A method of selecting the levels of regressor variables in lognormal regression model

Kupper and Meydrech and Myers and Lahoda introduced the mean squared error (MSE) approach to study response surface designs, Duncan and DeGroot derived a criterion for optimality of linear experimental designs based on minimum mean squared error. However, minimization of the MSE of an estimator maxr renuire some knowledge about the unknown parameters. Without such knowledge construction of designs optimal in the sense of MSE may not be possible. In this article a simple method of selecting the levels of regressor variables suitable for estimating some functions of the parameters of a lognormal regression model is developed using a criterion for optimality based on the variance of an estimator. For some special parametric functions, the criterion used here is equivalent to the criterion of minimizing the mean squared error. It is found that the maximum likelihood estimators of a class of parametric functions can be improved substantially (in the sense of MSE) by proper choice of the values of regressor variables. Moreover, our approach is applicable to analysis of variance as well as regression designs.     

Finite sample performance of sequential designs for model identification

Classical regression analysis is usually performed in two steps. In the first step, an appropriate model is identified to describe the data generating process and in the second step, statistical inference is performed in the identified model. An intuitively appealing approach to the design of experiment for these different purposes are sequential strategies, which use parts of the sample for model identification and adapt the design according to the outcome of the identification steps. In this article, we investigate the finite sample properties of two sequential design strategies, which were recently proposed in the literature. A detailed comparison of sequential designs for model discrimination in several regression models is given by means of a simulation study. Some non-sequential designs are also included in the study.     

Robust sequential designs for approximately linear models

We consider the problem of the sequential choice of design points in an approximately linear model. It is assumed that the fitted linear model is only approximately correct, in that the true response function contains a nonrandom, unknown term orthogonal to the fitted response. We also assume that the parameters are estimated by M-estimation. The goal is to choose the next design point in such a way as to minimize the resulting integrated squared bias of the estimated response, to order n^-1. Explicit applications to analysis of variance and regression are given. In a simulation study the sequential designs compare favourably with some fixed-sample-size designs which are optimal for the true response to which the sequential designs must adapt.     

An Adaptive Exploration-Exploitation Algorithm for Constructing Metamodels in Random Simulation Using a Novel Sequential Experimental Design

In this article, we propose a novel algorithm for sequential design of metamodels in random simulation, which combines the exploration capability of most one-shot space-filling designs with the exploitation feature of common sequential designs. The algorithm continuously maintains a balance between the exploration and the exploitation search throughout the search process in a sequential and adaptive manner. The numerical results indicate that the proposed approach is superior to one of the existing well-known sequential designs in terms of both the computational efficiency and speed in generating efficient experimental designs.     

Robust sequential designs for nonlinear regression

The authors introduce the formal notion of an approximately specified nonlinear regression model and investigate sequential design methodologies when the fitted model is possibly of an incorrect parametric form. They present small‐sample simulation studies which indicate that their new designs can be very successful, relative to some common competitors, in reducing mean squared error due to model misspecifi‐cation and to heteroscedastic variation. Their simulations also suggest that standard normal‐theory inference procedures remain approximately valid under the sequential sampling schemes. The methods are illustrated both by simulation and in an example using data from an experiment described in the chemical engineering literature.     

A stochastically curtailed two-arm randomised phase II trial design for binary outcomes

Randomised controlled trials are considered the gold standard in trial design. However, phase II oncology trials with a binary outcome are often single-arm. Although a number of reasons exist for choosing a single-arm trial, the primary reason is that single-arm designs require fewer participants than their randomised equivalents. Therefore, the development of novel methodology that makes randomised designs more efficient is of value to the trials community. This article introduces a randomised two-arm binary outcome trial design that includes stochastic curtailment (SC), allowing for the possibility of stopping a trial before the final conclusions are known with certainty. In addition to SC, the proposed design involves the use of a randomised block design, which allows investigators to control the number of interim analyses. This approach is compared with existing designs that also use early stopping, through the use of a loss function comprised of a weighted sum of design characteristics. Comparisons are also made using an example from a real trial. The comparisons show that for many possible loss functions, the proposed design is superior to existing designs. Further, the proposed design may be more practical, by allowing a flexible number of interim analyses. One existing design produces superior design realisations when the anticipated response rate is low. However, when using this design, the probability of rejecting the null hypothesis is sensitive to misspecification of the null response rate. Therefore, when considering randomised designs in phase II, we recommend the proposed approach be preferred over other sequential designs.     

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.     

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.     

Inference on Polychotomous Responses in Finite Populations

Abstract. A model‐based predictive estimator is proposed for the population proportions of a polychotomous response variable, based on a sample from the population and on auxiliary variables, whose values are known for the entire population. The responses for the non‐sample units are predicted using a multinomial logit model, which is a parametric function of the auxiliary variables. A bootstrap estimator is proposed for the variance of the predictive estimator, its consistency is proved and its small sample performance is compared with that of an analytical estimator. The proposed predictive estimator is compared with other available estimators, including model‐assisted ones, both in a simulation study involving different sampling designs and model mis‐specification, and using real data from an opinion survey. The results indicate that the prediction approach appears to use auxiliary information more efficiently than the model‐assisted approach.     

