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.     

中国农产量调查中几种可行的PPS系统抽样设计

PPS系统抽样设计是国际上比较流行的设计,它在实践中有着广泛的应用。我国农产量调查采用的是对称等距抽样设计,它实际上可理解为是一种变形的PPS系统抽样设计,使用的是以播种面积作为辅助变量。文章给出了几种可行的PPS系统抽样设计,辅助变量分别取为农户数、播种面积、耕地面积、切块数,并对这几种抽样设计进行了应用分析。     

Sampling design proportional to order statistic of auxiliary variable

The sampling designs dependent on sample moments of auxiliary variables are well known. Lahiri (Bull Int Stat Inst 33:133–140, 1951) considered a sampling design proportionate to a sample mean of an auxiliary variable. Sing and Srivastava (Biometrika 67(1):205–209, 1980) proposed the sampling design proportionate to a sample variance while Wywiał (J Indian Stat Assoc 37:73–87, 1999) a sampling design proportionate to a sample generalized variance of auxiliary variables. Some other sampling designs dependent on moments of an auxiliary variable were considered e.g. in Wywiał (Some contributions to multivariate methods in, survey sampling. Katowice University of Economics, Katowice, 2003a); Stat Transit 4(5):779–798, 2000) where accuracy of some sampling strategies were compared, too.These sampling designs cannot be useful in the case when there are some censored observations of the auxiliary variable. Moreover, they can be much too sensitive to outliers observations. In these cases the sampling design proportionate to the order statistic of an auxiliary variable can be more useful. That is why such an unequal probability sampling design is proposed here. Its particular cases as well as its conditional version are considered, too. The sampling scheme implementing this sampling design is proposed. The inclusion probabilities of the first and second orders were evaluated. The well known Horvitz–Thompson estimator is taken into account. A ratio estimator dependent on an order statistic is constructed. It is similar to the well known ratio estimator based on the population and sample means. Moreover, it is an unbiased estimator of the population mean when the sample is drawn according to the proposed sampling design dependent on the appropriate order statistic.     

Optimal design for classification of functional data

We study the design problem for the optimal classification of functional data. The goal is to select sampling time points so that functional data observed at these time points can be classified accurately. We propose optimal designs that are applicable to either dense or sparse functional data. Using linear discriminant analysis, we formulate our design objectives as explicit functions of the sampling points. We study the theoretical properties of the proposed design objectives and provide a practical implementation. The performance of the proposed design is evaluated through simulations and real data applications. The Canadian Journal of Statistics 48: 285–307; 2020 © 2019 Statistical Society of Canada     

Improving The Efficiency of The Case-Crossover Design

The case-crossover design has been used by many researchers to study the transient effect of an exposure on the risk of a rare outcome. In a case-crossover design, only cases are sampled and each case will act as his/her own control. The time of failure acts as the case and non failure times act as the controls. Case-crossover designs have frequently been used to study the effect of environmental exposures on rare diseases or mortality. Time trends and seasonal confounding may be present in environmental studies and thus need to be controlled for by the sampling design. Several sampling methods are available for this purpose. In time-stratified sampling, disjoint strata of equal size are formed and the control times within the case stratum are used for comparison. The random semi-symmetric sampling design randomly selects a control time for comparison from two possible control times. The fixed semi-symmetric sampling design is a modified version of the random semi-symmetric sampling design that removes the random selection. Simulations show that the fixed semi-symmetric sampling design improves the variance of the random semi-symmetric sampling estimator by at least 35% for the exposures we studied. We derive expressions for the asymptotic variance of risk estimators for these designs, and show, that while the designs are not theoretically equivalent, in many realistic situations, the random semi-symmetric sampling design has similar efficiency to a time-stratified sampling design of size two and the fixed semi-symmetric sampling design has similar efficiency to a time-stratified sampling design of size three.     

A review of optimal designs in survey sampling

Results in five areas of survey sampling dealing with the choice of the sampling design are reviewed. In Section 2, the results and discussions surrounding the purposive selection methods suggested by linear regression superpopulation models are reviewed. In Section 3, similar models to those in the previous section are considered; however, random sampling designs are considered and attention is focused on the optimal choice of π_j. Then in Section 4, systematic sampling methods obtained under autocorrelated superpopulation models are reviewed. The next section examines minimax sampling designs. The work in the final section is based solely on the randomization. In Section 6 methods of sample selection which yield inclusion probabilities π_j = n/N and π_ij = n(n - 1)/N(N - 1), but for which there are fewer than _NC_n possible samples, are mentioned briefly.     

