Multivariate analysis for the two-period repeated measures crossover design with application to clinical trials

Multivariate analysis techniques are applied to the two-period repeated measures crossover design. The approach considered in this paper has the advantage over the univariate analysis approach proposed recently by Wallenstein and Fisher (1977) that the former does not require any specific structure on the variance-covariance matrix of the repeated measures factor. (It should be noted that sums and differences of observations over periods are used for all tests. Therefore, there are two matrices under consideration, one for sums and one for differences.) Tests of significance are derived using the Wilks? criterion, and the procedure is illustrated with a numerical example from the area of clinical trials.     

Order Statistics from the Generalized Exponential Distribution and Applications

With linear dispersion effects, the standard factorial designs are not optimal estimation of a mean model. A sequential two-stage experimental design procedure has been proposed that first estimates the variance structure, and then uses the variance estimates and the variance optimality criterion to develop a second stage design that efficiency estimates the mean model. This procedure has been compared to an equal replicate design analyzed by ordinary least squares, and found to be a superior procedure in many situations.

However with small first stage sample sizes the variance estiamtes are not reliable, and hence an alternative procedure could be more beneficial. For this reason a Bayesian modification to the two-stage procedure is proposed which will combine the first stage variance estiamtes with some prior variance information that will produce a more efficient procedure. This Bayesian procedure will be compared to the non-Bayesian twostage procedure and to the two one-stage alternative procedures listed above. Finally, a recommendation will be made as to which procedure is preferred in certain situations.     

Rotation designs for experiments in high-bias situations

Many experiments in the physical and engineering sciences study complex processes in which bias due to model inadequacy dominates random error. A noteworthy example of this situation is the use of computer experiments, in which scientists simulate the phenomenon being studied by a computer code. Computer experiments are deterministic: replicate observations from running the code with the same inputs will be identical. Such high-bias settings demand different techniques for design and prediction. This paper will focus on the experimental design problem introducing a new class of designs called rotation designs. Rotation designs are found by taking an orthogonal starting design D and rotating it to obtain a new design matrix D_R=DR, where R is any orthonormal matrix. The new design is still orthogonal for a first-order model. In this paper, we study some of the properties of rotation designs and we present a method to generate rotation designs that have some appealing symmetry properties.     

Constructing optimal designs for fitting pharmacokinetic models

We consider some computational issues that arise when searching for optimal designs for pharmacokinetic (PK) studies. Special factors that distinguish these are (i) repeated observations are taken from each subject and the observations are usually described by a nonlinear mixed model (NLMM), (ii) design criteria depend on the model fitting procedure, (iii) in addition to providing efficient parameter estimates, the design must also permit model checking, (iv) in practice there are several design constraints, (v) the design criteria are computationally expensive to evaluate and often numerical integration is needed and finally (vi) local optimisation procedures may fail to converge or get trapped at local optima.We review current optimal design algorithms and explore the possibility of using global optimisation procedures. We use these latter procedures to find some optimal designs.For multi-purpose designs we suggest two surrogate design criteria for model checking and illustrate their use.     

Goodness-of-fit test for Gaussian regression with block correlated errors

We propose a procedure to test that the expectation of a Gaussian vector is linear against a nonparametric alternative. We consider the case where the covariance matrix of the observations has a block diagonal structure. This framework encompasses regression models with autocorrelated errors, heteroscedastic regression models, mixed-effects models and growth curves. Our procedure does not depend on any prior information about the alternative. We prove that the test is asymptotically of the nominal level and consistent. We characterize the set of vectors on which the test is powerful and prove the classical √log log (n)/n convergence rate over directional alternatives. We propose a bootstrap version of the test as an alternative to the initial one and provide a simulation study in order to evaluate both procedures for small sample sizes when the purpose is to test goodness of fit in a Gaussian mixed-effects model. Finally, we illustrate the procedures using a real data set.     

Admissibility of Test Procedures for Linear Hypotheses in General Linear Model

This article shows that an F-test procedure is admissible for testing a linear hypothesis concerning one of the split mean vectors in a general linear model and an F-test procedure is also admissible for testing a linear hypothesis concerning another of the split mean vectors in the same model. These results are proved by showing that the critical functions of the tests are unique Bayes procedures with respect to proper prior distributions set in common for the null hypotheses and for the alternative ones, respectively.     

Spacing of information in polynomial regression:a simple solution

Consider a k polynomial regression on a single real variable. If n uncorrelated observations are to be taken in a design with support on more than k+1 points, there is an approximate experiment, ν, with support on k+1 points and n observations such that both designs have the same information matrix for the model. A proof of this result is provided. A method to obtain the approximate design ν is given and illustrated by an example. The source of disagreement between Kiefer (1959) and De La Garza (1954) in the solution of this problem is clarified.     

