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 allocation of subjects in a matched pair cluster-randomized trial with fixed number of heterogeneous clusters

In cluster-randomized trials, investigators randomize clusters of individuals such as households, medical practices, schools or classrooms despite the unit of interest are the individuals. It results in the loss of efficiency in terms of the estimation of the unknown parameters as well as the power of the test for testing the treatment effects. To recoup this efficiency loss, some studies pair similar clusters and randomize treatment within pairs. However, the clusters within a treatment arm might be heterogeneous in nature. In this article, we propose a locally optimal design that accounts the clusters heterogeneity and optimally allocates the subjects within each cluster. To address the dependency of design on the unknown parameters, we also discuss Bayesian optimal designs. Performances of proposed designs are investigated numerically through some data examples.     

D-optimal designs for combined polynomial and trigonometric regression on a partial circle

Consider the D-optimal designs for a combined polynomial and trigonometric regression on a partial circle. It is shown that the optimal design is equally supported and the structure of the optimal design depends only on the length of the design interval and the support points are analytic functions of this parameter. Moreover, the Taylor expansion of the optimal support points can be determined efficiently by a recursive procedure. Examples are presented to illustrate the procedures for computing the optimal designs.     

On minimax designs when there are two candidate models

This work is motivated by the need to find experimental designs which are robust under different model assumptions. We measure robustness by calculating a measure of design efficiency with respect to a design optimality criterion and say that a design is robust if it is reasonably efficient under different model scenarios. We discuss two design criteria and an algorithm which can be used to obtain robust designs. The first criterion employs a Bayesian-type approach by putting a prior or weight on each candidate model and possibly priors on the corresponding model parameters. We define the first criterion as the expected value of the design efficiency over the priors. The second design criterion we study is the minimax design which minimizes the worst value of a design criterion over all candidate models. We establish conditions when these two criteria are equivalent when there are two candidate models. We apply our findings to the area of accelerated life testing and perform sensitivity analysis of designs with respect to priors and misspecification of planning values.     

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.     

On Kronecker block designs for factorial experiments

In this paper the use of Kronecker designs for factorial experiments is considered. The two-factor Kronecker design is considered in some detail and the efficiency factors of the main effects and interaction in such a design are derived. It is shown that the efficiency factor of the interaction is at least as large as the product of the efficiency factors of the two main effects and when both the component designs are totally balanced then its efficiency factor will be higher than the efficiency factor of either of the two main effects. If the component designs are nearly balanced then its efficiency factor will be approximately at least as large as the efficiency factor of either of the two main effects. It is argued that these designs are particularly useful for factorial experiments.Extensions to the multi-factor design are given and it is proved that the two-factor Kronecker design will be connected if the component designs are connected.     

Bayesian Experimental Design for Long-Term Longitudinal HIV Dynamic Studies

The study of HIV dynamics is one of the most important developments in recent AIDS research for understanding the pathogenesis of HIV-1 infection and antiviral treatment strategies. Currently a large number of AIDS clinical trials on HIV dynamics are in development worldwide. However, many design issues that arise from AIDS clinical trials have not been addressed. In this paper, we use a simulation-based approach to deal with design problems in Bayesian hierarchical nonlinear (mixed-effects) models. The underlying model characterizes the long-term viral dynamics with antiretroviral treatment where we directly incorporate drug susceptibility and exposure into a function of treatment efficacy. The Bayesian design method is investigated under the framework of hierarchical Bayesian (mixed-effects) models. We compare a finite number of feasible candidate designs numerically, which are currently used in AIDS clinical trials from different perspectives, and provide guidance on how a design might be chosen in practice.     

EFFICIENT BLOCK DESIGNS FOR CORRELATED OBSERVATIONS

Current methods for the design of efficient incomplete block experiments when the observations within a block are dependent usually involve computer searches of binary designs. These searches give little insight into the features that lead to efficiency, and can miss more efficient designs. This paper aims to develop some approximations which give some insight into the features of a design that lead to high efficiency under a generalized least-squares analysis for a known dependence structure, and to show that non-binary designs can be more efficient for some dependence structures. In particular, we show how neighbour balance and end plot balance are related to the design efficiency for low-order autoregressions, and that under moderate positive dependence, replication at lag two can sometimes increase efficiency.     

