Robust and efficient design of experiments for the Monod model

In this paper the problem of designing experiments for the Monod model, which is frequently used in microbiology, is studied. The model is defined implicitly by a differential equation and has numerous applications in microbial growth kinetics, environmental research, pharmacokinetics, and plant physiology. The designs presented so far in the literature are local optimal designs, which depend sensitively on a preliminary guess of the unknown parameters, and are for this reason in many cases not robust with respect to their misspecification. Uniform designs and maximin optimal designs are considered as a strategy to obtain robust and efficient designs for parameter estimation. In particular, standardized maximin D- and E-optimal designs are determined and compared with uniform designs, which are usually applied in these microbiological models. It is demonstrated that maximin optimal designs are substantially more efficient than uniform designs. Parameter variances can be decreased by a factor of two by simply sampling at optimal times during the experiment. Moreover, the maximin optimal designs usually provide the possibility for the experimenter to check the model assumptions, because they have more support points than parameters in the Monod model.     

On the Role of Baseline Measurements for Crossover Designs under the Self and Mixed Carryover Effects Model

Summary .  It is well known that optimal designs are strongly model dependent. In this article, we apply the Lagrange multiplier approach to the optimal design problem, using a recently proposed model for carryover effects. Generally, crossover designs are not recommended when carryover effects are present and when the primary goal is to obtain an unbiased estimate of the treatment effect. In some cases, baseline measurements are believed to improve design efficiency. This article examines the impact of baselines on optimal designs using two different assumptions about carryover effects during baseline periods and employing a nontraditional crossover design model. As anticipated, baseline observations improve design efficiency considerably for two-period designs, which use the data in the first period only to obtain unbiased estimates of treatment effects, while the improvement is rather modest for three- or four-period designs. Further, we find little additional benefits for measuring baselines at each treatment period as compared to measuring baselines only in the first period. Although our study of baselines did not change the results on optimal designs that are reported in the literature, the problem of strong model dependency problem is generally recognized. The advantage of using multiperiod designs is rather evident, as we found that extending two-period designs to three- or four-period designs significantly reduced variability in estimating the direct treatment effect contrast.     

Bayesian adaptive biased-coin designs for clinical trials with normal responses

Adaptive designs are used in phase III clinical trials for skewing the allocation pattern toward the better treatments. We use optimum design theory to derive a skewed Bayesian biased-coin procedure for sequential designs with continuous responses. The skewed designs are used to provide adaptive designs, the performance of which is studied numerically and theoretically. Important properties are loss and the proportion of allocation to the better treatment.     

Optimal adaptive two‐stage designs for phase II cancer clinical trials

In oncology, single‐arm two‐stage designs with binary endpoint are widely applied in phase II for the development of cytotoxic cancer therapies. Simon's optimal design with prefixed sample sizes in both stages minimizes the expected sample size under the null hypothesis and is one of the most popular designs. The search algorithms that are currently used to identify phase II designs showing prespecified characteristics are computationally intensive. For this reason, most authors impose restrictions on their search procedure. However, it remains unclear to what extent this approach influences the optimality of the resulting designs. This article describes an extension to fixed sample size phase II designs by allowing the sample size of stage two to depend on the number of responses observed in the first stage. Furthermore, we present a more efficient numerical algorithm that allows for an exhaustive search of designs. Comparisons between designs presented in the literature and the proposed optimal adaptive designs show that while the improvements are generally moderate, notable reductions in the average sample size can be achieved for specific parameter constellations when applying the new method and search strategy.     

Some Third-Order Rotatable Designs

Some new third-order rotatable designs are obtained in 5, 6, 7 and 8 dimensions. Many of these designs are of a sequential type and some require fewer experiments than the known designs with minimal number of experiments.     

Statistical Analyses for Multistage Experiment Designs

Suppose that t experiments are conducted simultaneously on the same set of experimental units. For example, suppose that t mutually orthogonal latin square experiment designs are used for the t experiments on n² experimental units. Statistical literature is voluminous on construction of such designs, but contains relatively little and incomplete results on statistical analyses for such designs. Six statistical analyses are presented for a pair of orthogonal latin square experiment designs. Then, the methods are generalized for t mutually orthogonal experiment designs. The results are also extended to a set of t mutually balanced Youden experiment designs.     

