Saturated main-effect designs for factorial experiments

The results of a computer search for saturated designs for 2ⁿ factorial experiments with n runs is reported, (where n = 2 mod 4). A complete search of the design space is avoided by focussing on designs constructed from cyclic generators. A method of searching quickly for the best generators is given. The resulting designs are as good as, and sometimes better than, designs obtained via search algorithms reported in the literature. The addition of a further factor having three levels is also considered. Here, too, a complete search is avoided by restricting attention to the most efficient part of the design space under p-efficiency.     

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.     

Constructing optimal designs for fitting pharmacokinetic models

We consider some computational issues that arise when searching for optimal designs for pharmacokinetic (PK) studies. Special factors that distinguish these are (i) repeated observations are taken from each subject and the observations are usually described by a nonlinear mixed model (NLMM), (ii) design criteria depend on the model fitting procedure, (iii) in addition to providing efficient parameter estimates, the design must also permit model checking, (iv) in practice there are several design constraints, (v) the design criteria are computationally expensive to evaluate and often numerical integration is needed and finally (vi) local optimisation procedures may fail to converge or get trapped at local optima.We review current optimal design algorithms and explore the possibility of using global optimisation procedures. We use these latter procedures to find some optimal designs.For multi-purpose designs we suggest two surrogate design criteria for model checking and illustrate their use.     

Identifiable finite mixtures of location models for clustering mixed-mode data

For clustering mixed categorical and continuous data, Lawrence and Krzanowski (1996) proposed a finite mixture model in which component densities conform to the location model. In the graphical models literature the location model is known as the homogeneous Conditional Gaussian model. In this paper it is shown that their model is not identifiable without imposing additional restrictions. Specifically, for g groups and m locations, (g!)m–1 distinct sets of parameter values (not including permutations of the group mixing parameters) produce the same likelihood function. Excessive shrinkage of parameter estimates in a simulation experiment reported by Lawrence and Krzanowski (1996) is shown to be an artifact of the model's non-identifiability. Identifiable finite mixture models can be obtained by imposing restrictions on the conditional means of the continuous variables. These new identified models are assessed in simulation experiments. The conditional mean structure of the continuous variables in the restricted location mixture models is similar to that in the underlying variable mixture models proposed by Everitt (1988), but the restricted location mixture models are more computationally tractable.     

Assessing robustness of crossover designsto subjects dropping out

In some crossover experiments, particularly in medical applications, subjects may fail to complete their sequences of treatments for reasons unconnected with the treatments received. A method is described of assessing the robustness of a planned crossover design, with more than two periods, to subjects leaving the study prematurely. The method involves computing measures of efficiency for every possible design that can result, and is therefore very computationally intensive. Summaries of these measures are used to choose between competing designs. The computational problem is reduced to a manageable size by a software implementation of Polya theory. The method is applied to comparing designs for crossover studies involving four treatments and four periods. Designs are identified that are more robust to subjects dropping out in the final period than those currently favoured in medical and clinical trials.     

Using quantile averages in matched observational studies

In two observational studies, one investigating the effects of minimum wage laws on employment and the other of the effects of exposures to lead, an estimated treatment effect's sensitivity to hidden bias is examined. The estimate uses the combined quantile averages that were introduced in 1981 by B. M. Brown as simple, efficient, robust estimates of location admitting both exact and approximate confidence intervals and significance tests. Closely related to Gastwirth's estimate and Tukey's trimean, the combined quantile average has asymptotic efficiency for normal data that is comparable with that of a 15% trimmed mean, and higher efficiency than the trimean, but it has resistance to extreme observations or breakdown comparable with that of the trimean and better than the 15% trimmed mean. Combined quantile averages provide consistent estimates of an additive treatment effect in a matched randomized experiment. Sensitivity analyses are discussed for combined quantile averages when used in a matched observational study in which treatments are not randomly assigned. In a sensitivity analysis in an observational study, subjects are assumed to differ with respect to an unobserved covariate that was not adequately controlled by the matching, so that treatments are assigned within pairs with probabilities that are unequal and unknown. The sensitivity analysis proposed here uses significance levels, point estimates and confidence intervals based on combined quantile averages and examines how these inferences change under a range of assumptions about biases due to an unobserved covariate. The procedures are applied in the studies of minimum wage laws and exposures to lead. The first example is also used to illustrate sensitivity analysis with an instrumental variable.     

Modelling Variability in the Branching Structure of Strawberry Inflorescences

The branching structure of inflorescences of the cultivated strawberry ( Fragaria × ananassa Duch.) is very variable. This paper demonstrates that some aspects of this variability are well described by a simple stochastic model of branching that has two adjustable parameters. The model is shown to provide a good fit to data from a set of almost 700 inflorescences of the cultivar Elsanta, collected over two successive years. For one parameter the maximum likelihood estimator is a moment estimator which is fully efficient even if the detailed branching structure of the inflorescences is not recorded. This parameter provides a convenient summary of branching vigour. The maximum likelihood estimator of the second parameter must be determined iteratively and can be quite inefficient unless the full branching structure is recorded. The model demonstrates that branching structure is affected by the order in which inflorescences emerge on the plant.     

A Discrete Variable Chain Graph for Applicants for Credit

A bank offering unsecured personal loans may be interested in several related outcome variables, including defaulting on the repayments, early repayment or failing to take up an offered loan. Current predictive models used by banks typically consider such variables individually. However, the fact that they are related to each other, and to many interrelated potential predictor variables, suggests that graphical models may provide an attractive alternative solution. We developed such a model for a data set of 15 variables measured on a set of 14 000 applications for unsecured personal loans. The resulting global model of behaviour enabled us to identify several previously unsuspected relationships of considerable interest to the bank. For example, we discovered important but obscure relationships between taking out insurance, prior delinquency with a credit card and delinquency with the loan.     

Detecting a changed segment in DNA sequences

Non-coding deoxyribonucleic acid (DNA) can typically be modelled by a sequence of Bernoulli random variables by coding one base, e.g. T, as 1 and other bases as 0. If a segment of a sequence is functionally important, the probability of a 1 will be different in this changed segment from that in the surrounding DNA. It is important to be able to see whether such a segment occurs in a particular DNA sequence and to pin-point it so that a molecular biologist can investigate its possible function. Here we discuss methods for testing the occurrence of such a changed segment and how to estimate the end points of it. Maximum-likelihood-based methods are not very tractable and so a nonparametric method based on the approach of Pettitt has been developed. The problem and its solution are illustrated by a specific DNA example.     

Likelihood Factorizations for Mixed Discrete and Continuous Variables

Some general remarks are made about likelihood factorizations, distinguishing parameter-based factorizations and concentration-graph factorizations. Two parametric families of distributions for mixed discrete and continuous variables are discussed. Conditions on graphs are given for the circumstances under which their joint analysis can be split into separate analyses, each involving a reduced set of component variables and parameters. The result shows marked differences between the two families although both involve the same necessary condition on prime graphs. This condition is both necessary and sufficient for simplified estimation in Gaussian and for discrete log linear models.