Likelihood Ratio Type Statistics for Repeated Measures Designs with Heterogeneous Covariance Matrices

Because of their simplicity, Wald statistics are typically used in complex experimental designs. Likelihood ratio statistics in factorial designs are more flexible than Wald statistics in the sense of adapting to non-saturated designs by fitting only as many parameters as the model calls for. This leads to a significant gain in power. Here we propose likelihood ratio type statistics for testing hypotheses in repeated measures designs with heterogeneous covariance matrices, and derive their asymptotic distribution in one general theorem that does not require normality or even continuity of the responses. Simulation studies demonstrate their advantages over the Wald statistics.     

Some sufficient conditions for the type 1 optimality of block designs

In this paper, we investigate the problem of determining block designs which are optimal under type 1 optimality criteria within various classes of designs having υ treatments arranged in b blocks of size k. The solutions to two optimization problems are given which are related to a general result obtained by Cheng (1978) and which are useful in this investigation. As one application of the solutions obtained, the definition of a regular graph design given in Mitchell and John (1977) is extended to that of a semi-regular graph design and some sufficient conditions are derived for the existence of a semi-regular graph design which is optimal under a given type 1 criterion. A result is also given which shows how the sufficient conditions derived can be used to establish the optimality under a specific type 1 criterion of some particular types of semi- regular graph designs having both equal and unequal numbers of replicates. Finally,some sufficient conditions are obtained for the dual of an A- or D-optimal design to be A- or D-optimal within an appropriate class of dual designs.     

αn–Designs

This paper defines a broad class of resolvable incomplete block designs called α_n–designs, of which the original α–designs are a special case with n = 1. The statistical and mathematical properties of α–designs extend naturally to these n –dimensional designs. They are a flexible class of resolvable designs appropriate for use in factorial experiments, in constructing efficient t –latinized resolvable block designs, and for enhancing the existing class of α–designs for a single treatment factor.     

On algorithmic construction of maximin distance designs

Maximin distance designs are useful for conducting expensive computer experiments. In this article, we compare some global optimization algorithms for constructing such designs. We also introduce several related space-filling designs, including nested maximin distance designs, sliced maximin distance designs, and general maximin distance designs with better projection properties. These designs possess more flexible structures than their analogs in the literature. Examples of these designs constructed by the algorithms are presented.     

On the efficiency of adaptive designs for flexible interim decisions in clinical trials

It is shown that the optimal group sequential designs considered in Tsiatis and Mehta [2003. On the inefficiency of the adaptive design for monitoring clinical trials. Biometrika 90, 367–378] are special cases of the more general flexible designs which allow for a valid inference after adapting a predetermined way to spend the rejection and acceptance probabilities. An unforeseen safety issue in a clinical trial, for example, could make a change of the preplanned number of interim analyses and their sample sizes appropriate. We derive flexible designs which have equivalent rejection and acceptance regions if no adaptation is performed, but at the same time allow for an adaptation of the spending functions, and have a conditional optimality property.     

Crossover designs based on type I orthogonal arrays for a self and simple mixed carryover effects model with correlated errors

We investigate the performance of crossover designs based on type I orthogonal arrays for a self and simple mixed carryover effects model in the presence of correlated errors. Assuming that between-subject errors are independent while within-subject errors behave according to the stationary first-order autoregressive and moving average processes, analytical optimality results for 3-period designs are established and, as an illustration, numerical details for a number of 4-period cases are tabulated.     

Resolvable block designs for factorial experiments

It is known that n-cyclic designs provide a flexible class of designs suitable for setting out factorial experiments. In this paper we show that many of these designs are resolvable. Further, an extensive class of practically useful designs can be derived from them by deleting replicates. The properties of the designs compare favourably with those obtained by the algorithm of Williams and John (1996) (Appl. Statist. 45, 39–46).     

Nested Latin Hypercube Designs with Sliced Structures

In computer experiments, space-filling designs with a sliced structure or nested structure have received much recent interest and been studied separately. However, it is likely that designs with both structures are needed in some situations, but there are no suitable designs so far. In this paper, we construct a special class of nested Latin hypercube designs with sliced structures, in such a design, a small sliced Latin hypercube design is nested within a large one. The construction method is easy to implement and the number of factors is flexible. Numerical simulations show the usefulness of the newly proposed designs.     

Generalized minimum aberration two-level split-plot designs

Split-plot experiments may arise when it is impractical to completely randomize the treatment combinations of a designed experiment. To provide more flexible design choices in the nonregular split-plot setting, we describe an approach for constructing minimum aberration orthogonal two-level split-plot designs having 12, 16, 20 and 24 runs. We consider five design scenarios that may be of importance to practitioners, and then propose an approach for assigning word lengths under these five scenarios. We then use the extended word length patterns to rank both regular and nonregular orthogonal split-plot designs. While most existing papers concerning orthogonal split-plot designs focus on regular orthogonal designs, we find that many minimum aberration split-plot designs are nonregular orthogonal designs.     

Efficient designs based on orthogonal arrays of type I and type II for experiments using units ordered over time or space

For a wide variety of applications, experiments are based on units ordered over time or space. Models for these experiments generally may include one or more of: correlations, systematic trends, carryover effects and interference effects. Since the standard optimal block designs may not be efficient in these situations, orthogonal arrays of type I and type II, which were introduced in 1961 by C.R. Rao [Combinatorial arrangements analogous to orthogonal arrays, Sankhya A 23 (1961) 283–286], have been recently used to construct optimal and efficient designs for many of these experiments. Results in this area are unified and the salient features are outlined.     

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.     

