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.     

Design of experiments for locally weighted regression

We consider the design of experiments when estimation is to be performed using locally weighted regression methods. We adopt criteria that consider both estimation error (variance) and error resulting from model misspecification (bias). Working with continuous designs, we use the ideas developed in convex design theory to analyze properties of the corresponding optimal designs. Numerical procedures for constructing optimal designs are developed and applied to a variety of design scenarios in one and two dimensions. Among the interesting properties of the constructed designs are the following: (1) Design points tend to be more spread throughout the design space than in the classical case. (2) The optimal designs appear to be less model and criterion dependent than their classical counterparts.(3) While the optimal designs are relatively insensitive to the specification of the design space boundaries, the allocation of supporting points is strongly governed by the points of interest and the selected weight function, if the latter is concentrated in areas significantly smaller than the design region. Some singular and unstable situations occur in the case of saturated designs. The corresponding phenomenon is discussed using a univariate linear regression example.     

Screening designs for model discrimination

We introduce new criteria for model discrimination and use these and existing criteria to evaluate standard orthogonal designs. We show that the capability of orthogonal designs for model discrimination is surprisingly varied. In fact, for specified sample sizes, number of factors, and model spaces, many orthogonal designs are not model discriminating by the definition given in this paper, while others in the same class of orthogonal designs are. We also use these criteria to construct optimal two-level model-discriminating designs for screening experiments. The efficacy of these designs is studied, both in terms of estimation efficiency and discrimination success. Simulation studies indicate that the constructed designs result in substantively higher likelihoods of identifying the correct model.     

Optimal designs for minimising covariances among parameter estimators in a linear model

We construct approximate optimal designs for minimising absolute covariances between least‐squares estimators of the parameters (or linear functions of the parameters) of a linear model, thereby rendering relevant parameter estimators approximately uncorrelated with each other. In particular, we consider first the case of the covariance between two linear combinations. We also consider the case of two such covariances. For this we first set up a compound optimisation problem which we transform to one of maximising two functions of the design weights simultaneously. The approaches are formulated for a general regression model and are explored through some examples including one practical problem arising in chemistry.     

Experimental designs and their efficiencies for spatially correlated observations in two dimensions

Optimality of experimental designs for spatially correlated observations is investigated.come two dimensional correlation structures are discussed and an attempt has been made to find optimal or nearly optimal design for each sitution.The solution lend to designs similar to that used for repeated measurements.The relative efficiency of the proposed designs in comparison to randomized latin square designs is tabulated for some cases.     

A geometric characterization of optimal designs for regression models with correlated observations

We consider the problem of optimal design of experiments for random effects models, especially population models, where a small number of correlated observations can be taken on each individual, while the observations corresponding to different individuals are assumed to be uncorrelated. We focus on c-optimal design problems and show that the classical equivalence theorem and the famous geometric characterization of Elfving (1952) from the case of uncorrelated data can be adapted to the problem of selecting optimal sets of observations for the n individual patients. The theory is demonstrated by finding optimal designs for a linear model with correlated observations and a nonlinear random effects population model, which is commonly used in pharmacokinetics.     

A comparison of inference procedures in unbalanced split-plot designs

Several procedures for constructing confidence intervals and testing hypotheses about fixed effects in unbalanced split-plot experiments are described in this paper. These procedures can also be used for unbalanced repeated measures experiments when the repeated measures satisfy the Huyhn-Feldt (1970) conditions. A number of these procedures require that the whole plot error mean square has a distribution proportional to a chi-square distribution and that it be independent of estimators of the parameter functions. Often, neither of these conditions are met in unbalanced split-plot experiments. Simulation studies of a small design of eight observations and larger designs with 34 to 48 observations are used to investigate the performance of the different procedures.     

Some adjusted orthogonal,variance balanced,multidimensional block designs

A multidimensional block design (MBD) is an experimental design with d > 1 blocking criteria geometrically represented as a d-dimensional lattice with treatment varieties assigned to some or all nodes of the lattice. Intrablock analysis of variance tables for some special classes of two- and three-dimensional block designs with some empty nodes are given. Design plans and efficiencies for 31 two-dimensional designs, each universally optimal in defined classes of designs, and 7 three-dimensional designs, each nearly optimal in defined classes of designs, are listed in the appendices. A need for such designs is apparent when the blocking criteria are implemented successively and empty nodes do not represent wasted experimental units.     

