Orthogonal three-level parallel flats designs for user-specified resolution

Orthogonal factorial and fractional factorial designs are very popular in many experimental studies, particularly the two-level and three-level designs used in screening experiments. When an experimenter is able to specify the set of possibly nonnegligible factorial effects, it is sometimes possible to obtain an orthogonal design belonging to the class of parallel flats designs, that has a smaller run-size than a suitable design from the class of classical fractional factorial designs belonging to the class of single flat designs. Sri-vastava and Li (1996) proved a fundamental theorem of orthogonal s-level, s being a prime, designs of parallel flats type for the user-specified resolution. They also tabulated a series of orthogonal designs for the two-level case. No orthogonal designs for three-level case are available in their paper. In this paper, we present a simple proof for the theorem given in Srivastava and Li (1996) for the three-level case. We also give a dual form of the theorem, which is more useful for developing an algorithm for construction of orthogonal designs. Some classes of three-level orthogonal designs with practical run-size are given in the paper.     

Bayesian and maximin optimal designs for heteroscedastic regression models

The authors consider the problem of constructing standardized maximin D‐optimal designs for weighted polynomial regression models. In particular they show that by following the approach to the construction of maximin designs introduced recently by Dette, Haines & Imhof (2003), such designs can be obtained as weak limits of the corresponding Bayesian _q‐optimal designs. They further demonstrate that the results are more broadly applicable to certain families of nonlinear models. The authors examine two specific weighted polynomial models in some detail and illustrate their results by means of a weighted quadratic regression model and the Bleasdale–Nelder model. They also present a capstone example involving a generalized exponential growth model.     

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.     

Optimal fractional factorial designs for estimating interactions of one factor with all others: 3m Series

In some experimental situations, only one factor is expected to interact with other factors. Designs which permit estimation of all main effects and the interactions of one factor ‘With All Others’, are termed WAO designs. This paper discusses the existence and construction of s^m WAO designs. A series of WAO designs are presented for the 3^m factorial, for m = 6, 7, ... , 14. The p non-negligible effects are estimable in 9f^? runs, where f^? is the smallest integer such that 9f^? ≥p. These designs are determinant optimal within the class of parallel flats fractions and, except for the case f^? = 9, are new. They are ideally suited for sequential experiments.     

Three Parallel Flats Designs for Two-level Factorial Experiments

This paper investigates the properties of the class of three parallel flats designs for two-level factorial experiments. It shows that the designs constructed from this class of designs can have a very simple correlation structure. The correlation of any pair of best linear unbiased estimators of factorial effects is 0, ⅓ or ¼. Furthermore, the designs obtained also have high D-efficiency. Finally, a class of designs is generated with run-size N = 12 to illustrate the use of the theorem.     

Robust estimation and design procedures for the random effects model

The authors discuss two robust estimators for estimating variance components in the random effects model, and they obtain finite‐sample breakdown points for the estimators. Based on the finite‐sample breakdown point, they propose a criterion for selecting robust designs. With robust designs, one can get efficient and reliable estimates for variance components regardless of outliers which may happen in the experiment. The authors give examples to show the performance of robust estimators and to compare robust designs with optimal designs based on the traditional analysis of variance estimation method.     

Pseudo‐empirical likelihood ratio confidence intervals for complex surveys

The authors show how an adjusted pseudo‐empirical likelihood ratio statistic that is asymptotically distributed as a chi‐square random variable can be used to construct confidence intervals for a finite population mean or a finite population distribution function from complex survey samples. They consider both non‐stratified and stratified sampling designs, with or without auxiliary information. They examine the behaviour of estimates of the mean and the distribution function at specific points using simulations calling on the Rao‐Sampford method of unequal probability sampling without replacement. They conclude that the pseudo‐empirical likelihood ratio confidence intervals are superior to those based on the normal approximation, whether in terms of coverage probability, tail error rates or average length of the intervals.     

The impact of period effects on dose level contrasts in alternating cross‐over designs for first‐time‐in‐human studies

For first‐time‐in‐human studies with small molecules alternating cross‐over designs are often employed and at study end are analyzed using linear models. We discuss the impact of including a period effect in the model on the precision with which dose level contrasts can be estimated and quantify the bias of least squares estimators if a period effect is inherent in the data that is not accounted for in the model. We also propose two alternative designs that allow a more precise estimation of dose level contrasts compared with the standard design when period effects are included in the model. Copyright © 2010 John Wiley & Sons, Ltd.     