Secondary design considerations for minimum bias estimation

Several authors have suggested the method of minimum bias estimation for estimating response surfaces. The minimum bias estimation procedure achieves minimum average squared bias of the fitted model without depending on the values of the unknown parameters of the true surface. The only requirement is that the design satisfies a simple estimability condition. Subject to providing minimum average squared bias, the minimum bias estimator also provides minimum average variance of ?(x) where ?(x) is the estimate of the response at the point x.

To support the estimation of the parameters in the fitted model, very little has been suggested in the way of experimental designs except to say that a full rank matrix X of independent variables should be used. This paper presents a closer look at the estimability conditions that are required for minimum bias estimation, and from the form of the matrix X, a formula is derived which measures the amount of design flexibility available. The design flexibility is termed “the degrees of freedom” of the X matrix and it is shown how the degrees of freedom can be used to decide if other design optimality criteria might be considered along with minimum bias estimation. Several examples are provided.     

E-optimal designs for regression models with quantitative factors— a reasonable choice?

For regression models with quantitative factors it is illustrated that the E-optimal design can be extremely inefficient in the sense that it degenerates to a design which takes all observations at only one point. This phenomenon is caused by the different size of the elements in the covariance matrix of the least-squares estimator for the unknown parameters. For these reasons we propose to replace the E-criterion by a corresponding standardized version. The advantage of this approach is demonstrated for the polynomial regression on a nonnegative interval, where the classical and standardized E-optimal designs can be found explicitly. The described phenomena are not restricted to the E-criterion but appear for nearly all optimality criteria proposed in the literature. Therefore standardization is recommended for optimal experimental design in regression models with quantitative factors. The optimal designs with respect to the new standardized criteria satisfy a similar invariance property as the famous D-optimal designs, which allows an easy calculation of standardized optimal designs on many linearly transformed design spaces.     

Optimal designs for estimating a choice hierarchy by a general nested multinomial logit model

Abstract

In choice experiments the process of decision-making can be more complex than the proposed by the Multinomial Logit Model (MNL). In these scenarios, models such as the Nested Multinomial Logit Model (NMNL) are often employed to model a more complex decision-making. Understanding the decision-making process is important in some fields such as marketing. Achieving a precise estimation of the models is crucial to the understanding of this process. To do this, optimal experimental designs are required. To construct an optimal design, information matrix is key. A previous research by others has developed the expression for the information matrix of the two-level NMNL model with two nests: Alternatives nest (J alternatives) and No-Choice nest (1 alternative). In this paper, we developed the likelihood function for a two-stage NMNL model for M nests and we present the expression for the information matrix for 2 nests with any amount of alternatives in them. We also show alternative D-optimal designs for No-Choice scenarios with similar relative efficiency but with less complex alternatives which can help to obtain more reliable answers and one application of these designs.     

Some theoretical results on approximation methods 1

In this paper we give an approximation procedure to surfaces which are defined on a _p-dimensional region and are observable (disturbed with some noice) according to an experimental design. In this procedure we combine clustering methods, discriminant analysis and smoothing techniques.

In the second part of the paper is considered some investigations on statistical properties of linear smoothing procedures. We assume linear models and for a broad class of models we prove the consistence of the estimation of the expectation of observations after smoothing.

In the last section we give some results on efficiency.     

ESTIMATION OF THE CONCENTRATION PARAMETERS OF THE FISHER MATRIX DISTRIBUTION ON 50(3) AND THE BINGHAM DISTRIBUTION ON Sq, q≥ 2

Two procedures are considered for estimating the concentration parameters of the Fisher matrix distribution for rotations or orientations in three dimensions. The first is maximum likelihood. The use of a convenient 1-dimensional integral representation of the normalising constant, which greatly simplifies the computation, is suggested. The second approach exploits the equivalence of the Fisher distribution for rotations in three dimensions, and the Bingham distribution for axes in four dimensions. We describe a pseudo likelihood procedure which works for the Bingham distribution in any dimension. This alternative approach does not require numerical integration. Results on the asymptotic efficiency of the pseudo likelihood estimator relative to the maximum likelihood estimator are given, and the two estimators are compared in the analysis of a well-known vectorcardiography dataset.     

