Randomization of neighbour balanced generalized Youden designs

If a crossover design with more than two treatments is carryover balanced, then the usual randomization of experimental units and periods would destroy the neighbour structure of the design. As an alternative, Bailey [1985. Restricted randomization for neighbour-balanced designs. Statist. Decisions Suppl. 2, 237–248] considered randomization of experimental units and of treatment labels, which leaves the neighbour structure intact. She has shown that, if there are no carryover effects, this randomization validates the row–column model, provided the starting design is a generalized Latin square. We extend this result to generalized Youden designs where either the number of experimental units is a multiple of the number of treatments or the number of periods is equal to the number of treatments. For the situation when there are carryover effects we show for so-called totally balanced designs that the variance of the estimates of treatment differences does not change in the presence of carryover effects, while the estimated variance of this estimate becomes conservative.     

Nonparametric approaches for comparing three-period,two-treatment,four-sequence crossover designs

The paper describes nonparametric approaches for comparing three-period, two-treatment, four-sequence crossover designs through testing the hypothesis that the treatments are interchangeable. The proposed approaches are based on a model which incorporates, along with the direct treatment effects, self and mixed carryover effects. Related asymptotic results are obtained. Comparisons among the designs are made numerically with respect to type I error rate and power of the tests considering compound symmetry and autoregressive covariance structures of the response variables. Lengths of the confidence intervals of the treatment differences are also used to make comparative study among the designs.     

Optimal Designs for the Carryover Model with Random Interactions Between Subjects and Treatments

The paper considers a model for crossover designs with carryover effects and a random interaction between treatments and subjects. Under this model, two observations of the same treatment on the same subject are positively correlated and therefore provide less information than two observations of the same treatment on different subjects. The introduction of the interaction makes the determination of optimal designs much harder than is the case for the traditional model. Generalising the results of Bludowsky's thesis, the present paper uses Kushner's method to determine optimal approximate designs. We restrict attention to the case where the number of periods is less than or equal to the number of treatments. We determine the optimal designs in the important special cases that the number of periods is 3, 4 or 5. It turns out that the optimal designs depend on the variance of the random interactions and in most cases are not binary. However, we can show that neighbour balanced binary designs are highly efficient, regardless of the number of periods and of the size of the variance of the interaction effects.     

Efficient crossover designs in the presence of interactions between direct and carry-over treatment effects

Crossover designs, or repeated measurements designs, are used for experiments in which t treatments are applied to each of n experimental units successively over p time periods. Such experiments are widely used in areas such as clinical trials, experimental psychology and agricultural field trials. In addition to the direct effect on the response of the treatment in the period of application, there is also the possible presence of a residual, or carry-over, effect of a treatment from one or more previous periods. We use a model in which the residual effect from a treatment depends upon the treatment applied in the succeeding period; that is, a model which includes interactions between the treatment direct and residual effects. We assume that residual effects do not persist further than one succeeding period.A particular class of strongly balanced repeated measurements designs with n=t² units and which are uniform on the periods is examined. A lower bound for the A-efficiency of the designs for estimating the direct effects is derived and it is shown that such designs are highly efficient for any number of periods p=2,…,2t.     

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.     

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.     

Minimal balanced repeated measurements designs

Experimental designs in which treatments are applied to the experimental units, one at a time, in sequences over a number of periods, have been used in several scientific investigations and are known as repeated measurements designs. Besides direct effects, these designs allow estimation of residual effects of treatments along with adjustment for them. Assuming the existence of first-order residual effects of treatments, Hedayat & Afsarinejad (1975) gave a method of constructing minimal balanced repeated measurements [RM(v,n,p)] design for v treatments using n=2v experimental units for p [=(v+1)/2] periods when v is a prime or prime power. Here, a general method of construction of these designs for all odd v has been given along with an outline for their analysis. In terms of variances of estimated elementary contrasts between treatment effects (direct and residual), these designs are seen to be partially variance balanced based on the circular association scheme.     