Optimal design for epidemiological studies subject to designed missingness

In large epidemiological studies, budgetary or logistical constraints will typically preclude study investigators from measuring all exposures, covariates and outcomes of interest on all study subjects. We develop a flexible theoretical framework that incorporates a number of familiar designs such as case control and cohort studies, as well as multistage sampling designs. Our framework also allows for designed missingness and includes the option for outcome dependent designs. Our formulation is based on maximum likelihood and generalizes well known results for inference with missing data to the multistage setting. A variety of techniques are applied to streamline the computation of the Hessian matrix for these designs, facilitating the development of an efficient software tool to implement a wide variety of designs.     

A candidate-set-free algorithm for generating D-optimal split-plot designs

Summary.  We introduce a new method for generating optimal split-plot designs. These designs are optimal in the sense that they are efficient for estimating the fixed effects of the statistical model that is appropriate given the split-plot design structure. One advantage of the method is that it does not require the prior specification of a candidate set. This makes the production of split-plot designs computationally feasible in situations where the candidate set is too large to be tractable. The method allows for flexible choice of the sample size and supports inclusion of both continuous and categorical factors. The model can be any linear regression model and may include arbitrary polynomial terms in the continuous factors and interaction terms of any order. We demonstrate the usefulness of this flexibility with a 100-run polypropylene experiment involving 11 factors where we found a design that is substantially more efficient than designs that are produced by using other approaches.     

A-optimal diallel crosses for test versus control comparisons

A-optimality of block designs for control versus test comparisons in diallel crosses is investigated. A sufficient condition for designs to be A-optimal is derived. Type S₀ designs are defined and A-optimal type S₀ designs are characterized. A lower bound to the A-efficiency of type S₀ designs is also given. Using the lower bound to A-efficiency, type S₀ designs are shown to yield efficient designs for test versus control comparisons.     

An efficient algorithm for constructing optimal design of computer experiments

The long computational time required in constructing optimal designs for computer experiments has limited their uses in practice. In this paper, a new algorithm for constructing optimal experimental designs is developed. There are two major developments involved in this work. One is on developing an efficient global optimal search algorithm, named as enhanced stochastic evolutionary (ESE) algorithm. The other is on developing efficient methods for evaluating optimality criteria. The proposed algorithm is compared to existing techniques and found to be much more efficient in terms of the computation time, the number of exchanges needed for generating new designs, and the achieved optimality criteria. The algorithm is also very flexible to construct various classes of optimal designs to retain certain desired structural properties.     

Symmetric designs of types V and VI

In Butler (1984a) a semi-translation block was defined and a classification given of all symmetric 2-(υ,k,λ) designs with λ>1, which contain more than one such block. In this paper we consider symmetric designs of type V and VI. We show that symmetric designs of type V are also of type VI, and in addition we show that all such designs can be obtained from a P_n,q by a construction which we give. Finally examples of proper symmetric designs of type V which are not of type VI are given.     

P-splines regression smoothing and difference type of penalty

P-splines regression provides a flexible smoothing tool. In this paper we consider difference type penalties in a context of nonparametric generalized linear models, and investigate the impact of the order of the differencing operator. Minimizing Akaike’s information criterion we search for a possible best data-driven value of the differencing order. Theoretical derivations are established for the normal model and provide insights into a possible ‘optimal’ choice of the differencing order and its interrelation with other parameters. Applications of the selection procedure to non-normal models, such as Poisson models, are given. Simulation studies investigate the performance of the selection procedure and we illustrate its use on real data examples.     

Some results on optimal design under a first-order autoregression and on finite williams type ii designs

It was shown, essentially, by Kiefer (1961) that the type II (a) design of Williams (1952) is asymptotically universally optimum for a first-order autoregression with parameter λ >0. We investigate any optimality properties these designs have when finite. We show that small differences in the definitions of the autoregression or of the design can lead to standard results in the theory of optiaml design no longer being applicable. We include some useful results on patterned matrices.     

Balanced and partially balanced incomplete block designs with autocorrelation errors

The paper aims to find variance balanced and variance partially balanced incomplete block designs when observations within blocks are autocorrelated and we call them BIBAC and PBIBAC designs. Orthogonal arrays of type I and type II when used as BIBAC designs have smaller average variance of elementary contrasts of treatment effects compared to the corresponding Balanced Incomplete Block (BIB) designs with homoscedastic, uncorrelated errors. The relative efficiency of BIB designs compared to BIBAC designs depends on the block size k and the autocorrelation ρ and is independent of the number of treatments. Further this relative efficiency increases with increasing k. Partially balanced incomplete block designs with autocorrelated errors are introduced using partially balanced incomplete block designs and orthogonal arrays of type I and type II.     

Robust Small Sample Inference for Generalised Estimating Equations: An Application of the Anova‐type Test

Asymptotically, the Wald‐type test for generalised estimating equations (GEE) models can control the type I error rate at the nominal level. However in small sample studies, it may lead to inflated type I error rates. Even with currently available small sample corrections for the GEE Wald‐type test, the type I error rate inflation is still serious when the tested contrast is multidimensional. This paper extends the ANOVA‐type test for heteroscedastic factorial designs to GEE and shows that the proposed ANOVA‐type test can also control the type I error rate at the nominal level in small sample studies while still maintaining robustness with respect to mis‐specification of the working correlation matrix. Differences of inference between the Wald‐type test and the proposed test are observed in a two‐way repeated measures ANOVA model for a diet‐induced obesity study and a two‐way repeated measures logistic regression for a collagen‐induced arthritis study. Simulation studies confirm that the proposed test has better control of the type I error rate than the Wald‐type test in small sample repeated measures models. Additional simulation studies further show that the proposed test can even achieve larger power than the Wald‐type test in some cases of the large sample repeated measures ANOVA models that were investigated.