Sample reuse simulation in optimal design for Tmax in pharmacokinetic experiments

T _max and C _max are important pharmacokinetic parameters in drug development processes. Often a nonparametric procedure is needed to estimate them when model independence is required. This paper proposes a simulation-based optimal design procedure for finding optimal sampling times for nonparametric estimates of T _max and C _max for each subject, assuming that the drug concentration follows a non-linear mixed model. The main difficulty of using standard optimal design procedures is that the property of the nonparametric estimate is very complicated. This procedure uses a sample reuse simulation to calculate the design criterion, which is an integral of multiple dimension, so that effective optimization procedures such as Newton-type procedures can be used directly to find optimal designs. This procedure is used to construct optimal designs for an open one-compartment model. An approximation based on the Taylor expansion is also derived and showed results that were consistent with those based on the sample reuse simulation.     

p-Value adjustment to control type I errors in linear regression models

The paper is devoted to a new randomization method that yields unbiased adjustments of p-values for linear regression model predictors by incorporating the number of potential explanatory variables, their variance–covariance matrix and its uncertainty, based on the number of observations. This adjustment helps control type I errors in scientific studies, significantly decreasing the number of publications that report false relations to be authentic ones. Comparative analysis with such existing methods as Bonferroni correction and Shehata and White adjustments explicitly shows their imperfections, especially in case when the number of observations and the number of potential explanatory variables are approximately equal. Proposed method is easy to program and can be integrated into any statistical software package.     

IS THE ASSUMPTION OF UNIFORM INTRA-CLASS CORRELATION EVER NEEDED?

When modelling a finite population it is sometimes assumed that the residuals from the regression model expectations are distributed with a uniform non-zero intra-class correlation. It is shown that if a certain vector is spanned by the columns of the design matrix (in the homoskedastic case this vector corresponds to the inclusion of a constant term) then such a model is underidentified and the assumption of a known non-zero correlation has almost no impact on the results of the regression analysis. When this vector is not spanned by the columns of the design matrix, a simpler alternative model can usually be fitted equally well to observations from any single population. The only exception occurs when the the intra-class correlation required is negative in sign.     

Continuous single attribute control chart for Markov-dependent processes

Most of the times, the observations related to the quality characteristic of a process do not need to be independent. In such cases, control charts based on the assumption of independence of the observations are not appropriate. When the characteristic under study is qualitative, Markov model serves as a simple model to account for the dependency of the observations. For this purpose, we develop an attribute control chart under 100% inspection for a Markov dependent process by controlling the error probabilities. This chart consists of two sub-charts. For a given sample, depending upon the state of the last observation of previous sample (if any), one of these two will be used. Optimal values of the design parameters of the control chart are obtained. Chart’s performance is studied by using its capability (probability) of detecting a shift in process parameters.     

Universal optimality of experimental designs: Definitions and a criterion

Several definitions of universal optimality of experimental designs are found in the Literature; we discuss the interrelations of these definitions using a recent characterization due to Friedland of convex functions of matrices. An easily checked criterion is given for a design to satisfy the main definition of universal optimality; this criterion says that a certain set of linear functions of the eigenvalues of the information matrix is maximized by the information matrix of a design if and only if that design is universally optimal. Examples are given; in particular we show that any universally optimal design is (M, S)-optimal in the sense of K. Shah.     

Examples of the application of matrix factors of a design matrix

When the elements of a design matrix are rational numbers and the variances of the observations are rational multiples of a common real constant, the covariances being zero, the design matrix may be factorised into a product of matrices which have usefil statistical interpretations. The main factor matrices have integer elements, while the other factor matrices are diagonal with rational elements. Weights which are rational numbers, and missing observations, are readily accommodated. A computer is usually needed to find the factors. This paper shows how, once the factors have been found, they may be employed for any suitable set of observations without further need for such assistance.     

Evaluation of quadratic forms and traces for iterative estimation in first-order moving average models

This paper deals with the evaluation of certain quadratic forms and traces associated with the irst-order moving average model. The problem arose while considering the maximum likelihood estimation under normality of the parameters of this model. The quadratic forms are y¹R-^jy, where y is a vector of observations generated by the models and R is the correlation matrix of the model; the traces are trR-^j j cam be any natural number, but emphasis is placed on small Yalues, j = 1,2,3. Procedures in the time and frequency domains are studied, and the amount of computations needed in each case are considered and compared, from which a preferred approach emerges. The computations are compared with several alternative procedures suggested in the literature.     

APPROXIMATIONS TO SOME TEST STATISTICS FOR PERMUTATION TESTS IN A COMPLETELY RANDOMIZED DESIGN1

Under a randomization model for a completely randomized design permutation tests are considered based on the usual F statistic and on a multi-response permutation procedure statistic. For the first statistic the first two moments are obtained so a comparision with the distribution under the normal theory model can be made. The second statistic is shown to converge in distribution to an infinite weighted sum of chi-squared variates, the weights being the limits of the eigenvalues of a matrix depending on the distance measure used and the order statistics of the observations.