Optimal two-point designs for the michaelis-menten model with heteroscedastic errors

We construct D-optimal designs for the Michaelis-Menten model when the variance of the response depends on the independent variable. However, this dependence is only partially known. A Bayesian approacn is used to find an optimal design by incorporating the prior lnformation about the variance structure. We demonstrate the method for a class of error variance structures and present efficiencies of these optimal designs under prior mis-specifications. In particular, we show that an erroneous assumption on the variance structure for the Michaelis-Menten model can have serious consequences.     

D-optimal minimax design criterion for two-level fractional factorial designs

A D-optimal minimax design criterion is proposed to construct two-level fractional factorial designs, which can be used to estimate a linear model with main effects and some specified interactions. D-optimal minimax designs are robust against model misspecification and have small biases if the linear model contains more interaction terms. When the D-optimal minimax criterion is compared with the D-optimal design criterion, we find that the D-optimal design criterion is quite robust against model misspecification. Lower and upper bounds derived for the loss functions of optimal designs can be used to estimate the efficiencies of any design and evaluate the effectiveness of a search algorithm. Four algorithms to search for optimal designs for any run size are discussed and compared through several examples. An annealing algorithm and a sequential algorithm are particularly effective to search for optimal designs.     

Robust designs for experiments with blocks

ABSTRACT

For experiments running in field plots or over time, the observations are often correlated due to spatial or serial correlation, which leads to correlated errors in a linear model analyzing the treatment means. Without knowing the exact correlation matrix of the errors, it is not possible to compute the generalized least-squares estimator for the treatment means and use it to construct optimal designs for the experiments. In this paper, we propose to use neighborhoods to model the covariance matrix of the errors, and apply a modified generalized least-squares estimator to construct robust designs for experiments with blocks. A minimax design criterion is investigated, and a simulated annealing algorithm is developed to find robust designs. We have derived several theoretical results, and representative examples are presented.     

Optimal minimax designs for prediction in heteroscedastic models

We construct optimal designs for heteroscedastic models when the goal is to make efficient prediction over a compact interval. It is assumed that the point or points which are interesting to predict are not known before the experiment is run. Two minimax strategies for minimizing the maximum fitted variance and maximum predictive variance across the interval of interest are proposed and, optimal designs are found and compared. An algorithm for generating these designs is included.     

D‐optimal minimax fractional factorial designs

The D‐optimal minimax criterion is proposed to construct fractional factorial designs. The resulting designs are very efficient, and robust against misspecification of the effects in the linear model. The criterion was first proposed by Wilmut & Zhou (2011); their work is limited to two‐level factorial designs, however. In this paper we extend this criterion to designs with factors having any levels (including mixed levels) and explore several important properties of this criterion. Theoretical results are obtained for construction of fractional factorial designs in general. This minimax criterion is not only scale invariant, but also invariant under level permutations. Moreover, it can be applied to any run size. This is an advantage over some other existing criteria. The Canadian Journal of Statistics 41: 325–340; 2013 © 2013 Statistical Society of Canada     

Discrete M-robust designs for regression models

M-robust designs are defined and constructed for misspecified linear regression models with possibly autocorrelated errors on a discrete design space. These designs minimize the mean-squared errors if linear regression models are correct with uncorrelated errors, subject to two robust constraints which control the change of the bias and the change of variance under model departures. Simulated annealing algorithm is applied to construct M-robust designs. Examples are given to show M-robust designs and compare them with minimax robust designs.     