A nonparametric procedure for the analysis of balanced crossover designs

The authors propose nonparametric tests for the hypothesis of no direct treatment effects, as well as for the hypothesis of no carryover effects, for balanced crossover designs in which the number of treatments equals the number of periods p, where p ≥ 3. They suppose that the design consists of n replications of balanced crossover designs, each formed by m Latin squares of order p. Their tests are permutation tests which are based on the n vectors of least squares estimators of the parameters of interest obtained from the n replications of the experiment. They obtain both the exact and limiting distribution of the test statistics, and they show that the tests have, asymptotically, the same power as the F‐ratio test.     

Designs with Repeated Measurements on Any Number of Units over Varying Periods

In the usual repeated measurements designs (RMDs), the subjects are all observed for the same number of periods and the optimum RMDs require specified numbers of subjects, usually depending on the number of treatments to be used. In practice, it is sometimes not feasible to meet these requirements. To overcome this problem, alternative designs are suggested where any number of available subjects may be used and they may be observed for different periods. These designs are based on suitable serially balanced sequences which are shown to be optimal. Moreover, besides the usual direct and residual effects, the model considered has an extra term due to the interaction effect between them. The recommended designs are universally optimal in a very general class.     

Efficient circular neighbour designs for spatial interference model

We consider circular block designs for field-trials when there are two-sided spatial interference between neighbouring plots of the same blocks. The parameter of interest is total effects that is the sum of direct effect of treatment and neighbour effects, which correspond to the use of a single treatment in the whole field. We determine universally optimal approximate designs. When the number of blocks may be large, we propose efficient exact designs generated by a single sequence of treatment. We also give efficiency factors of the usual binary block neighbour balanced designs which can be used when the number of blocks is small.     

A construction of repeated measurements designs with balance for residual effects

Families of Repeated Measurements Designs balanced for residual effects are constructed (whenever the divisibility conditions allow), under the assumption that the number of periods is less than the number of treatments and that each treatment precedes each other treatment once. These designs are then shown to be connected for both residual and direct treatment effects.     

Parameter Orthogonality in Mixed Regression Models for Survival Data

The implications of parameter orthogonality for the robustness of survival regression models are considered. The question of which of the proportional hazards or the accelerated life families of models would be more appropriate for analysis is usually ignored, and the proportional hazards family is applied, particularly in medicine, for convenience. Accelerated life models have conventionally been used in reliability applications. We propose a one-parameter family mixture survival model which includes both the accelerated life and the proportional hazards models. By orthogonalizing relative to the mixture parameter, we can show that, for small effects of the covariates, the regression parameters under the alternative families agree to within a constant. This recovers a known misspecification result. We use notions of parameter orthogonality to explore robustness to other types of misspecification including misspecified base-line hazards. The results hold in the presence of censoring. We also study the important question of when proportionality matters.     

A Frailty Model in Crossover Studies with Time-to-Event Response Variable

In this article, we develop a model to study treatment, period, carryover, and other applicable effects in a crossover design with a time-to-event response variable. Because time-to-event outcomes on different treatment regimens within the crossover design are correlated for an individual, we adopt a proportional hazards frailty model. If the frailty is assumed to have a gamma distribution, and the hazard rates are piecewise constant, then the likelihood function can be determined via closed-form expressions. We illustrate the methodology via an application to a data set from an asthma clinical trial and run simulations that investigate sensitivity of the model to data generated from different distributions.     

Generalized linear models and transformations for unreplicated factorial experiments in the presence of dispersion effects

For the analysis of replicated designs, many different methods have been suggested. These allow for the estimation of functional dependencies between mean and variance as well as possible dispersion effects within the same model framework. However, in the situation of unreplicated designs, most methods known so far rely on the assumption of constant variances, or a functional relationship between mean and variance as the only source of heteroscedasticity. In this paper, we propose two methods for dealing with unreplicated data, when dispersion effects might also be of importance. One of these is an extension of the Box–Cox-method [Box, G.E.P., Cox, D.R., 1964. An analysis of transformations. Journal of the Royal Statistical Society B 26, 211–252], the other is based on double generalized linear models. Both these methods turn out to yield approximately equivalent results in the case of comparable assumptions, whereas the double generalized linear model is the more general one and allows further extensions. If this class of models is assumed, consistency, asymptotic efficiency and normality of the resulting estimates are shown.     