Robust estimators for additive models using backfitting

Additive models provide an attractive setup to estimate regression functions in a nonparametric context. They provide a flexible and interpretable model, where each regression function depends only on a single explanatory variable and can be estimated at an optimal univariate rate. Most estimation procedures for these models are highly sensitive to the presence of even a small proportion of outliers in the data. In this paper, we show that a relatively simple robust version of the backfitting algorithm (consisting of using robust local polynomial smoothers) corresponds to the solution of a well-defined optimisation problem. This formulation allows us to find mild conditions to show Fisher consistency and to study the convergence of the algorithm. Our numerical experiments show that the resulting estimators have good robustness and efficiency properties. We illustrate the use of these estimators on a real data set where the robust fit reveals the presence of influential outliers.     

E-optimal designs for regression models with quantitative factors— a reasonable choice?

For regression models with quantitative factors it is illustrated that the E-optimal design can be extremely inefficient in the sense that it degenerates to a design which takes all observations at only one point. This phenomenon is caused by the different size of the elements in the covariance matrix of the least-squares estimator for the unknown parameters. For these reasons we propose to replace the E-criterion by a corresponding standardized version. The advantage of this approach is demonstrated for the polynomial regression on a nonnegative interval, where the classical and standardized E-optimal designs can be found explicitly. The described phenomena are not restricted to the E-criterion but appear for nearly all optimality criteria proposed in the literature. Therefore standardization is recommended for optimal experimental design in regression models with quantitative factors. The optimal designs with respect to the new standardized criteria satisfy a similar invariance property as the famous D-optimal designs, which allows an easy calculation of standardized optimal designs on many linearly transformed design spaces.     

CVX‐based algorithms for constructing various optimal regression designs

CVX‐based numerical algorithms are widely and freely available for solving convex optimization problems but their applications to solve optimal design problems are limited. Using the CVX programs in MATLAB, we demonstrate their utility and flexibility over traditional algorithms in statistics for finding different types of optimal approximate designs under a convex criterion for nonlinear models. They are generally fast and easy to implement for any model and any convex optimality criterion. We derive theoretical properties of the algorithms and use them to generate new A‐, c‐, D‐ and E‐optimal designs for various nonlinear models, including multi‐stage and multi‐objective optimal designs. We report properties of the optimal designs and provide sample CVX program codes for some of our examples that users can amend to find tailored optimal designs for their problems. The Canadian Journal of Statistics 47: 374–391; 2019 © 2019 Statistical Society of Canada     

Optimal designs for the logit and probit models for binary data

We consider optimal designs for a class of symmetric models for binary data which includes the common probit and logit models. We show that for a large group of optimality criteria which includes the main ones in the literature (e.g. A-, D-, E-, F- and G-optimality) the optimal design for our class of models is a two-point design with support points symmetrically placed about the ED50 but with possibly unequal weighting. We demonstrate how one can further reduce the problem to a one-variable optimization by characterizing various of the common criteria. We also use the results to demonstrate major qualitative differences between the F - and c-optimal designs, two design criteria which have similar motivation.     

Optimal designs for generalized linear models

Summary This paper solves some D-optimal design problems for certain Generalized Linear Models where the mean depends on two parameters and two explanatory variables. In all of the cases considered the support point of the optimal designs are found to be independent of the unknown parameters. While in some cases the optimal design measures are given by two points with equal weights, in others the support is given by three point with weights depending on the unknown parameters, hence the designs are locally optimal in general. Empirical results on the efficiency of the locally optimal designs are also given. Some of the designs found can also be used for planning D-optimal experiments for the normal linear model, where the mean must be positive. This research was carried out in part at University College, London as an M.Sc. project. Thanks are due to Prof. I. Ford (University of Glasgow) and Prof. A. Giovagnoli (University of Perugia) for their valuable suggestions and critical observations.     

