Multiphase experiments with at least one later laboratory phase. II. Nonorthogonal designs

Principles and laws that apply to nonorthogonal multiphase experiments are developed and illustrated using examples that are nonorthogonal but structure‐balanced, not structure, but first‐order, balanced or unbalanced, thus exposing the differences between the different design types. The design of such experiments using standard designs, a catalogue of designs and computer searches is exemplified. Factor–allocation diagrams are employed to depict the allocations in the examples, and used in producing the anatomies of designs or, when possible, the related skeleton‐analysis‐of‐variance tables, to assess the properties of designs. The formulation of mixed models based on them is also described. Tools used for structure‐balanced experiments are also shown to be applicable to those experiments that are not.     

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.     

PkStaMp Library for Constructing Optimal Population Designs for PK/PD Studies

We discuss a Matlab-based library for constructing optimal sampling schemes for pharmacokinetic (PK) and pharmacodynamic (PD) studies. The software relies on optimal design theory for nonlinear mixed effects models and, in particular, on the first-order optimization algorithm. The library includes a number of popular compartmental PK and combined PK/PD models and can be extended to include more models. An outline of inputs/outputs is provided, some algorithmic details and examples are presented, and future work is discussed.     

Optimal parametric design with applications to pharmacokinetic and pharmacodynamic trials

This paper considers optimal parametric designs, i.e. designs represented by probability measures determined by a set of parameters, for nonlinear models and illustrates their use in designs for pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/PD) trials. For some practical problems, such as designs for modelling PK/PD relationship, this is often the only feasible type of design, as the design points follow a PK model and cannot be directly controlled. Even for ordinary design problems the parametric designs have some advantages over the traditional designs, which often have too few design points for model checking and may not be robust to model and parameter misspecifications. We first describe methods and algorithms to construct the parametric design for ordinary nonlinear design problems and show that the parametric designs are robust to parameter misspecification and have good power for model discrimination. Then we extend this design method to construct optimal repeated measurement designs for nonlinear mixed models. We also use this parametric design for modelling a PK/PD relationship and propose a simulation based algorithm. The application of parametric designs is illustrated with a three-parameter open one-compartment PK model for the ordinary design and repeated measurement design, and an Emax model for the phamacokinetic/pharmacodynamic trial design.     

Robust designs for linear mixed effects models

Summary.  In health sciences, medicine and social sciences linear mixed effects models are often used to analyse time-structured data. The search for optimal designs for these models is often hampered by two problems. The first problem is that these designs are only locally optimal. The second problem is that an optimal design for one model may not be optimal for other models. In this paper the maximin principle is adopted to handle both problems, simultaneously. The maximin criterion is formulated by means of a relative efficiency measure, which gives an indication of how much efficiency is lost when the uncertainty about the models over a prior domain of parameters is taken into account. The procedure is illustrated by means of three growth studies. Results are presented for a vocabulary growth study from education, a bone gain study from medical research and an epidemiological decline in height study. It is shown that, for the mixed effects polynomial models that are applied to these studies, the maximin designs remain highly efficient for different sets of models and combinations of parameter values.     

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.     

Two-stage Adaptive Designs in Nonlinear Mixed Effects Models: Application to Pharmacokinetics in Children

Nonlinear mixed effects models (NLMEM) are used in pharmacokinetics to analyse concentrations of patients during drug development, particularly for pediatric studies. Approaches based on the Fisher information matrix can be used to optimize their design. Local design needs some a priori parameter values which might be difficult to guess. Therefore, two-stage adaptive designs are useful to provide some flexibility. We implemented in the R function PFIM the Fisher matrix for two-stage designs in NLMEM. We evaluated, with simulations, the impact of one-stage and two-stage designs on the precision of parameter estimation when the true and a priori parameters are different.     

A characterization of a universally optimal design within a class of block designs

It is shown that within the class of connected binary designs with arbitrary block sizes and arbitrary replications only a symmetic balanced incomplete block design produces a completely symmetric information matrix for the treatment effects whenever the number of blocks is equal to the number of treatments and the number of experimental units is an integer multiple of the number of treatments. Such a design is known to be universally optimal.     

Design optimisation for pharmacokinetic modeling of a cocktail of phenotyping drugs

Our paper proposes a methodological strategy to select optimal sampling designs for phenotyping studies including a cocktail of drugs. A cocktail approach is of high interest to determine the simultaneous activity of enzymes responsible for drug metabolism and pharmacokinetics, therefore useful in anticipating drug–drug interactions and in personalized medicine. Phenotyping indexes, which are area under the concentration‐time curves, can be derived from a few samples using nonlinear mixed effect models and maximum a posteriori estimation. Because of clinical constraints in phenotyping studies, the number of samples that can be collected in individuals is limited and the sampling times must be as flexible as possible. Therefore to optimize joint design for several drugs (i.e., to determine a compromise between informative times that best characterize each drug's kinetics), we proposed to use a compound optimality criterion based on the expected population Fisher information matrix in nonlinear mixed effect models. This criterion allows weighting different models, which might be useful to take into account the importance accorded to each target in a phenotyping test. We also computed windows around the optimal times based on recursive random sampling and Monte‐Carlo simulation while maintaining a reasonable level of efficiency for parameter estimation. We illustrated this strategy for two drugs often included in phenotyping cocktails, midazolam (probe for CYP3A) and digoxin (P‐glycoprotein), based on the data of a previous study, and were able to find a sparse and flexible design. The obtained design was evaluated by clinical trial simulations and shown to be efficient for the estimation of population and individual parameters. Copyright © 2015 John Wiley & Sons, Ltd.     

