Improving The Efficiency of The Case-Crossover Design

The case-crossover design has been used by many researchers to study the transient effect of an exposure on the risk of a rare outcome. In a case-crossover design, only cases are sampled and each case will act as his/her own control. The time of failure acts as the case and non failure times act as the controls. Case-crossover designs have frequently been used to study the effect of environmental exposures on rare diseases or mortality. Time trends and seasonal confounding may be present in environmental studies and thus need to be controlled for by the sampling design. Several sampling methods are available for this purpose. In time-stratified sampling, disjoint strata of equal size are formed and the control times within the case stratum are used for comparison. The random semi-symmetric sampling design randomly selects a control time for comparison from two possible control times. The fixed semi-symmetric sampling design is a modified version of the random semi-symmetric sampling design that removes the random selection. Simulations show that the fixed semi-symmetric sampling design improves the variance of the random semi-symmetric sampling estimator by at least 35% for the exposures we studied. We derive expressions for the asymptotic variance of risk estimators for these designs, and show, that while the designs are not theoretically equivalent, in many realistic situations, the random semi-symmetric sampling design has similar efficiency to a time-stratified sampling design of size two and the fixed semi-symmetric sampling design has similar efficiency to a time-stratified sampling design of size three.     

A case study comparing a randomized withdrawal trial and a double-blind long-term trial for assessing the long-term efficacy of an antidepressant

Assessing long-term efficacy in psychiatric drugs involves a number of complex questions, and the priaority of these questions is different for different disorders and for different stakeholders. Therefore, it is essential that we not adopt a one-method-fits-all approach, but rather adapt the specific details of the designs and analysis of data from long-term trials to individual disease states. Randomized withdrawal (RW) designs, even though addressing a specific question of particular interest, face some difficult methodological and ethical challenges. A less common alternative design, termed the double-blind long-term efficacy (DBLE) design, is logistically similar to traditional responder extension designs. However, use of an analytic approach that includes all randomized patients rather than only the selected subset that continued beyond acute treatment avoids the major criticism of the extender design. The present paper illustrates the attributes of the RW and DBLE designs by analyzing data from trials adopting these designs. The RW and DBLE designs address different questions, and are thus not directly comparable. Potential benefits of the DBLE design include: (1) the parsimonious use of patients and the resultant reduced exposure to placebo as each patient can contribute to multiple developmental objectives; (2) the results are generalizable to actual clinical practice as the design matches treatment guidelines; and, (3) results of safety assessments are meaningful as they involve all randomized patients. Our case study suggests that the DBLE design can provide definitive answers to important questions and may be a useful design for assessing long-term treatment effects.     

Spacing of information in polynomial regression:a simple solution

Consider a k polynomial regression on a single real variable. If n uncorrelated observations are to be taken in a design with support on more than k+1 points, there is an approximate experiment, ν, with support on k+1 points and n observations such that both designs have the same information matrix for the model. A proof of this result is provided. A method to obtain the approximate design ν is given and illustrated by an example. The source of disagreement between Kiefer (1959) and De La Garza (1954) in the solution of this problem is clarified.     

Designs for two-colour microarray experiments

Summary.  Designs for two-colour microarray experiments can be viewed as block designs with two treatments per block. Explicit formulae for the A- and D-criteria are given for the case that the number of blocks is equal to the number of treatments. These show that the A- and D-optimality criteria conflict badly if there are 10 or more treatments. A similar analysis shows that designs with one or two extra blocks perform very much better, but again there is a conflict between the two optimality criteria for moderately large numbers of treatments. It is shown that this problem can be avoided by slightly increasing the number of blocks. The two colours that are used in each block effectively turn the block design into a row–column design. There is no need to use a design in which every treatment has each colour equally often: rather, an efficient row–column design should be used. For odd replication, it is recommended that the row–column design should be based on a bipartite graph, and it is proved that the optimal such design corresponds to an optimal block design for half the number of treatments. Efficient row–column designs are given for replications 3–6. It is shown how to adapt them for experiments in which some treatments have replication only 2.     

The robustness of response surface designs with errors in factor levels

ABSRTACT

Since errors in factor levels affect the traditional statistical properties of response surface designs, an important question to consider is robustness of design to errors. However, when the actual design could be observed in the experimental settings, its optimality and prediction are of interest. Various numerical and graphical methods are useful tools for understanding the behavior of the designs. The D- and G-efficiencies and the fraction of design space plot are adapted to assess second-order response surface designs where the predictor variables are disturbed by a random error. Our study shows that the D-efficiencies of the competing designs are considerably low for big variance of the error, while the G-efficiencies are quite good. Fraction of design space plots display the distribution of the scaled prediction variance through the design space with and without errors in factor levels. The robustness of experimental designs against factor errors is explored through comparative study. The construction and use of the D- and G-efficiencies and the fraction of design space plots are demonstrated with several examples of different designs with errors.     

