where the groups are usually geographic entities such as census tracts. We consider the problem of estimating the correlation between two jointly normal random variables where only ecological data (group means) are available. Two empirical Bayes estimators and one fully Bayesian estimator are derived and compared with the usual ecological estimator, which is simply the Pearson correlation coefficient of the group sample means. We simulate the bias and mean squared error performance of these estimators, and also give an example employing a dataset where the individual level data are available for model checking. The results indicate superiority of the empirical Bayes estimators in a variety of practical situations where, though we lack individual level data, other relevant prior information is available.     

Layered clays in PP polymer dispersion: the effect of the processing conditions

The effect of processing conditions of material and interfacial/ interphase properties in clay/polymer nanocomposites are usually studied through experimental results of X-ray diffraction, transmission electron microscopy and rheology mechanical tests. In this paper, the interaction of the experimental parameters and properties measure results are studied by employing multivariate analysis of variance technique. This model is used to establish relations between several material and interfacial/interphase characteristics with the processing conditions. These results are then analyzed in detail, using univariate approach (analysis of variance), to point out the existing significant relations. In general, agreement with experimental observations was found, but few other nonagreeable things are found out, which must be studied in the future. The effects of all parameters are thus determined, using these new approach, to predict the relations between material and interfacial/interphase properties, without the need to duplicate experiments in laboratory.     

Evaluating the effect of education on earnings: models, methods and results from the National Child Development Survey

Summary.  Regression, matching, control function and instrumental variables methods for recovering the effect of education on individual earnings are reviewed for single treatments and sequential multiple treatments with and without heterogeneous returns. The sensitivity of the estimates once applied to a common data set is then explored. We show the importance of correcting for detailed test score and family background differences and of allowing for (observable) heterogeneity in returns. We find an average return of 27% for those completing higher education versus anything less. Compared with stopping at 16 years of age without qualifications, we find an average return to O-levels of 18%, to A-levels of 24% and to higher education of 48%.     

On the distribution of the correlation coefficient when sampling from a mixture of two bivariate normal densities: Robustness and the effect of outliers

The distribution of the sample correlation coefficient is derived when the population is a mixture of two bivariate normal distributions with zero mean but different covariances and mixing proportions 1 - λ and λ respectively; λ will be called the proportion of contamination. The test of ρ = 0 based on Student's t, Fisher's z, arcsine, or Ruben's transformation is shown numerically to be nonrobust when λ, the proportion of contamination, lies between 0.05 and 0.50 and the contaminated population has 9 times the variance of the standard (bivariate normal) population. These tests are also sensitive to the presence of outliers.