Cost‐efficient higher‐order crossover designs for two‐treatment clinical trials

Higher‐order crossover designs have drawn considerable attention in clinical trials, because of their ability to test direct treatment effects in the presence of carry‐over effects. The important question, when applying higher‐order crossover designs in practice, is how to choose a design with both statistical and cost efficiencies from various alternatives. In this paper, we propose a general cost function and compare five statistically optimal or near‐optimal designs with this cost function for a two‐treatment study under different carry‐over models. Based on our study, to achieve both statistical and cost efficiencies, a four‐period, four‐sequence crossover design is generally recommended under the simple carry‐over or no carry‐over models, and a three‐period, two‐sequence crossover design is generally recommended under the steady‐state carry‐over models. Copyright © 2005 John Wiley & Sons, Ltd.     

Optimizing trial design in pharmacogenetics research: comparing a fixed parallel group,group sequential,and adaptive selection design on sample size requirements

Two‐stage clinical trial designs may be efficient in pharmacogenetics research when there is some but inconclusive evidence of effect modification by a genomic marker. Two‐stage designs allow to stop early for efficacy or futility and can offer the additional opportunity to enrich the study population to a specific patient subgroup after an interim analysis. This study compared sample size requirements for fixed parallel group, group sequential, and adaptive selection designs with equal overall power and control of the family‐wise type I error rate. The designs were evaluated across scenarios that defined the effect sizes in the marker positive and marker negative subgroups and the prevalence of marker positive patients in the overall study population. Effect sizes were chosen to reflect realistic planning scenarios, where at least some effect is present in the marker negative subgroup. In addition, scenarios were considered in which the assumed ‘true’ subgroup effects (i.e., the postulated effects) differed from those hypothesized at the planning stage. As expected, both two‐stage designs generally required fewer patients than a fixed parallel group design, and the advantage increased as the difference between subgroups increased. The adaptive selection design added little further reduction in sample size, as compared with the group sequential design, when the postulated effect sizes were equal to those hypothesized at the planning stage. However, when the postulated effects deviated strongly in favor of enrichment, the comparative advantage of the adaptive selection design increased, which precisely reflects the adaptive nature of the design. Copyright © 2013 John Wiley & Sons, Ltd.     

Evaluating dynamic treatment strategies: does it have to be more costly?

Dynamic treatment strategies are designed to change treatments over time in response to intermediate outcomes. They can be deployed for primary treatment as well as for the introduction of adjuvant treatment or other treatment‐enhancing interventions. When treatment interventions are delayed until needed, more cost‐efficient strategies will result. Sequential multiple assignment randomized (SMAR) trials allow for unbiased estimation of the marginal effects of different sequences of history‐dependent treatment decisions. Because a single SMAR trial enables evaluation of many different dynamic regimes at once, it is naturally thought to require larger sample sizes than the parallel randomized trial. In this paper, we compare power between SMAR trials studying a regime, where treatment boosting enters when triggered by an observed event, versus the parallel design, where a treatment boost is consistently prescribed over the entire study period. In some settings, we found that the dynamic design yields the more efficient trial for the detection of treatment activity. We develop one particular trial to compare a dynamic nursing intervention with telemonitoring for the enhancement of medication adherence in epilepsy patients. To this end, we derive from the SMAR trial data either an average of conditional treatment effects (‘conditional estimator’) or the population‐averaged (‘marginal’) estimator of the dynamic regimes. Analytical sample size calculations for the parallel design and the conditional estimator are compared with simulated results for the population‐averaged estimator. We conclude that in specific settings, well‐chosen SMAR designs may require fewer data for the development of more cost‐efficient treatment strategies than parallel designs. Copyright © 2012 John Wiley & Sons, Ltd.     

The weighted likelihood

The authors consider a weighted version of the classical likelihood that applies when the need is felt to diminish the role of some of the data in order to trade bias for precision. They propose an axiomatic derivation of the weighted likelihood, for which they show that aspects of classical theory continue to obtain. They suggest a data‐based method of selecting the weights and show that it leads to the James‐Stein estimator in various contexts. They also provide applications.     

Projection estimators of Pickands dependence functions

The authors consider the construction of intrinsic estimators for the Pickands dependence function of an extreme‐value copula. They show how an arbitrary initial estimator can be modified to satisfy the required shape constraints. Their solution consists in projecting this estimator in the space of Pickands functions, which forms a closed and convex subset of a Hilbert space. As the solution is not explicit, they replace this functional parameter space by a sieve of finite‐dimensional subsets. They establish the asymptotic distribution of the projection estimator and its finite‐dimensional approximations, from which they conclude that the projected estimator is at least as efficient as the initial one.     