The utility of experimental design short courses?

This paper describes the one‐day introduction to experimental design training course at GlaxoSmithKline. In particular, the use of paper helicopter experiments has been an effective and efficient method for teaching experimental design techniques to scientific and other staff. A good supporting strategy by which the statistics department provides back‐up following the course is essential. Copyright © 2002 John Wiley & Sons, Ltd.     

Bayesian design for estimating the turning point of a quadratic regression

The problem of designing an experiment to estimate the point at which a quadratic regression is a maximum, or minimum. is studied. The efficiency of a design depends on the value of the unknown parameters and sequential design is, therefore, more efficient than non-sequential design. We use a Bayesian criterion which is a weighted trace of the inverse of the information matrix with the weights depending on a prior distribution. If design occurs sequentially the weights can be updated. Both sequential and non-sequential Bayesian designs are compared to non-Bayesian sequential designs. The comparison is both theoretical and by simulation.     

On Second-Order A-, D- and E-Minimax Designs for Estimating Slopes in Extrapolation and Restricted Interpolation Regions

Summary

The concepts of D-, A- and E-minimax optimality criteria of designs for estimating the slopes of a response surface are considered for situations where the region of interest may not be identical to the experimental region. Optimal second-order designs are derived for the situation where the experimental region and the region of interest are both hyperspherical with a common centre. The dependence of the optimal design on the relative sizes of the regions is investigated. Further, the perfomance of designs optimal for one region in estimating slopes in other regions is also examined.     

Bayesian two-stage optimal design for mixture models

In this paper, a Bayesian two-stage D–D optimal design for mixture experimental models under model uncertainty is developed. A Bayesian D-optimality criterion is used in the first stage to minimize the determinant of the posterior variances of the parameters. The second stage design is then generated according to an optimalityprocedure that collaborates with the improved model from the first stage data. The results show that a Bayesian two-stage D–D-optimal design for mixture experiments under model uncertainty is more efficient than both the Bayesian one-stage D-optimal design and the non-Bayesian one-stage D-optimal design in most situations. Furthermore, simulations are used to obtain a reasonable ratio of the sample sizes between the two stages.     

Adaptive Crossover Design for Normal Responses

In a response-adaptive design, we review and update the trial on the basis of outcomes in order to achive a specific goal. In clinical trials our goal is to allocate a larger number of patients to the better treatment. In the present paper, we use a response adaptive design in a two-treatment two-period crossover trial where the treatment responses are continuous. We provide probability measures to choose between the possible treatment combinations AA, AB, BA, or BB. The goal is to use the better treatment combination a larger number of times. We calculate the allocation proportions to the possible treatment combinations and their standard errors. We also derive some asymptotic results and provide solutions on related inferential problems. The proposed procedure is compared with a possible competitor. Finally, we use a data set to illustrate the applicability of our proposed design.     

Randomized response multivariate designs for categorical data

Three approaches to multivariate estimation for categorical data using randomized response (RR) are described. In the first approach, practical only for 2×2 contingency tables, a multi-proportions design is used. In the second approach, a separate RR trial is used for each variate and it is noted that the multi­variate design matrix of conditional probabilities is given by the Kroneeker product of the univariate design matrices of each trial, provided that the trials are independent of each other in a certain sense. The third approach requires only a single randomization and thus may be viewed as the use of vector response. Finally, a special-purpose bivariate design is presented.     

An introduction to designh optimality with an overview of the literature

A brief introduction to oprimal design theorv is given for those who are not familiar with the subject. A list of 312 selected articles on the theory of optimal design is provided. The bibliography should be sufficiently thorough to be of use to researchers in the field.     

Constructions of efficiency-balanced designs

We present a number of methods of constructing efficiency-balanced binary block designs which are design patterns for simplification of statistical analysis. Furthermore, a method of construction of an efficiency-balanced block design with v+1 treatments from one with v treatments is generally characterized.     

Characterizing projected designs: repeat and mirror-image runs

Two-level designs are useful to examine a large number of factors in an efficient manner. It is typically anticipated that only a few factors will be identified as important ones. The results can then be reanalyzed using a projection of the original design, projected into the space of the factors that matter. An interesting question is how many intrinsically different type of projections are possible from an initial given design. We examine this question here for the Plackett and Burman screening series with N= 12, 20 and 24 runs and projected dimensions k≤5. As a characterization criterion, we look at the number of repeat and mirror-image runs in the projections. The idea can be applied toany two-level design projected into fewer dimensions.     