Wavelet designs for estimating nonparametric curves with heteroscedastic error

In this paper, we discuss the problem of constructing designs in order to maximize the accuracy of nonparametric curve estimation in the possible presence of heteroscedastic errors. Our approach is to exploit the flexibility of wavelet approximations to approximate the unknown response curve by its wavelet expansion thereby eliminating the mathematical difficulty associated with the unknown structure. It is expected that only finitely many parameters in the resulting wavelet response can be estimated by weighted least squares. The bias arising from this, compounds the natural variation of the estimates. Robust minimax designs and weights are then constructed to minimize mean-squared-error-based loss functions of the estimates. We find the periodic and symmetric properties of the Euclidean norm of the multiwavelet system useful in eliminating some of the mathematical difficulties involved. These properties lead us to restrict the search for robust minimax designs to a specific class of symmetric designs. We also construct minimum variance unbiased designs and weights which minimize the loss functions subject to a side condition of unbiasedness. We discuss an example from the nonparametric literature.     

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.     

Two-stage phase II trials with early stopping for effectiveness and safety as well as ineffectiveness or harm

This article proposes new optimal and minimax designs, which allow early stopping not only for ineffectiveness or toxicity but also for sufficient effectiveness and safety. These designs may facilitate effective drug development by detecting sufficient effectiveness and safety at an early stage or by detecting ineffectiveness or excessive toxicity at an early stage. The proposed design has advantage over other designs in the sense that it can control the type I error rate and is robust against the real association parameter. Comparing to Jin's design, it is always advantageous in terms of expected sample size.     

D-optimal minimax regression designs on discrete design space

One classical design criterion is to minimize the determinant of the covariance matrix of the regression estimates, and the designs are called D-optimal designs. To reflect the nature that the proposed models are only approximately true, we propose a robust design criterion to study response surface designs. Both the variance and bias are considered in the criterion. In particular, D-optimal minimax designs are investigated and constructed. Examples are given to compare D-optimal minimax designs with classical D-optimal designs.     

A relaxation procedure for calculating (G–)minimax optimal designs

Summary: In nonlinear statistical models, standard optimality functions for experimental designs depend on the unknown parameters of the model. An appealing and robust concept for choosing a design is the minimax criterion. However, so far, minimax optimal designs have been calculated efficiently under various restrictive conditions only. We extend an iterative relaxation scheme originally proposed by Shimizu and Aiyoshi (1980) and prove its convergence under very general assumptions which cover a variety of situations considered in experimental design. Application to different specific design criteria is discussed and issues of practical implementation are addressed. First numerical results suggest that the method may be very efficient with respect to the number of iterations required.*Supported by a grant from the Deutsche Forschungsgemeinschaft. We are grateful to a referee for his constructive suggestions.     

Restricted minimax robust designs for misspecified regression models

The authors propose and explore new regression designs. Within a particular parametric class, these designs are minimax robust against bias caused by model misspecification while attaining reasonable levels of efficiency as well. The introduction of this restricted class of designs is motivated by a desire to avoid the mathematical and numerical intractability found in the unrestricted minimax theory. Robustness is provided against a family of model departures sufficiently broad that the minimax design measures are necessarily absolutely continuous. Examples of implementation involve approximate polynomial and second order multiple regression.     

A semi-infinite programming based algorithm for finding minimax optimal designs for nonlinear models

Minimax optimal experimental designs are notoriously difficult to study largely because the optimality criterion is not differentiable and there is no effective algorithm for generating them. We apply semi-infinite programming (SIP) to solve minimax design problems for nonlinear models in a systematic way using a discretization based strategy and solvers from the General Algebraic Modeling System (GAMS). Using popular models from the biological sciences, we show our approach produces minimax optimal designs that coincide with the few theoretical and numerical optimal designs in the literature. We also show our method can be readily modified to find standardized maximin optimal designs and minimax optimal designs for more complicated problems, such as when the ranges of plausible values for the model parameters are dependent and we want to find a design to minimize the maximal inefficiency of estimates for the model parameters.     

Search for optimal designs in a three stagenested random model

In this paper we define a class of unbalanced designs, denoted by C_k,s,t, for estimating the components of variance in a k-stage nested random effects linear model. This class contains many of the designs proposed in the literature for nested components of variance models. We focus on the three-state model and discuss the determination of locally optimal designs within this class using a systematic computer search. For large sample sizes we show that approximate optimal designs may be obtained using a limit argument combined with numerical optimization. A comparison of our designs with previously published designs suggests that, in many cases, our designs result in substantial gains in efficiency.     