Group Divisible Second Order Rotatable Designs

The Group Divisible Rotatable (GDR) designs are the designs in which the factors get divided into groups such that for the factors within group, the designs are rotatable. In the present paper we have obtained a series of Group Divisible Second Order Rotatable designs, by decomposing the v-dimensional space corresponding to v-factors under consideration into three mutually orthogonal spaces. We have given the least squares estimates of the parameters, the analysis and construction of such designs.     

Efficiency Indices for Second-Order Designs

Design efficiencies are studied for inferences regarding the coefficients of second-order models. Subspaces of parameters are identified wherein each of two designs dominates the other locally, or the two designs are equally efficient. Both Fisher efficiency in estimation and Pitman efficiency in hypothesis testing are considered. Eight small second-order designs in k=3 regressor variables are screened using a four-part efficiency index. Of these, the central composite, Box-Behnken, small composite, and hybrid H310 and H311 B designs are found to be generally superior and roughly comparable. Detailed comparisons among these five designs are then undertaken. This work provides further tools for use in design evaluation, requiring only basic matrix operations independently of experimental data.     

Minimax D-optimal designs for the logistic model

We propose an algorithm for constructing minimax D-optimal designs for the logistic model when only the ranges of the values for both parameters are assumed known. Properties of these designs are studied and compared with optimal Bayesian designs and Sitter's (1992, Biometrics, 48, 1145-1155) minimax D-optimal kk-designs. Examples of minimax D-optimal designs are presented for the logistic and power logistic models, including a dose-response design for rheumatoid arthritis patients.     

Single subject (small N) research designs and zoo research

This paper presents single case (small N) research designs as a design option for research in zoos. Because of the small numbers of animals in zoos, traditional large group designs using inferential statistics are often not feasible. Single subject research designs are discussed with respect to logic, specific design options, and validity. Specific examples are used throughout to demonstrate how these designs would be used in zoo research. © 1996 Wiley-Liss, Inc.     

Robustness and Efficiency of D‐optimal Experimental Designs in a Growth Problem

To assess tree growth, for example in diameter, a forester typically measures the trees at regular time points. We call such designs equidistant. In this paper we look at the robustness and efficiency of several experimental designs, using the D‐optimality criterion, in a case study of diameter growth in cork oaks. We compare D‐optimal designs (unrestricted and replication‐free) with equidistant designs. We further compare designs in different experimental regions. Results indicate that the experimental region should be adequate to the problem, and that D‐optimal designs are substantially more efficient than equidistant designs, even under parameter mis‐specification.     

On the Construction of Balanced and Partially Balanced Ternary Design

A method of constructing balanced and partially balanced ternary designs from balanced and partially balanced incomplete block designs, respectively, and two methods of constructing partially balanced ternary designs from association schemes are obtained. Two new and efficient balanced ternary designs having K < V and R ≦ 20 are obtained by the first method.     

Non-Iterative Least Squares Estimation of Missing Values in Hyper-Graeco-Latin Square Designs

In this paper an attempt has been made to obtain explicit expressions for the estimators of the several missing values in hyper-graeco-latin square designs. Further it has been shown that the estimates of the missing values in latin square designs and graeco-latin square designs are obtained as a particular case of the estimates of the missing values in hyper-graeco-latin square designs.     

Conditional Point Estimation in Adaptive Group Sequential Test Designs

It is well known that point estimates in group sequential designs are biased. This also applies to adaptive designs that enable, e.g., data driven reassessments of group sample sizes. For triangular designs, Whitehead (1986) (Biometrika 73 , 573–581) proposed a bias adjusted estimate. But this estimate is not feasible in adaptive designs although it is in group sequential designs. Furthermore, there is a waste of information because it does not use the information at which stage the trial was stopped. We present a modification which does use this information and which is applicable to adaptive designs. The modified estimate achieves an improvement in group sequential designs and shows similar results in adaptive designs.     

Construction of Resolvable Designs with Nested Treatment Structure

The construction of resolvable incomplete block and row-column designs is investigated when the treatments have a nested structure. Some theoretical results are derived for lattice designs. Efficient designs for unequal-sized treatment groups are obtained by defining a multiple objective function and carrying out a computer search using an interchange algorithm.     

The design and analysis of breeders' trials of sugar beet (Beta vulgaris) using two-dimensional blocking structures

A method for generating two-dimensional blocking designs to fit any shape and size of experimental area is presented. The method takes an alpha design appropriate to the experimental area and imposes additional blocking perpendicular to the alpha blocks. Improvements to the design are then made by repositioning entries within the alpha blocks. Although this method of construction is less sophisticated than for other two-dimensional designs, the designs are particularly suited to large scale breeders trials where no alternative two-dimensional design may exist. The designs have been used for 3 yr in a sugar beet breeding programme, and have given improvements in efficiency over one-dimensional alpha designs.     

