Parametric non-mixture cure models for schedule finding of therapeutic agents

We propose a phase I clinical trial design that seeks to determine the cumulative safety of a series of administrations of a fixed dose of an investigational agent. In contrast with traditional phase I trials that are designed solely to find the maximum tolerated dose of the agent, our design instead identifies a maximum tolerated schedule that includes a maximum tolerated dose as well as a vector of recommended administration times. Our model is based on a non-mixture cure model that constrains the probability of dose limiting toxicity for all patients to increase monotonically with both dose and the number of administrations received. We assume a specific parametric hazard function for each administration and compute the total hazard of dose limiting toxicity for a schedule as a sum of individual administration hazards. Throughout a variety of settings motivated by an actual study in allogeneic bone marrow transplant recipients, we demonstrate that our approach has excellent operating characteristics and performs as well as the only other currently published design for schedule finding studies. We also present arguments for the preference of our non-mixture cure model over the existing model.     

On pseudo-values for regression analysis in competing risks models

For regression on state and transition probabilities in multi-state models Andersen et al. (Biometrika 90:15–27, 2003) propose a technique based on jackknife pseudo-values. In this article we analyze the pseudo-values suggested for competing risks models and prove some conjectures regarding their asymptotics (Klein and Andersen, Biometrics 61:223–229, 2005). The key is a second order von Mises expansion of the Aalen-Johansen estimator which yields an appropriate representation of the pseudo-values. The method is illustrated with data from a clinical study on total joint replacement. In the application we consider for comparison the estimates obtained with the Fine and Gray approach (J Am Stat Assoc 94:496–509, 1999) and also time-dependent solutions of pseudo-value regression equations.     

A Bayesian approach to non-parametric monotone function estimation

Summary.  The paper proposes two Bayesian approaches to non-parametric monotone function estimation. The first approach uses a hierarchical Bayes framework and a characterization of smooth monotone functions given by Ramsay that allows unconstrained estimation. The second approach uses a Bayesian regression spline model of Smith and Kohn with a mixture distribution of constrained normal distributions as the prior for the regression coefficients to ensure the monotonicity of the resulting function estimate. The small sample properties of the two function estimators across a range of functions are provided via simulation and compared with existing methods. Asymptotic results are also given that show that Bayesian methods provide consistent function estimators for a large class of smooth functions. An example is provided involving economic demand functions that illustrates the application of the constrained regression spline estimator in the context of a multiple-regression model where two functions are constrained to be monotone.     

A course in constructing effective displays of data for pharmaceutical research personnel

Interpreting data and communicating effectively through graphs and tables are requisite skills for statisticians and non‐statisticians in the pharmaceutical industry. However, the quality of visual displays of data in the medical and pharmaceutical literature and at scientific conferences is severely lacking. We describe an interactive, workshop‐driven, 2‐day short course that we constructed for pharmaceutical research personnel to learn these skills. The examples in the course and the workshop datasets source from our professional experiences, the scientific literature, and the mass media. During the course, the participants are exposed to and gain hands‐on experience with the principles of visual and graphical perception, design, and construction of both graphic and tabular displays of quantitative and qualitative information. After completing the course, with a critical eye, the participants are able to construct, revise, critique, and interpret graphic and tabular displays according to an extensive set of guidelines. Copyright © 2013 John Wiley & Sons, Ltd.     

Non-negative estimation of variance components in heteroscedastic one-way random-effects ANOVA models

There is a considerable amount of literature dealing with inference about the parameters in a heteroscedastic one-way random-effects ANOVA model. In this paper, we primarily address the problem of improved quadratic estimation of the random-effect variance component. It turns out that such estimators with a smaller mean squared error compared with some standard unbiased quadratic estimators exist under quite general conditions. Improved estimators of the error variance components are also established.     

The computational aspects of multiple attribute sampling procedures

One method of controlling the quality of incoming lots is through attribute sampling. To simultaneously control several (possibly dependent) attributes, properly chosen single attribute sampling plans can be merged into a multiple attribute sampling plan. The general form of such a plan is given and various alternatives are discussed. The multinomial distribution is used to develop formulae necessary for an analysis of a multiple attribute plan. Due to the lengthy nature of the calculations involved, a computer algorithm is outlined.     

On the use of curve fitting to model the error of the Cornish-Fisher expansion of the pearson type-VI distribution

The Cornish-Fisher expansion of the Pearson type VI distribution is known to be reasonably accurate when both degrees of freedom are relatively large (say greater than or equal to 5). However, when either or both degrees of freedom are less than 5, the accuracy of the computed percentage point begins to suffer; in some cases severely. To correct for this, the error surface in the degrees of freedom plane is modeled by least squares curve fitting for selected levels of tail probability (.025, .05, and .10) which can be used to adjust the percentage point obtained from the usual Cornish-Fisher expansion. This adjustment procedure produces a computing algorithm that computes percentage points of the Pearson type VI distribution at the above probability levels, accurate to at least + 1 in 3 digits in approximately 11 milliseconds per subroutine call on an IBM 370/145. This adjusted routine is valid for both degrees of freedom greater than or equal to 1.     

Tests of hypotheses based on ranks in the general linear model

A unified approach is developed for testing hypotheses in the general linear model based on the ranks of the residuals. It complements the nonparametric estimation procedures recently reported in the literature. The testing and estimation procedures together provide a robust alternative to least squares. The methods are similar in spirit to least squares so that results are simple to interpret. Hypotheses concerning a subset of specified parameters can be tested, while the remaining parameters are treated as nuisance parameters. Asymptotically, the test statistic is shown to have a chi-square distribution under the null hypothesis. This result is then extended to cover a sequence of contiguous alternatives from which the Pitman efficacy is derived. The general application of the test requires the consistent estimation of a functional of the underlying distribution and one such estimate is furnished.     

Using regression mixture models with non-normal data: examining an ordered polytomous approach

Mild to moderate skew in errors can substantially impact regression mixture model results; one approach for overcoming this includes transforming the outcome into an ordered categorical variable and using a polytomous regression mixture model. This is effective for retaining differential effects in the population; however, bias in parameter estimates and model fit warrant further examination of this approach at higher levels of skew. The current study used Monte Carlo simulations; 3000 observations were drawn from each of two subpopulations differing in the effect of X on Y. Five hundred simulations were performed in each of the 10 scenarios varying in levels of skew in one or both classes. Model comparison criteria supported the accurate two-class model, preserving the differential effects, while parameter estimates were notably biased. The appropriate number of effects can be captured with this approach but we suggest caution when interpreting the magnitude of the effects.     

Gaining insight with recursive partitioning of generalized linear models

Recursive partitioning algorithms separate a feature space into a set of disjoint rectangles. Then, usually, a constant in every partition is fitted. While this is a simple and intuitive approach, it may still lack interpretability as to how a specific relationship between dependent and independent variables may look. Or it may be that a certain model is assumed or of interest and there is a number of candidate variables that may non-linearly give rise to different model parameter values. We present an approach that combines generalized linear models (GLM) with recursive partitioning that offers enhanced interpretability of classical trees as well as providing an explorative way to assess a candidate variable's influence on a parametric model. This method conducts recursive partitioning of a GLM by (1) fitting the model to the data set, (2) testing for parameter instability over a set of partitioning variables, (3) splitting the data set with respect to the variable associated with the highest instability. The outcome is a tree where each terminal node is associated with a GLM. We will show the method's versatility and suitability to gain additional insight into the relationship of dependent and independent variables by two examples, modelling voting behaviour and a failure model for debt amortization, and compare it to alternative approaches.