Model robust extrapolation designs

We seek designs which are optimal in some sense for extrapolation when the true regression function is in a certain class of regression functions. More precisely, the class is defined to be the collection of regression functions such that its (h + 1)-th derivative is bounded. The class can be viewed as representing possible departures from an ‘ideal’ model and thus describes a model robust setting. The estimates are restricted to be linear and the designs are restricted to be with minimal number of points. The design and estimate sought is minimax for mean square error. The optimal designs for cases X = [0, ∞] and X = [-1, 1], where X is the place where observations can be taken, are discussed.     

Minimax Designs for the Stability of Slope Estimation on Second-order Response Surfaces

In this paper, designs for the stability of the slope estimation on a second-order response surface are considered. Minimization of the point dispersion measure, which is maximized over all points in the region of interest is taken as the optimality criterion, and the minimax properties in some class of designs are derived in spherical and cubic regions of interest. We study the efficiencies of the minimax designs relative to other optimal designs with various criteria.     

I-robust and D-robust designs on a finite design space

We present and discuss the theory of minimax I- and D-robust designs on a finite design space, and detail three methods for their construction that are new in this context: (i) a numerical search for the optimal parameters in a provably minimax robust parametric class of designs, (ii) a first-order iterative algorithm similar to that of Wynn (Ann Math Stat 5:1655–1664, 1970), and (iii) response-adaptive designs. These designs minimize a loss function, based on the mean squared error of the predicted responses or the parameter estimates, when the regression response is possibly misspecified. The loss function being minimized has first been maximized over a neighbourhood of the approximate and possibly inadequate response being fitted by the experimenter. The methods presented are all vastly more economical, in terms of the computing time required, than previously available algorithms.     

Designs for weighted least squares regression, with estimated weights

We study designs, optimal up to and including terms that are O(n ^?1), for weighted least squares regression, when the weights are intended to be inversely proportional to the variances but are estimated with random error. We take a finite, but arbitrarily large, design space from which the support points are to be chosen, and obtain the optimal proportions of observations to be assigned to each point. Specific examples of D- and I-optimal design for polynomial responses are studied. In some cases the same designs that are optimal under homoscedasticity remain so for a range of variance functions; in others there tend to be more support points than are required in the homoscedastic case. We also exhibit minimax designs, that minimize the maximum, over finite classes of variance functions, value of the loss. These also tend to have more support points, often resulting from the breaking down of replicates into clusters.     

On Exact K-optimal Designs Minimizing the Condition Number

A new design criterion based on the condition number of an information matrix is proposed to construct optimal designs for linear models, and the resulting designs are called K-optimal designs. The relationship between exact and asymptotic K-optimal designs is derived. Since it is usually hard to find exact optimal designs analytically, we apply a simulated annealing algorithm to compute K-optimal design points on continuous design spaces. Specific issues are addressed to make the algorithm effective. Through exact designs, we can examine some properties of the K-optimal designs such as symmetry and the number of support points. Examples and results are given for polynomial regression models and linear models for fractional factorial experiments. In addition, K-optimal designs are compared with A-optimal and D-optimal designs for polynomial regression models, showing that K-optimal designs are quite similar to A-optimal designs.     

Optimal designs for estimating the slope of a regression

In the common linear model with quantitative predictors we consider the problem of designing experiments for estimating the slope of the expected response in a regression. We discuss locally optimal designs, where the experimenter is only interested in the slope at a particular point, and standardized minimax optimal designs, which could be used if precise estimation of the slope over a given region is required. General results on the number of support points of locally optimal designs are derived if the regression functions form a Chebyshev system. For polynomial regression and Fourier regression models of arbitrary degree the optimal designs for estimating the slope of the regression are determined explicitly for many cases of practical interest.