Optimal designs for the Michaelis–Menten model with correlated observations

In this paper we investigate the problem of designing experiments for generalized least-squares analysis in the Michaelis–Menten model. We study the structure of exact D-optimal designs in a model with an autoregressive error structure. Explicit results for locally D-optimal designs are derived for the case where two observations can be taken per subject. Additionally standardized maximin D-optimal designs are obtained in this case. The results illustrate the enormous difficulties to find exact optimal designs explicitly for nonlinear regression models with correlated observations.     

Optimal designs for the power logistic model

We investigate non-sequential designs for estimating model parameters in a power logistic model when the power is assumed to be approximately known and only the ranges for the other two parameters are available. The sensitivity of these designs to nominal values of all the three parameters are studied and our proposed optimal designs are shown to be reasonably robust under moderate deviation from the assumed model. An application to a toxicity experiment involving adult beetles is discussed, including the benefits of using an optimal design.     

A Comparison of Spatial Designs for Field Variety Trials

Experimental designs can be constructed to be efficient in the presence of spatial correlation. Available construction methods include those based on autoregressive and linear variance models. This paper investigates spatial designs across a range of assumed autoregressive structures. Results show that when the spatial component is low relative to the independent error term, efficient spatial designs can be constructed without having to specify parameters for the spatial structure.     

Step-wise group screening designs with errors in observations

The performance of step-wise group screening In terms of the expected number of runs and the expected number of incorrect decisions, Is considered. A method for obtaining optimal step-wise designs Is presented, for the cases in which the direction of each defective factor is assumed to be known a-priori and the observations are subject to error.     

Minimax designs for approximately linear models with AR(1) errors

We obtain designs for linear regression models under two main departures from the classical assumptions: (1) the response is taken to be only approximately linear, and (2) the errors are not assumed to be independent, but to instead follow a first-order autoregressive process. These designs have the property that they minimize (a modification of) the maximum integrated mean squared error of the estimated response, with the maximum taken over a class of departures from strict linearity and over all autoregression parameters ρ,|ρ,| < 1, of fixed sign. Specific methods of implementation are discussed. We find that an asymptotically optimal procedure for AR(1) models consists of choosing points from that design measure which is optimal for uncorrelated errors, and then implementing them in an appropriate order.     

Optimal crossover designs when carryover effects are proportional to direct effects

Crossover designs are used for a variety of different applications. While these designs have a number of attractive features, they also induce a number of special problems and concerns. One of these is the possible presence of carryover effects. Even with the use of washout periods, which are for many applications widely accepted as an indispensable component, the effect of a treatment from a previous period may not be completely eliminated. A model that has recently received renewed attention in the literature is the model in which first-order carryover effects are assumed to be proportional to direct treatment effects. Under this model, assuming that the constant of proportionality is known, we identify optimal and efficient designs for the direct effects for different values of the constant of proportionality. We also consider the implication of these results for the case that the constant of proportionality is not known.     

Optimal designs for contingent response models with application to toxicity–efficacy studies

We describe a general family of contingent response models. These models have ternary outcomes constructed from two Bernoulli outcomes, where one outcome is only observed if the other outcome is positive. This family is represented in a canonical form which yields general results for its Fisher information. A bivariate extreme value distribution illustrates the model and optimal design results. To provide a motivating context, we call the two binary events that compose the contingent responses toxicity and efficacy. Efficacy or lack thereof is assumed only to be observable in the absence of toxicity, resulting in the ternary response (toxicity, efficacy without toxicity, neither efficacy nor toxicity). The rate of toxicity, and the rate of efficacy conditional on no toxicity, are assumed to increase with dose. While optimal designs for contingent response models are numerically found, limiting optimal designs can be expressed in closed forms. In particular, in the family of four parameter bivariate location-scale models we study, as the marginal probability functions of toxicity and no efficacy diverge, limiting D optimal designs are shown to consist of a mixture of the D optimal designs for each failure (toxicity and no efficacy) univariately. Limiting designs are also obtained for the case of equal scale parameters.     