A new estimation procedure for a partially nonlinear model via a mixed‐effects approach

The authors consider the estimation of the parametric component of a partially nonlinear semiparametric regression model whose nonparametric component is viewed as a nuisance parameter. They show how estimation can proceed through a nonlinear mixed‐effects model approach. They prove that under certain regularity conditions, the proposed estimate is consistent and asymptotically Gaussian. They investigate its finite‐sample properties through simulations and illustrate its use with data on the relation between the photosynthetically active radiation and the net ecosystem‐atmosphere exchange of carbon dioxide.     

Consistency of semiparametric maximum likelihood estimators for two‐phase sampling

Semiparametric maximum likelihood estimators have recently been proposed for a class of two‐phase, outcome‐dependent sampling models. All of them were “restricted” maximum likelihood estimators, in the sense that the maximization is carried out only over distributions concentrated on the observed values of the covariate vectors. In this paper, the authors give conditions for consistency of these restricted maximum likelihood estimators. They also consider the corresponding unrestricted maximization problems, in which the “absolute” maximum likelihood estimators may then have support on additional points in the covariate space. Their main consistency result also covers these unrestricted maximum likelihood estimators, when they exist for all sample sizes.     

Semiparametric efficient estimation for the auxiliary outcome problem with the conditional mean model

The authors consider semiparametric efficient estimation of parameters in the conditional mean model for a simple incomplete data structure in which the outcome of interest is observed only for a random subset of subjects but covariates and surrogate (auxiliary) outcomes are observed for all. They use optimal estimating function theory to derive the semiparametric efficient score in closed form. They show that when covariates and auxiliary outcomes are discrete, a Horvitz‐Thompson type estimator with empirically estimated weights is semiparametric efficient. The authors give simulation studies validating the finite‐sample behaviour of the semiparametric efficient estimator and its asymptotic variance; they demonstrate the efficiency of the estimator in realistic settings.     

Two‐stage phase II survival trial design

Recently, molecularly targeted agents and immunotherapy have been advanced for the treatment of relapse or refractory cancer patients, where disease progression‐free survival or event‐free survival is often a primary endpoint for the trial design. However, methods to evaluate two‐stage single‐arm phase II trials with a time‐to‐event endpoint are currently processed under an exponential distribution, which limits application of real trial designs. In this paper, we developed an optimal two‐stage design, which is applied to the four commonly used parametric survival distributions. The proposed method has advantages compared with existing methods in that the choice of underlying survival model is more flexible and the power of the study is more adequately addressed. Therefore, the proposed two‐stage design can be routinely used for single‐arm phase II trial designs with a time‐to‐event endpoint as a complement to the commonly used Simon's two‐stage design for the binary outcome.     

Regression analysis of interval‐censored failure time data with linear transformation models

The authors consider the estimation of regression parameters in the context of a class of generalized proportional hazards models, termed linear transformation models, in the presence of interval‐censored data. They present an estimating equation approach whose good performance is demonstrated through simulations and which they illustrate in a few concrete cases.     

Analyzing multivariate longitudinal binary data: A generalized estimating equations approach

The authors consider regression analysis for binary data collected repeatedly over time on members of numerous small clusters of individuals sharing a common random effect that induces dependence among them. They propose a mixed model that can accommodate both these structural and longitudinal dependencies. They estimate the parameters of the model consistently and efficiently using generalized estimating equations. They show through simulations that their approach yields significant gains in mean squared error when estimating the random effects variance and the longitudinal correlations, while providing estimates of the fixed effects that are just as precise as under a generalized penalized quasi‐likelihood approach. Their method is illustrated using smoking prevention data.     

Optimal split‐plot orthogonal arrays

It is well known that many industrial experiments have split‐plot structures. Compared to completely randomised experiments, split‐plot designs are more economical and thus have received much attention among researchers. Much work has been done for two‐level split‐plot designs. In this article, we consider split‐plot designs with factors of three, more than three, or mixed levels and with both qualitative and quantitative factors. We show that if two designs with both qualitative and quantitative factors are geometrically isomorphic, then their generalised wordlength patterns are identical. Three design scenarios are considered for optimal designs. The corresponding wordlength patterns are defined and the minimum aberration mixed‐level split‐plot designs having 18 and 36 runs are tabulated.