Robust designs for misspecified logistic models

We develop criteria that generate robust designs and use such criteria for the construction of designs that insure against possible misspecifications in logistic regression models. The design criteria we propose are different from the classical in that we do not focus on sampling error alone. Instead we use design criteria that account as well for error due to bias engendered by the model misspecification. Our robust designs optimize the average of a function of the sampling error and bias error over a specified misspecification neighbourhood. Examples of robust designs for logistic models are presented, including a case study implementing the methodologies using beetle mortality data.     

Selection and screening procedures to determine optimal product designs

To compare several promising product designs, manufacturers must measure their performance under multiple environmental conditions. In many applications, a product design is considered to be seriously flawed if its performance is poor for any level of the environmental factor. For example, if a particular automobile battery design does not function well under temperature extremes, then a manufacturer may not want to put this design into production. Thus, this paper considers the measure of a product's quality to be its worst performance over the levels of the environmental factor. We develop statistical procedures to identify (a near) optimal product design among a given set of product designs, i.e., the manufacturing design that maximizes the worst product performance over the levels of the environmental variable. We accomplish this by intuitive procedures based on the split-plot experimental design (and the randomized complete block design as a special case); split-plot designs have the essential structure of a product array and the practical convenience of local randomization. Two classes of statistical procedures are provided. In the first, the δ-best formulation of selection problems, we determine the number of replications of the basic split-plot design that are needed to guarantee, with a given confidence level, the selection of a product design whose minimum performance is within a specified amount, δ, of the performance of the optimal product design. In particular, if the difference between the quality of the best and second best manufacturing designs is δ or more, then the procedure guarantees that the best design will be selected with specified probability. For applications where a split-plot experiment that involves several product designs has been completed without the planning required of the δ-best formulation, we provide procedures to construct a ‘confidence subset’ of the manufacturing designs; the selected subset contains the optimal product design with a prespecified confidence level. The latter is called the subset selection formulation of selection problems. Examples are provided to illustrate the procedures.     

Optimal designs for estimating a choice hierarchy by a general nested multinomial logit model

Abstract

In choice experiments the process of decision-making can be more complex than the proposed by the Multinomial Logit Model (MNL). In these scenarios, models such as the Nested Multinomial Logit Model (NMNL) are often employed to model a more complex decision-making. Understanding the decision-making process is important in some fields such as marketing. Achieving a precise estimation of the models is crucial to the understanding of this process. To do this, optimal experimental designs are required. To construct an optimal design, information matrix is key. A previous research by others has developed the expression for the information matrix of the two-level NMNL model with two nests: Alternatives nest (J alternatives) and No-Choice nest (1 alternative). In this paper, we developed the likelihood function for a two-stage NMNL model for M nests and we present the expression for the information matrix for 2 nests with any amount of alternatives in them. We also show alternative D-optimal designs for No-Choice scenarios with similar relative efficiency but with less complex alternatives which can help to obtain more reliable answers and one application of these designs.     

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.     

Bayesian adaptive dose‐escalation designs for simultaneously estimating the optimal and maximum safe dose based on safety and efficacy

The main purpose of dose‐escalation trials is to identify the dose(s) that is/are safe and efficacious for further investigations in later studies. In this paper, we introduce dose‐escalation designs that incorporate both the dose‐limiting events and dose‐limiting toxicities (DLTs) and indicative responses of efficacy into the procedure. A flexible nonparametric model is used for modelling the continuous efficacy responses while a logistic model is used for the binary DLTs. Escalation decisions are based on the combination of the probabilities of DLTs and expected efficacy through a gain function. On the basis of this setup, we then introduce 2 types of Bayesian adaptive dose‐escalation strategies. The first type of procedures, called “single objective,” aims to identify and recommend a single dose, either the maximum tolerated dose, the highest dose that is considered as safe, or the optimal dose, a safe dose that gives optimum benefit risk. The second type, called “dual objective,” aims to jointly estimate both the maximum tolerated dose and the optimal dose accurately. The recommended doses obtained under these dose‐escalation procedures provide information about the safety and efficacy profile of the novel drug to facilitate later studies. We evaluate different strategies via simulations based on an example constructed from a real trial on patients with type 2 diabetes, and the use of stopping rules is assessed. We find that the nonparametric model estimates the efficacy responses well for different underlying true shapes. The dual‐objective designs give better results in terms of identifying the 2 real target doses compared to the single‐objective designs.     

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.