Marginally restricted sequential D‐optimal designs

In many experiments, not all explanatory variables can be controlled. When the units arise sequentially, different approaches may be used. The authors study a natural sequential procedure for “marginally restricted” D‐optimal designs. They assume that one set of explanatory variables (x₁) is observed sequentially, and that the experimenter responds by choosing an appropriate value of the explanatory variable x₂. In order to solve the sequential problem a priori, the authors consider the problem of constructing optimal designs with a prior marginal distribution for x₁. This eliminates the influence of units already observed on the next unit to be designed. They give explicit designs for various cases in which the mean response follows a linear regression model; they also consider a case study with a nonlinear logistic response. They find that the optimal strategy often consists of randomizing the assignment of the values of x₂.     

A Compromise Experimental Design Method for Parametric Polynomial Response Surface Approximations

This study presents a compromise approach to augmentation of experimental designs, necessitated by the expense of performing each experiment (computational or physical), that yields higher quality parametric polynomial response surface approximations than traditional augmentation. Based on the D-optimality criterion as a measure of experimental design quality, the method simultaneously considers several polynomial models during the experimental design, resulting in good quality designs for all models under consideration, as opposed to good quality designs only for lower-order models, as in the case of traditional augmentation. Several numerical examples and an engineering example are presented to illustrate the efficacy of the approach.     

Non-parametric group sequential designs in randomized clinical trials

This paper examines some non‐parametric group sequential designs applicable for randomized clinical trials, for comparing two continuous treatment effects taking the observations in matched pairs, or applicable in event‐based analysis. Two inverse binomial sampling schemes are considered, of which the second one is an adaptive data‐dependent design. These designs are compared with some fixed sample size competitors. Power and expected sample sizes are calculated for the proposed procedures.     

The plan of enrichment designs for dealing with high placebo response

To deal with high placebo response in clinical trials for psychiatric and other diseases, different enrichment designs, such as the sequential parallel design, two‐way enriched design, and sequential enriched design, have been proposed and implemented recently. Depending on the historical trial information and the trial sponsors' resources, detailed design elements are needed for determining which design to adopt. To assist in making more suitable decisions, we perform evaluations for selecting required design elements in terms of power optimization and sample size planning. We also discuss the implementation of the interim analysis related to its applicability.     

An Introduction to Practical Sequential Inferences via Single-Arm Binary Response Studies Using the binseqtest R Package

We review sequential designs, including group sequential and two-stage designs, for testing or estimating a single binary parameter. We use this simple case to introduce ideas common to many sequential designs, which in this case can be explained without explicitly using stochastic processes. We focus on methods provided by our newly developed R package, binseqtest, which exactly bound the Type I error rate of tests and exactly maintain proper coverage of confidence intervals. Within this framework, we review some allowable practical adaptations of the sequential design. We explore issues such as the following: How should the design be modified if no assessment was made at one of the planned sequential stopping times? How should the parameter be estimated if the study needs to be stopped early? What reasons for stopping early are allowed? How should inferences be made when the study is stopped for crossing the boundary, but later information is collected about responses of subjects that had enrolled before the decision to stop but had not responded by that time? Answers to these questions are demonstrated using basic methods that are available in our binseqtest R package. Supplementary materials for this article are available online.     

The treatment versus experimentation dilemma in dose finding studies

Phase I clinical trials are conducted in order to find the maximum tolerated dose (MTD) of a given drug from a finite set of doses. For ethical reasons, these studies are usually sequential, treating patients or groups of patients with the optimal dose according to the current knowledge, with the hope that this will lead to using the true MTD from some time on. However, the first result proved here is that this goal is infeasible, and that such designs, and, more generally, designs that concentrate on one dose from some time on, cannot provide consistent estimators for the MTD unless very strong parametric assumptions hold. Allowing some non-MTD treatment, we construct a randomized design that assigns the MTD with probability that approaches one as the size of the experiment goes to infinity and estimates the MTD consistently. We compare the suggested design with several methods by simulations, studying their performances in terms of correct estimation of the MTD and the proportion of individuals treated with the MTD.     

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.     

Robust designs for first-order multiple design multivariate models

This paper deals with the methodology of obtaining designs that are robust to nonnormality of the error distribution for tests associated with first-order multiple design multivariate linear models.A sequential procedure is given for the generation of the proposed designs.     

Construction of neighbor designs of block size 4 for all values of v ≥ 5 by using the method of addition

In this article, a general method of construction of neighbor block designs is given. The designs are constructed using variation of a simple method which we refer to as the method of addition (renamed as the method of cyclic shifts). We give complete solution of neighbor balanced designs for k = 4 for any value of v. We also give many series of generalized neighbor designs (GNDs). In the last section, we have constructed GNDs in a sequential manner (as Did John 1981) for v ≤ 50 and r is multiple of k.     

A Bayesian sequential design with binary outcome

Several researchers have proposed solutions to control type I error rate in sequential designs. The use of Bayesian sequential design becomes more common; however, these designs are subject to inflation of the type I error rate. We propose a Bayesian sequential design for binary outcome using an alpha‐spending function to control the overall type I error rate. Algorithms are presented for calculating critical values and power for the proposed designs. We also propose a new stopping rule for futility. Sensitivity analysis is implemented for assessing the effects of varying the parameters of the prior distribution and maximum total sample size on critical values. Alpha‐spending functions are compared using power and actual sample size through simulations. Further simulations show that, when total sample size is fixed, the proposed design has greater power than the traditional Bayesian sequential design, which sets equal stopping bounds at all interim analyses. We also find that the proposed design with the new stopping for futility rule results in greater power and can stop earlier with a smaller actual sample size, compared with the traditional stopping rule for futility when all other conditions are held constant. Finally, we apply the proposed method to a real data set and compare the results with traditional designs.