Optimal designs for covariates’ models

A linear model with one treatment at V levels and first order regression on K continuous covariates with values on a K-cube is considered. The D-criterion is used to judge the ‘goodness’ of any design for estimating the parameters of this model. Since this criterion is based on the determinant of the information matrix M(d) of a design d, upper bounds for |M(d)| yield lower bounds for the D-efficiency of any design d in estimating the vector of parameters in the model. We consider here only classes of designs d for which the number N of observations to be taken is a multiple of V, that is, there exists R≥2 such that N=V×R.Under these conditions, we determine the maximum of |M(d)|, and conditions under which the maximum is attained. These conditions include R being even, each treatment level being observed the same number of times, that is, R times, and N being a multiple of four. For the other cases of congruence of N (modulo 4) we further determine upper bounds on |M (d)| for equireplicated designs, i.e. for designs with equal number of observations per treatment level. These upper bounds are shown to depend also on the congruence of V (modulo 4). For some triples (N,V,K), the upper bounds determined are shown to be attained.Construction methods yielding families of designs which attain the upper bounds of |M(d)| are presented, for each of the sixteen cases of congruence of N and V.We also determine the upper bound for D-optimal designs for estimating only the treatment parameters, when first order regression on one continuous covariate is present.     

Construction of (M,S)-optimal design for block size 3

(M,S)-optimal designs are constructed for block size three when the number of treatments is of the form 6t + 3.     

Universal optimality of experimental designs: Definitions and a criterion

Several definitions of universal optimality of experimental designs are found in the Literature; we discuss the interrelations of these definitions using a recent characterization due to Friedland of convex functions of matrices. An easily checked criterion is given for a design to satisfy the main definition of universal optimality; this criterion says that a certain set of linear functions of the eigenvalues of the information matrix is maximized by the information matrix of a design if and only if that design is universally optimal. Examples are given; in particular we show that any universally optimal design is (M, S)-optimal in the sense of K. Shah.     

SOME PROPERTIES OF A FOLDOVER DESIGN

The foldover design of the 12-run Plackett-Burman design is shown to give a 2⁴and 2^4-1design in every set of four factors, and to be resolution V in every set of five factors. In addition, the design allows the search and estimation of up to two non-zero interactions.     

Resolvable systems of 8-tuples

Let R be a family of k-element blocks of a v-element set V such that any two elements of V are contained in λ blocks of R and R=R₁∪…∪R_v?1, R_i∩ R_j=? (i≠j) and ?{B_i∈R_j∣i=1,…,v?k}=V (B_i a block in R_j), i.e. R is a resolvable block design RB(v, k, λ). In this paper it will be shown that a sufficient condition for the existence of an RB(v, 8, 7) is that v≡0 (mod 8) and v is nondivisible by 3, 5, 7.     

Graphical evaluation of robust parameter designs based on extended scaled prediction variance and extended spherical average prediction variance

For any response surface design, there are locations in the design region where responses are estimated well and locations where estimation is relatively poor. Consequently, graphical evaluation—such as variance dispersion graphs and the fraction of design space—is used as an alternative to a single-valued criterion. Such plots are used to investigate and compare the prediction capabilities of certain response surface designs currently available to the researcher. In this article, we propose the extended scaled prediction variance and extended spherical average prediction variance as prediction methods. We also illustrate how graphical methods can be employed to evaluate robust parameter designs.     

Determining the minimum duration of treatment in tuberculosis: An order restricted non-inferiority trial design

Tuberculosis (TB) is one of the biggest killers among infectious diseases worldwide. Together with the identification of drugs that can provide benefits to patients, the challenge in TB is also the optimisation of the duration of these treatments. While conventional duration of treatment in TB is 6 months, there is evidence that shorter durations might be as effective but could be associated with fewer side effects and may be associated with better adherence. Based on a recent proposal of an adaptive order-restricted superiority design that employs the ordering assumptions within various duration of the same drug, we propose a non-inferiority (typically used in TB trials) adaptive design that effectively uses the order assumption. Together with the general construction of the hypothesis testing and expression for type I and type II errors, we focus on how the novel design was proposed for a TB trial concept. We consider a number of practical aspects such as choice of the design parameters, randomisation ratios, and timings of the interim analyses, and how these were discussed with the clinical team.     

A comparative study of adaptive trial designs for dose optimization

Recently, the US Food and Drug Administration Oncology Center of Excellence initiated Project Optimus to reform the dose optimization and dose selection paradigm in oncology drug development. The agency pointed out that the current paradigm for dose selection—based on the maximum tolerated dose (MTD)—is not sufficient for molecularly targeted therapies and immunotherapies, for which efficacy may not increase after the dose reaches a certain level. In these cases, it is more appropriate to identify the optimal biological dose (OBD) that optimizes the risk–benefit tradeoff of the drug. Project Optimus has spurred tremendous interest and urgent need for guidance on designing dose optimization trials. In this article, we review several representative dose optimization designs, including model-based and model-assisted designs, and compare their operating characteristics based on 10,000 randomly generated scenarios with various dose-toxicity and dose-efficacy curves and some fixed representative scenarios. The results show that, compared with model-based designs, model-assisted methods have advantages of easy-to-implement, robustness, and high accuracy to identify OBD. Some guidance is provided to help biostatisticians and clinicians to choose appropriate dose optimization methods in practice.