Comparison of designs for computer experiments

For many complex processes laboratory experimentation is too expensive or too time-consuming to be carried out. A practical alternative is to simulate these phenomena by a computer code. This article considers the choice of an experimental design for computer experiments. We illustrate some drawbacks to criteria that have been proposed and suggest an alternative, based on the Bayesian interpretation of the alias matrix in Draper and Guttman (Ann. Inst. Statist. Math. 44 (1992) 659). Then we compare different design criteria by studying how they rate a variety of candidate designs for computer experiments such as Latin hypercube plans, U-designs, lattice designs and rotation designs.     

An algorithmic approach to construct D-optimal saturated designs for logistic model

In this paper, locally D-optimal saturated designs for a logistic model with one and two continuous input variables have been constructed by modifying the famous Fedorov exchange algorithm. A saturated design not only ensures the minimum number of runs in the design but also simplifies the row exchange computation. The basic idea is to exchange a design point with a point from the design space. The algorithm performs the best row exchange between design points and points form a candidate set representing the design space. Naturally, the resultant designs depend on the candidate set. For gain in precision, intuitively a candidate set with a larger number of points and the low discrepancy is desirable, but it increases the computational cost. Apart from the modification in row exchange computation, we propose implementing the algorithm in two stages. Initially, construct a design with a candidate set of affordable size and then later generate a new candidate set around the points of design searched in the former stage. In order to validate the optimality of constructed designs, we have used the general equivalence theorem. Algorithms for the construction of optimal designs have been implemented by developing suitable codes in R.     

Application of genetic algorithms to the construction of exact D-optimal designs

This paper studies the application of genetic algorithms to the construction of exact D-optimal experimental designs. The concept of genetic algorithms is introduced in the general context of the problem of finding optimal designs. The algorithm is then applied specifically to finding exact D-optimal designs for three different types of model. The performance of genetic algorithms is compared with that of the modified Fedorov algorithm in terms of computing time and relative efficiency. Finally, potential applications of genetic algorithms to other optimality criteria and to other types of model are discussed, along with some open problems for possible future research.     

Maximin efficient design of experiment for exponential regression models

In this paper robust and efficient designs are derived for several exponential decay models. These models are widely used in chemistry, pharmacokinetics or microbiology. We propose a maximin approach, which determines the optimal design such that a minimum of the D-efficiencies (taken over a certain range) becomes maximal. Analytic solutions are derived if optimization is performed in the class of minimal supported designs. In general the optimal designs with respect to the maximin criterion have to be determined numerically and some properties of these designs are also studied. We also illustrate the benefits of our approach by reanalysing a data example from the literature.     

Order Statistics from the Generalized Exponential Distribution and Applications

With linear dispersion effects, the standard factorial designs are not optimal estimation of a mean model. A sequential two-stage experimental design procedure has been proposed that first estimates the variance structure, and then uses the variance estimates and the variance optimality criterion to develop a second stage design that efficiency estimates the mean model. This procedure has been compared to an equal replicate design analyzed by ordinary least squares, and found to be a superior procedure in many situations.

However with small first stage sample sizes the variance estiamtes are not reliable, and hence an alternative procedure could be more beneficial. For this reason a Bayesian modification to the two-stage procedure is proposed which will combine the first stage variance estiamtes with some prior variance information that will produce a more efficient procedure. This Bayesian procedure will be compared to the non-Bayesian twostage procedure and to the two one-stage alternative procedures listed above. Finally, a recommendation will be made as to which procedure is preferred in certain situations.     