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.     

Optimality of circular neighbor-balanced designs for total effects with autoregressive correlated observations

This paper studies the optimality of circular neighbor-balanced designs (CNBDs) for total effects when the one-sided or two-sided neighbor effects are present in the model and the observation errors are correlated according to a first-order circular autoregressive (AR(1,C$C$)) process. Some optimality results under some specified conditions are provided and the efficiency of a CNBD relative to the optimal block design is investigated. In order to discuss the efficiency of a CNBD among all possible block designs with the same size, the optimal equivalence classes of sequences under the one-sided neighbor effects model are characterized and the efficiencies of CNBDs with blocks of small size are illustrated.     

Modeling and forecasting realized covariance matrices with accounting for leverage

The existing dynamic models for realized covariance matrices do not account for an asymmetry with respect to price directions. We modify the recently proposed conditional autoregressive Wishart (CAW) model to allow for the leverage effect. In the conditional threshold autoregressive Wishart (CTAW) model and its variations the parameters governing each asset's volatility and covolatility dynamics are subject to switches that depend on signs of previous asset returns or previous market returns. We evaluate the predictive ability of the CTAW model and its restricted and extended specifications from both statistical and economic points of view. We find strong evidence that many CTAW specifications have a better in-sample fit and tend to have a better out-of-sample predictive ability than the original CAW model and its modifications.     

Crossover designs for comparing test treatments to a control treatment when subject effects are random

We study crossover designs for the comparisons of several test treatments versus a control treatment and partially generalize the results of Hedayat and Yang (2005) to the situation in which subject effects are assumed to be random. More specifically, we establish lower bounds for the trace of the inverse of the information matrix for the test treatments versus control comparisons under a random subject effects model and show that most of the small size (3-, 4- and 5-period) designs introduced by Hedayat and Yang (2005) are highly efficient in the class of designs in which the control treatment appears equally often in all periods and no treatment is immediately preceded by itself.     

Optimal few-stage designs

Optimal designs are presented for experiments in which sampling is carried out in stages. There are two Bernoulli populations and it is assumed that the outcomes of the previous stage are available before the sampling design for the next stage is determined. At each stage, the design specifies the number of observations to be taken and the relative proportion to be sampled from each population. Of particular interest are 2- and 3-stage designs.To illustrate that the designs can be used for experiments of useful sample sizes, they are applied to estimation and optimization problems. Results indicate that, for problems of moderate size, published asymptotic analyses do not always represent the true behavior of the optimal stage sizes, and efficiency may be lost if the analytical results are used instead of the true optimal allocation.The exactly optimal few stage designs discussed here are generated computationally, and the examples presented indicate the ease with which this approach can be used to solve problems that present analytical difficulties. The algorithms described are flexible and provide for the accurate representation of important characteristics of the problem.     

Forecasting births in post-transition population: stochastic renewal with serially correlated fertility

Time series analysis of fertility can improve demographic forecasts. The optimal forecast and its variance for births to an age-structured population subject to serially correlated random fertility are developed. The general case in which the fertility process had arbitrary autoregressive structure is dealt with and then the 4 special cases of white noise, 1st-order autoregressive, 2nd-order autoregressive, and random walk are considered. Consequently, it is determined that the predictions and their variances are highly sensitive to the autoregressive structure of fertility and, therefore, if stochastic models are to be used for prediction, they must emphasize this aspect of the problem. Preliminary empirical efforts to model the time series of U.S. fertility from 1917 to 1972 proved unsuccessful, but it is obvious that at least a 2nd-order autoregressive scheme is require d. The analysis proveded should be helpful in: 1) any application of the procedures requires a successful parameterization of the fertility process; 2) fertility variations could be decomposed into the effects of nuptiality and marital fertility and then births and marriages could be jointly predicted; and 3) the simplifying approximations should be dropped and each age-specific rate could be analyzed and predicted.     