PARTIALLY EQUINEIGHBOURED DESIGNS

This paper presents further results on a class of designs called equineighboured designs, ED. These designs are intended for field and related experiments, especially whenever there is evidence that observations in the same block are correlated. An ED has the property that every unordered pair of treatments occurs as nearest neighbours equally frequently at each level. Ipinyomi (1986) has defined and shown that ED are balanced designs when neighbouring observations are correlated. He has also presented ED as a continuation of the development of optimal block designs. An ED would often require many times the number of experimental materials needed for the construction of an ordinary balanced incomplete block, BIB, design for the same number of treatments and block sizes. Thus for a relatively large number of treatments and block sizes the required minimum number of blocks may be excessively large for practical use of ED. In this paper we shall define and examine partially equineighboured designs with n concurrences, PED (n), as alternatives where ED are practically unachievable. Particular attention will be given to designs with smaller numbers of blocks and for which only as little balance as possible may be lost.     

Optimal Circular Block Designs for Neighbouring Competition Effects

Competition or interference occurs when the responses to treatments in experimental units are affected by the treatments in neighbouring units. This may contribute to variability in experimental results and lead to substantial losses in efficiency. The study of a competing situation needs designs in which the competing units appear in a predetermined pattern. This paper deals with optimality aspects of circular block designs for studying the competition among treatments applied to neighbouring experimental units. The model considered is a four-way classified model consisting of direct effect of the treatment applied to a particular plot, the effect of those treatments applied to the immediate left and right neighbouring units and the block effect. Conditions have been obtained for the block design to be universally optimal for estimating direct and neighbour effects. Some classes of balanced and strongly balanced complete block designs have been identified to be universally optimal for the estimation of direct, left and right neighbour effects and a list of universally optimal designs for v<20 and r<100 has been prepared.     

Optimal block designs with non additive mixed effects interference

This paper deals with optimality aspects of block designs balanced for interference effects from neighboring units on both sides under a general non additive model along with random block effects. Here, a class of complete, circular block designs strongly balanced for interference effects has been shown to be universally optimal for the estimation of direct effects and interference effects (left and right) of treatments under a non additive mixed effects model.     

Optimal repeated measurements designs for comparing test treatments with a control

A-optimal and mv optimal repeated measurments designs for comparing serveral test treatments with a control are considered. the models considered are basically of two types: without preperides and the cirular model. It is shown known that some known strongly balanced uniform repeated measurements designs can be modified to obtain optimal designs for this problem. Some other methods of finding optimal designs are also given.     

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.     

Practical modeling strategies for unbalanced longitudinal data analysis

In practice, data are often measured repeatedly on the same individual at several points in time. Main interest often relies in characterizing the way the response changes in time, and the predictors of that change. Marginal, mixed and transition are frequently considered to be the main models for continuous longitudinal data analysis. These approaches are proposed primarily for balanced longitudinal design. However, in clinic studies, data are usually not balanced and some restrictions are necessary in order to use these models. This paper was motivated by a data set related to longitudinal height measurements in children of HIV-infected mothers that was recorded at the university hospital of the Federal University in Minas Gerais, Brazil. This data set is severely unbalanced. The goal of this paper is to assess the application of continuous longitudinal models for the analysis of unbalanced data set.     

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.     

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.     

Optimal partially balanced nested row-column designs

A partially balanced nested row-column design, referred to as PBNRC, is defined as an arrangement of v treatments in b p × q blocks for which, with the convention that p q, the information matrix for the estimation of treatment parameters is equal to that of the column component design which is itself a partially balanced incomplete block design. In this paper, previously known optimal incomplete block designs, and row-column and nested row-column designs are utilized to develop some methods of constructing optimal PBNRC designs. In particular, it is shown that an optimal group divisible PBNRC design for v = mn kn treatments in p × q blocks can be constructed whenever a balanced incomplete block design for m treatments in blocks of size k each and a group divisible PBNRC design for kn treatments in p × q blocks exist. A simple sufficient condition is given under which a group divisible PBNRC is Ψ_f-better for all f> 0 than the corresponding balanced nested row-column designs having binary blocks. It is also shown that the construction techniques developed particularly for group divisible designs can be generalized to obtain PBNRC designs based on rectangular association schemes.     

Repeated measurements designs with unequal period sizes

Summary This paper is concerned with the designs in which each experimental unit is assigned more than once to a treatment, either different or identical. An easy method of constructing balanced minimal repeated measurements designs with unequal period sizes is presented whenever the number of periods is less than the number of treatments. Strongly balanced minimal repeated measurements designs with unequal period sizes are also constructed whenever the number of periods is less than the number of treatments.