Optimal allocation of time points for the random effects model

In this article the problem of the optimal selection and allocation of time points in repeated measures experiments is considered. D‐ optimal designs for linear regression models with a random intercept and first order auto‐regressive serial correlations are computed numerically and compared with designs having equally spaced time points. When the order of the polynomial is known and the serial correlations are not too small, the comparison shows that for any fixed number of repeated measures, a design with equally spaced time points is almost as efficient as the D‐ optimal design. When, however, there is no prior knowledge about the order of the underlying polynomial, the best choice in terms of efficiency is a D‐ optimal design for the highest possible relevant order of the polynomial. A design with equally‐spaced time points is the second best choice     

Strategies for Cohort Sampling Under the Cox Proportional Hazards Model,Application to an AIDS Clinical Trial

In some studies that relate covariates to times of failure it is not feasible to observe all covariates for all subjects. For example, some covariates may be too costly in terms of time, money, or effect on the subject to record for all subjects. This paper considers the relative efficiencies of several designs for sampling a portion of the cohort on which the costly covariates will be observed. Such designs typically measure all covariates for each failure and control for covariates of lesser interest. Control subjects are sampled either from risk sets at times of observed failures or from the entire cohort. A new design in which the sampling probability for each individual depends on the amount of information that the individual can contribute to estimated coefficients is shown to be superior to other sampling designs under certain conditions. Primary focus of our designs is on time-invariant covariates, but some methods easily generalize to the time-varying setting. Data from a study conducted by the AIDS Clinical Trials Group are used to illustrate the new sampling procedure and to explore the relative efficiency of several sampling schemes.     

A candidate-set-free algorithm for generating D-optimal split-plot designs

Summary.  We introduce a new method for generating optimal split-plot designs. These designs are optimal in the sense that they are efficient for estimating the fixed effects of the statistical model that is appropriate given the split-plot design structure. One advantage of the method is that it does not require the prior specification of a candidate set. This makes the production of split-plot designs computationally feasible in situations where the candidate set is too large to be tractable. The method allows for flexible choice of the sample size and supports inclusion of both continuous and categorical factors. The model can be any linear regression model and may include arbitrary polynomial terms in the continuous factors and interaction terms of any order. We demonstrate the usefulness of this flexibility with a 100-run polypropylene experiment involving 11 factors where we found a design that is substantially more efficient than designs that are produced by using other approaches.     

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.     

Response surface design evaluation and comparison

Designing an experiment to fit a response surface model typically involves selecting among several candidate designs. There are often many competing criteria that could be considered in selecting the design, and practitioners are typically forced to make trade-offs between these objectives when choosing the final design. Traditional alphabetic optimality criteria are often used in evaluating and comparing competing designs. These optimality criteria are single-number summaries for quality properties of the design such as the precision with which the model parameters are estimated or the uncertainty associated with prediction. Other important considerations include the robustness of the design to model misspecification and potential problems arising from spurious or missing data. Several qualitative and quantitative properties of good response surface designs are discussed, and some of their important trade-offs are considered. Graphical methods for evaluating design performance for several important response surface problems are discussed and we show how these techniques can be used to compare competing designs. These graphical methods are generally superior to the simplistic summaries of alphabetic optimality criteria. Several special cases are considered, including robust parameter designs, split-plot designs, mixture experiment designs, and designs for generalized linear models.     

One-and two-sample sign tests for ranked set sample selective designs

Statistical inference based on a ranked set sample depends very much on the location of the quantified observations. A selective design which determines the location of the quantified observations in a ranked set sample is introduced. The paper investigates the effects of selective designs on one and two sample sign test statistics. The Pitman efficiencies of one- and two sample sign tests are calculated for selective designs and compared with ranked set samples of the same size. If the design quantifies observations at the center points, then the proposed procedure is superior to a ranked set sample of the same size in the sense of Pitman efficiency. Some practical problems are addressed for the two-sample sign test.     

A Bayesian adaptive design for biosimilar trials with time-to-event endpoint

A biosimilar drug is a biological product that is highly similar to and at the same time has no clinically meaningful difference from licensed product in terms of safety, purity, and potency. Biosimilar study design is essential to demonstrate the equivalence between biosimilar drug and reference product. However, existing designs and assessment methods are primarily based on binary and continuous endpoints. We propose a Bayesian adaptive design for biosimilarity trials with time-to-event endpoint. The features of the proposed design are twofold. First, we employ the calibrated power prior to precisely borrow relevant information from historical data for the reference drug. Second, we propose a two-stage procedure using the Bayesian biosimilarity index (BBI) to allow early stop and improve the efficiency. Extensive simulations are conducted to demonstrate the operating characteristics of the proposed method in contrast with some naive method. Sensitivity analysis and extension with respect to the assumptions are presented.