Optimal experimental designs when an independent variable is potentially censored

This paper considers the problem of constructing optimal approximate designs when an independent variable might be censored. The problem is which design should be applied in practice to obtain the best approximate design when a censoring distribution is assumed known in advance. The approach for finite or continuous design spaces deserves different attention. In both cases, equivalent theorems and algorithms are provided in order to calculate optimal designs. Some examples illustrate this approach for D-optimality.     

Selection of number of dose levels and its robustness for binary response data

Müller & Schmitt (1990) have considered the question of how to choose the number of doses for estimating the median effective dose (ED50) when a probit dose-response curve is correctly assumed. However, they restricted their investigation to designs with doses symmetrical about the true ED50. In this paper, we investigate how the conclusions of Müller & Schmitt may change as the dose designs become slightly asymmetric about the true ED50. In addition, we address the question of the robustness of the number of doses chosen for an incorrectly assumed logistic model, when the dose designs are asymmetric about the assumed ED50. The underlying true dose-response curves considered here include the probit, cubic logistic and Aranda- Ordaz asymmetric models. The simulation results show that, for various underlying true dose-response curves and the uniform design density with doses spaced asymmetrically around the assumed ED50, the choice of as many doses as possible is almost optimal. This agrees with the results obtained for a correctly assumed probit or logistic dose-response curve when the dose designs are symmetric or slightly asymmetric about the ED50.     

CONSTRUCTION OF CROSSOVER DESIGNS WITH CORRELATED ERRORS

Crossover experiments are widely used, particularly where a sequence of treatments is given to subjects. Correlations between observations on the same subject are therefore likely and should be considered in both the design and analysis of crossover experiments. This paper presents an algorithm for the generation of efficient crossover designs with autoregressive and linear variance structures. The algorithm has been implemented as a module in the experimental design generation package CycDesigN (Release 3.0; CycSoftware, Hamilton, New Zealand). Output from the algorithm is compared with earlier work. Some results are given from the analysis of a crossover experiment assuming correlated errors.     

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.     

On Mixture Double Autoregressive Time Series Models

This article proposes a mixture double autoregressive model by introducing the flexibility of mixture models to the double autoregressive model, a novel conditional heteroscedastic model recently proposed in the literature. To make it more flexible, the mixing proportions are further assumed to be time varying, and probabilistic properties including strict stationarity and higher order moments are derived. Inference tools including the maximum likelihood estimation, an expectation–maximization (EM) algorithm for searching the estimator and an information criterion for model selection are carefully studied for the logistic mixture double autoregressive model, which has two components and is encountered more frequently in practice. Monte Carlo experiments give further support to the new models, and the analysis of an empirical example is also reported.     

Optimality in the presence of two factor interactions among the nuisance factors

Here we consider an m way heterogeneity settingin the presence of two factor interactions among the heterogeneity directions . The set of experimental units considered do not exhaust all possible level combinations of the heterogeneity directions ; but the set is such that all heterogeneity effects assumed i n the model are orthogonally estmable.In such a setting , calleda doubly balanced m-way setting , the C-matrix of the reduced normal equations for the treatment effects is derived . Universally optimal designs are obtained in the cases where the settingis (i) Completely regular or (ii) partly regular of a special type . An interesting observation is that there are situations where the universally optimal designsin the present setting are totally different from the designs known t o be universally optimal when there is no interaction effect among the heterogeneity directions. This indicates that the usual optimality criteria are sensitive to validity or otherwise of the usual assumptions of lack of interactions among heterogeneity directions.     

A geometric characterization of optimal designs for regression models with correlated observations

We consider the problem of optimal design of experiments for random effects models, especially population models, where a small number of correlated observations can be taken on each individual, while the observations corresponding to different individuals are assumed to be uncorrelated. We focus on c-optimal design problems and show that the classical equivalence theorem and the famous geometric characterization of Elfving (1952) from the case of uncorrelated data can be adapted to the problem of selecting optimal sets of observations for the n individual patients. The theory is demonstrated by finding optimal designs for a linear model with correlated observations and a nonlinear random effects population model, which is commonly used in pharmacokinetics.