Cross-over Designs in the Presence of Higher Order Carry-overs

In cross-over experiments, where different treatments are applied successively to the same experimental unit over a number of time periods, it is often expected that a treatment has a carry-over effect in one or more periods following its period of application. The effect of interaction between the treatments in the successive periods may also affect the response. However, it seems that all systematic studies of the optimality properties of cross-over designs have been done under models where carry-over effects are assumed to persist for only one subsequent period. This paper proposes a model which allows for the possible presence of carry-over effects up to k subsequent periods, together with all the interactions between treatments applied at k + 1 successive periods. This model allows the practitioner to choose k for any experiment according to the requirements of that particular experiment. Under this model, the cross-over designs are studied and the class of optimal designs is obtained. A method of constructing these optimal designs is also given.     

Sample size calculation for the Power Model for dose proportionality studies

There are several approaches to assess or demonstrate pharmacokinetic dose proportionality. One statistical method is the traditional ANOVA model, where dose proportionality is evaluated using the bioequivalence limits. A more informative method is the mixed effects Power Model, where dose proportionality is assessed using a decision rule for the estimated slope. Here we propose analytical derivations of sample sizes for various designs (including crossover, incomplete block and parallel group designs) to be analysed according to the Power Model.     

On totally balanced block designs for competition effects

Competition between neighbouring units in field experiments is a serious source of bias. The study of a competing situation needs construction of an environment in which it can happen and the competing units have to appear in a predetermined pattern. This paper describes methods of constructing incomplete block designs balanced for neighbouring competition effects. The designs obtained are totally balanced in the sense that all the effects, direct and neighbours, are estimated with the same variance. The efficiency of these designs has been computed as compared to a complete block design balanced for neighbours and a catalogue has also been prepared.     

A joint model for incomplete data in crossover trials

Crossover designs are popular in early phases of clinical trials and in bioavailability and bioequivalence studies. Assessment of carryover effects, in addition to the treatment effects, is a critical issue in crossover trails. The observed data from a crossover trial can be incomplete because of potential dropouts. A joint model for analyzing incomplete data from crossover trials is proposed in this article; the model includes a measurement model and an outcome dependent informative model for the dropout process. The informative-dropout model is compared with the ignorable-dropout model as specific cases of the latter are nested subcases of the proposed joint model. Markov chain sampling methods are used for Bayesian analysis of this model. The joint model is used to analyze depression score data from a clinical trial in women with late luteal phase dysphoric disorder. Interestingly, carryover effect is found to have a strong effect in the informative dropout model, but it is less significant when dropout is considered ignorable.     

The two-period crossover design with baseline measurements

We consider a two-period crossover study in which each patients measured on the response variable at the start as well as at the end of both periods. We examine models in which the carryover effect at the start of the second period may be different from the carryover effect at the end, and in which the correlations between observations decrease as a function of the time between them.

In trials with a relatively short washout period, we recommend that the second baseline measurement not be incorporated into the analysis and that the data be evaluated by analysis of covariance, with the difference between the post-treatment values as the response variable and the first period's baseline value as the covariate. The absence of carryover effects must be assumed.

When the washout period is moderately long (comparable in length to either treatment period), the preferred analysis for a difference between direct treatment effects will again generally be based on the differences between post-treatment values. An analysis based on changes from baseline would, under certain assumptions about the form of the variance-covariance matrix, be preferred only for quite long washout periods and large correlations between observations. Even then, the efficiency of the test for equality of direct effects is improved if the difference between the baseline values is used as the covariate.     

Neighbor-Balanced Row-column Designs

In this article, row-column designs incorporating directional neighbor effects have been studied. A row-column design is said to be neighbor balanced if every treatment has all other treatments appearing as a neighbor a constant number of times. We considered here three different situations under row-column setup incorporating neighbor effects viz., row-column design with one-sided neighbor effect, two-sided neighbor effect, and four-sided neighbor effect. The information matrices for all the situations for estimating the direct and neighbor effects of treatments have been derived. Methods of constructing neighbor-balanced row-column designs have been developed and its characterization properties have been studied.