CDT-optimum designs for model discrimination, parameter estimation and estimation of a parametric function

After initiating the theory of optimal design by Smith (1918), many optimality criteria were introduced. Atkinson et al. (2007) used the definition of compound design criteria to combine two optimality criteria and introduced the DT- and CD-optimalities criteria. This paper introduces the CDT-optimum design that provides a specified balance between model discrimination, parameter estimation and estimation of a parametric function such as the area under curve in models for drug absorbance. An equivalence theorem is presented for the case of two models.     

Optimal design in average for inference in generalized linear models

This paper considers the problem of optimal design for inference in Generalized Linear Models, when prior information about the parameters is available. The general theory of optimum design usually requires knowledge of the parameter values. These are usually unknown and optimal design can, therefore, not be used in practice. However, one way to circumvent this problem is through so-called “optimal design in average”, or shortly, “ave optimal”. The ave optimal design is chosen to minimize the expected value of some criterion function over a prior distribution. We focus our interest on the aveD _A-optimality, including aveD- and avec-optimality and show the appropriate equivalence theorems for these optimality criterions, which give necessary conditions for an optimal design. Ave optimal designs are of interest when e.g. a factorial experiment with a binary or a Poisson response in to be conducted. The results are applied to factorial experiments, including a control group experiment and a 2×2 experiment.     

Simplex based space filling designs

Space filling designs are important for deterministic computer experiments. Even a single experiment can be very time consuming and can have many input parameters. Furthermore the underlying function generating the output is often nonlinear. Thus, the computer experiment has to be designed carefully. There exist many design criteria, which can be numerically optimized. Here, a method is developed, which does not need algorithmic optimization. A mesh of nearly regular simplices is constructed and the vertices of the simplices are used as potential design points. The extraction of a design from these meshes is very fast and easy to implement once the underlying mesh has been constructed. The extracted designs are highly competitive regarding the maximin design criterion and it is easy to extract designs for nonstandard design spaces.     

Implementation of maximin efficient designs in dose‐finding studies

This paper considers the maximin approach for designing clinical studies. A maximin efficient design maximizes the smallest efficiency when compared with a standard design, as the parameters vary in a specified subset of the parameter space. To specify this subset of parameters in a real situation, a four‐step procedure using elicitation based on expert opinions is proposed. Further, we describe why and how we extend the initially chosen subset of parameters to a much larger set in our procedure. By this procedure, the maximin approach becomes feasible for dose‐finding studies. Maximin efficient designs have shown to be numerically difficult to construct. However, a new algorithm, the H‐algorithm, considerably simplifies the construction of these designs. We exemplify the maximin efficient approach by considering a sigmoid Emax model describing a dose–response relationship and compare inferential precision with that obtained when using a uniform design. The design obtained is shown to be at least 15% more efficient than the uniform design. © 2014 The Authors. Pharmaceutical Statistics Published by John Wiley & Sons Ltd.     

Optimal parametric design with applications to pharmacokinetic and pharmacodynamic trials

This paper considers optimal parametric designs, i.e. designs represented by probability measures determined by a set of parameters, for nonlinear models and illustrates their use in designs for pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/PD) trials. For some practical problems, such as designs for modelling PK/PD relationship, this is often the only feasible type of design, as the design points follow a PK model and cannot be directly controlled. Even for ordinary design problems the parametric designs have some advantages over the traditional designs, which often have too few design points for model checking and may not be robust to model and parameter misspecifications. We first describe methods and algorithms to construct the parametric design for ordinary nonlinear design problems and show that the parametric designs are robust to parameter misspecification and have good power for model discrimination. Then we extend this design method to construct optimal repeated measurement designs for nonlinear mixed models. We also use this parametric design for modelling a PK/PD relationship and propose a simulation based algorithm. The application of parametric designs is illustrated with a three-parameter open one-compartment PK model for the ordinary design and repeated measurement design, and an Emax model for the phamacokinetic/pharmacodynamic trial design.     

Some remarks on experimental design for estimating the expectation of a stationary random process

For estimation of the mean of a stationary random process the variance-optimal choice of the observation points (the so called experimental design) is considered. For this discrete and continuous designs are introduced, some known results of process statistics are interpreted to experimental design and a proposal for simplification of the minimization problem is offered, moreover it is proved, that for monotone decreasing eovarianee functions a design, for which the points near the ends of the observation interval are more dense than in the middle, is better than the equidistant design.