An adaptive sampling scheme guided by BART—with an application to predict processor performance

The evaluation of new processor designs is an important issue in electrical and computer engineering. Architects use simulations to evaluate designs and to understand trade‐offs and interactions among design parameters. However, due to the lengthy simulation time and limited resources, it is often practically impossible to simulate a full factorial design space. Effective sampling methods and predictive models are required. In this paper, the authors propose an automated performance predictive approach which employs an adaptive sampling scheme that interactively works with the predictive model to select samples for simulation. These samples are then used to build Bayesian additive regression trees, which in turn are used to predict the whole design space. Both real data analysis and simulation studies show that the method is effective in that, though sampling at very few design points, it generates highly accurate predictions on the unsampled points. Furthermore, the proposed model provides quantitative interpretation tools with which investigators can efficiently tune design parameters in order to improve processor performance. The Canadian Journal of Statistics 38: 136–152; 2010 © 2010 Statistical Society of Canada     

Remainder modified systematic sampling in the presence of linear trend

If the population size is not a multiple of the sample size, then the usual linear systematic sampling design is unattractive, since the sample size obtained will either vary, or be constant and different to the required sample size. Only a few modified systematic sampling designs are known to deal with this problem and in the presence of linear trend, most of these designs do not provide favorable results. In this paper, a modified systematic sampling design, known as remainder modified systematic sampling (RMSS), is introduced. There are seven cases of RMSS and the results in this paper suggest that the proposed design is favorable, regardless of each case, while providing linear trend-free sampling results for three of the seven cases. To obtain linear trend-free sampling for the other cases and thus improve results, an end corrections estimator is constructed.     

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.     

Finding maximum G-criterion values for central composite designs on the hypercube

For quadratic regression on the hypercube, G—efficiencies are often used in the selection process of an experimental design. To calculate a design's G—efficiency, it is necessary to maximize the prediction variance over the experimental design region. However, it is common to approximate a G—efficiency. This is achieved by calculating the prediction variances generated from a subset of points in the design space and taking the maximum to estimate the maximum prediction variance. This estimate is then applied to approximate the G—efficiency. In this paper, it will be shown that over the class of central composite designs (CCDs) on the hypercube. the prediction variance can be expressed in a closed-form. An exact value of the maximum prediction variance can then be determined by evaluating this closed-form expression over a finite subset of barycentric points. Tables of exact G—efficiencies will be presented. Design optimality criteria, quadratic regression on the hypercube, and the structures of the design matrix X, X'X, and (X'X)^?1 for any CCD will be discussed.     

Applications and Implementations of Continuous Robust Designs

In the literature concerning the construction of robust optimal designs, many resulting designs turn out to have densities. In practice, an exact design should tell the experimenter what the support points are and how many subjects should be allocated to each of these points. In particular, we consider a practical situation in which the number of support points allowed is constrained. We discuss an intuitive approach, which motivates a new implementation scheme that minimizes the loss function based on the Kolmogorov and Smirnov distance between an exact design and the optimal design having a density. We present three examples to illustrate the application and implementation of a robust design constructed: one for a nonlinear dose-response experiment and the other two for general linear regression. Additionally, we perform some simulation studies to compare the efficiencies of the exact designs obtained by our optimal implementation with those by other commonly used implementation methods.     

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.     

Construction on non-adaptive hypergeometric group testing desings for identifying at most two defectives

In the literature a systematic method of obtaining a group testing design is not available at present. Weideman and Raghavarao (1987a, b) gave methods for the construction of non - adaptive hypergeometric group testing designs for identifying at most two defectives by using a dual method. In the present investigation we have developed a method of construction of group testing designs from (i) Hypercubic Designs for t ≡ 3 (mod 6) and (ii) Balanced Incomplete Block Designs for t ≡ 1 (mod 6) and t ≡ 3 (mod 6). These constructions are accomplished by the use of dual designs. The designs so constructed satisfy specified properties and attained an optimal bound as discussed by Weidman and Raghavarao (1987a,b). Here it is also shown that the condition for pairwise disjoint sets of BIBD for t ≡ 1 (mod 6) given by Weideman and Raghavarao (1987b) is not true for all such designs.     