Efficiency of augmented p-rep designs in multi-environmental trials

Key message

The paper shows that unreplicated designs in multi-environmental trials are most efficient. If replication per environment is needed then augmented p-rep designs outperform augmented and replicated designs in triticale and maize.

Abstract

In plant breeding, augmented designs with unreplicated entries are frequently used for early generation testing. With limited amount of seed, this design allows to use a maximum number of environments in multi-environmental trials (METs). Check plots enable the estimation of block effects, error variances and a connection of otherwise unconnected trials in METs. Cullis et al. (J Agri Biol Environ Stat 11:381–393, 2006) propose to replace check plots from a grid-plot design by plots of replicated entries leading to partially replicated (p-rep) designs. Williams et al. (Biom J 53:19–27, 2011) apply this idea to augmented designs (augmented p-rep designs). While p-rep designs are increasingly used in METs, a comparison of the efficiency of augmented p-rep designs and augmented designs in the range between replicated and unreplicated designs in METs is lacking. We simulated genetic effects and allocated them according to these four designs to plot yields of a triticale and a maize uniformity trial. The designs varied in the number of environments, but have a fixed number of entries and total plots. The error model and the assumption of fixed or random entry effects were varied in simulations. We extended our simulation for the triticale data by including correlated entry effects which are common in genomic selection. Results show an advantage of unreplicated and augmented p-rep designs and a preference for using random entry effects, especially in case of correlated effects reflecting relationships among entries. Spatial error models had minor advantages compared to purely randomization-based models.     

Statistical designs for two-color spotted microarray experiments

Two-color cDNA or oligonucleotide-based spotted microarrays have been commonly used in measuring the expression levels of thousands of genes simultaneously. To realize the immense potential of this powerful new technology, budgeted within limited resources or other constraints, practical designs with high efficiencies are in demand. In this study, we address the design issue concerning the arrangement of the mRNA samples labeled with fluorescent dyes and hybridized on the slides. A normalization model is proposed to characterize major sources of systematic variation in a two-color microarray experiment. This normalization model establishes a connection between designs for two-color microarray experiments with a particular class of classical row-column designs. A heuristic algorithm for constructing A-optimal or highly efficient designs is provided. Statistical optimality results are found for some of the designs generated from the algorithm. It is believed that the constructed designs are the best or very close to the best possible for estimating the relative gene expression levels among the mRNA samples of interest.     

Analysis of data from incomplete block designs

This paper presents an organized solution to the problem of computing inter- and intrablock analyses of incomplete block designs, based on the modified maximum likelihood principle proposed by Patterson and Thompson (1971, Biometrika 58, 545-554). The calculations are set out to be easily programmed on a microcomputer. The method is attractive because it is simple, yet sufficiently general to handle a wide class of designs, including partially balanced incomplete block designs, designs with unequal block sizes, designs with missing values, and generally unbalanced split-plot experiments.     

Adaptive trial designs: a review of barriers and opportunities

ABSTRACT: Adaptive designs allow planned modifications based on data accumulating within a study. The promise of greater flexibility and efficiency stimulates increasing interest in adaptive designs from clinical, academic, and regulatory parties. When adaptive designs are used properly, efficiencies can include a smaller sample size, a more efficient treatment development process, and an increased chance of correctly answering the clinical question of interest. However, improper adaptations can lead to biased studies. A broad definition of adaptive designs allows for countless variations, which creates confusion as to the statistical validity and practical feasibility of many designs. Determining properties of a particular adaptive design requires careful consideration of the scientific context and statistical assumptions. We first review several adaptive designs that garner the most current interest. We focus on the design principles and research issues that lead to particular designs being appealing or unappealing in particular applications. We separately discuss exploratory and confirmatory stage designs in order to account for the differences in regulatory concerns. We include adaptive seamless designs, which combine stages in a unified approach. We also highlight a number of applied areas, such as comparative effectiveness research, that would benefit from the use of adaptive designs. Finally, we describe a number of current barriers and provide initial suggestions for overcoming them in order to promote wider use of appropriate adaptive designs. Given the breadth of the coverage all mathematical and most implementation details are omitted for the sake of brevity. However, the interested reader will find that we provide current references to focused reviews and original theoretical sources which lead to details of the current state of the art in theory and practice.