Some remarks on experimental design for estimating the expectation of a stationary random process

For estimation of the mean of a stationary random process the variance-optimal choice of the observation points (the so called experimental design) is considered. For this discrete and continuous designs are introduced, some known results of process statistics are interpreted to experimental design and a proposal for simplification of the minimization problem is offered, moreover it is proved, that for monotone decreasing eovarianee functions a design, for which the points near the ends of the observation interval are more dense than in the middle, is better than the equidistant design.     

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.     

SPIRIT: A seamless phase I/II randomized design for immunotherapy trials

Immunotherapy—treatments that enlist the immune system to battle tumors—has received widespread attention in cancer research. Due to its unique features and mechanisms for treating cancer, immunotherapy requires novel clinical trial designs. We propose a Bayesian seamless phase I/II randomized design for immunotherapy trials (SPIRIT) to find the optimal biological dose (OBD) defined in terms of the restricted mean survival time. We jointly model progression‐free survival and the immune response. Progression‐free survival is used as the primary endpoint to determine the OBD, and the immune response is used as an ancillary endpoint to quickly screen out futile doses. Toxicity is monitored throughout the trial. The design consists of two seamlessly connected stages. The first stage identifies a set of safe doses. The second stage adaptively randomizes patients to the safe doses identified and uses their progression‐free survival and immune response to find the OBD. The simulation study shows that the SPIRIT has desirable operating characteristics and outperforms the conventional design.     

A clustering-based coordinate exchange algorithm for generating G-optimal experimental designs

In the optimal experimental design literature, the G-optimality is defined as minimizing the maximum prediction variance over the entire experimental design space. Although the G-optimality is a highly desirable property in many applications, there are few computer algorithms developed for constructing G-optimal designs. Some existing methods employ an exhaustive search over all candidate designs, which is time-consuming and inefficient. In this paper, a new algorithm for constructing G-optimal experimental designs is developed for both linear and generalized linear models. The new algorithm is made based on the clustering of candidate or evaluation points over the design space and it is a combination of point exchange algorithm and coordinate exchange algorithm. In addition, a robust design algorithm is proposed for generalized linear models with modification of an existing method. The proposed algorithm are compared with the methods proposed by Rodriguez et al. [Generating and assessing exact G-optimal designs. J. Qual. Technol. 2010;42(1):3–20] and Borkowski [Using a genetic algorithm to generate small exact response surface designs. J. Prob. Stat. Sci. 2003;1(1):65–88] for linear models and with the simulated annealing method and the genetic algorithm for generalized linear models through several examples in terms of the G-efficiency and computation time. The result shows that the proposed algorithm can obtain a design with higher G-efficiency in a much shorter time. Moreover, the computation time of the proposed algorithm only increases polynomially when the size of model increases.     

Generalized Systematic Sampling

In this paper, we introduce a new systematic sampling design, called a Generalized Systematic Sampling (GSS), for estimation of finite population mean. The proposed design is found to be better than Simple Random Sampling (SRS) and the generalization of the several existing systematic sampling schemes such as, Linear Systematic Sampling (LSS), Diagonal Systematic Sampling (DSS), and Generalized Diagonal Systematic Sampling (GDSS). All of these designs become special cases of the proposed design.     

Supersaturated design including an orthogonal base

Recently, many supersaturated designs have been proposed. A supersaturated design is a fractional factorial design in which the number of factors is greater than the number of experimental runs. The main thrust of the previous studies has been to generate more columns while avoiding large values of squared inner products among all design columns. These designs would be appropriate if the probability for each factor being active is uniformly distributed. When factors can be partitioned into two groups, namely, with high and low probabilities of each factor being active, it is desirable to maintain orthogonality among columns to be assigned to the factors in the high-probability group. We discuss a supersaturated design including an orthogonal base which is suitable for this common situation. Mathematical results on the existence of the supersaturated designs are shown, and the construction of supersaturated designs is presented. We next discuss some properties of the proposed supersaturated designs based on the squared inner products.     

An algorithm for the design of factorial experiments when the data are correlated

Since the development of methods for the analysis of experiments with dependent data, see for example Gleeson and Cullis (1987), the design of such experiments has been an area of active research. We investigate the design of factorial experiments, complete and fractional, for various dependency structures. An algorithm for generating optimal or near optimal designs is presented and shown to be useful across a wide range of dependency structures.