Locally optimal designs for some dose–response models with continuous endpoints

We consider the problem of constructing static (or non sequential), approximate optimal designs for a class of dose–response models with continuous outcomes. We obtain conditions for a design being D-optimal or c-optimal. The designs are locally optimal in that they depend on the model parameters. The efficiency studies show that these designs have high efficiency when the mis-specification of the initial values of model parameters is not severe. A case study indicates that using an optimal design may result in a significant saving of resources.     

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 discriminating between some extensions of the Michaelis–Menten model

In this paper some results on the computation of optimal designs for discriminating between nonlinear models are provided. In particular, some typical deviations of the Michaelis–Menten model are considered. A common deviation of this pharmacokinetic model consists on adding a linear term. If two linear models differ in one parameter the T-optimal design for discriminating between them is c-optimal for estimating the added linear term. This is not the case for nonlinear models.     

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.     

Orthogonally blocked mixture component–amount designs via projections of F-squares

Orthogonal block designs for Scheffé’s quadratic model have been considered previously by Draper et al. (1993), John (1984), Lewis et al. (1994) and Prescott, Draper, Dean, and Lewis (1993). Prescott and Draper (2004) obtained mixture component–amount designs via projections of standard mixture designs, viz., the simplex-lattice, the simplex-centroid and the orthogonally blocked mixture designs based on latin squares. Aggarwal, Singh, Sarin, and Husain (2009) considered the case of components assuming equal volume fractions and obtained mixture designs in orthogonal blocks using F-squares. In this paper, we construct orthogonal blocks of two and three mixture component–amount blends by projecting the class of four component mixture designs presented by Aggarwal et al. (2009).     

Synergy evaluation of non-normalizable dose–response data: Generalization of combination index for the linear effect of drugs

The study of drug synergy plays a prominent role in the search for drug combinations with beneficial interactions. Firstly, in this process, the drug-effect response of individual parts and the mixture needs to be derived. This function is usually well described by Hill (or other logistic or sigmoid) curve. Due to its boundedness, it allows the measured data to be normalized. The normalized data can then be processed by interaction analysis using the Loewe, Bliss, or other models to evaluate possible synergy or antagonism of two or more drugs. However, sometimes, the drug-effect responses observed in pharmaceutical research do not appear to be bounded. Theoretically, the drug-effect curve cannot grow to infinity, but it may be impossible to determine its upper bound within the observed region. In this case, standard models cannot be used, since they assume that data are normalized. The approach of this article bypasses the need to normalize the data, allowing its broader application and usefulness in finding potential synergies in pharmaceutical research.     

Testing for the partial Koziol–Green model with covariates

In this paper we consider some non-parametric goodness-of-fit statistics for testing the partial Koziol–Green regression model. In this model, the response at a given covariate value is subject to random right censoring by two independent censoring times. One of these censoring times is informative in the sense that its survival function is some power of the survival function of the response. The goodness-of-fit statistics are based on an underlying empirical process for which large sample theory is obtained.     

Test for homogeneity in Hardy–Weinberg normal mixture model

The phenotype of a quantitative trait locus (QTL) is often modeled by a finite mixture of normal distributions. If the QTL effect depends on the number of copies of a specific allele one carries, then the mixture model has three components. In this case, the mixing proportions have a binomial structure according to the Hardy–Weinberg equilibrium. In the search for QTL, a significance test of homogeneity against the Hardy–Weinberg normal mixture model alternative is an important first step. The LOD score method, a likelihood ratio test used in genetics, is a favored choice. However, there is not yet a general theory for the limiting distribution of the likelihood ratio statistic in the presence of unknown variance. This paper derives the limiting distribution of the likelihood ratio statistic, which can be described by the supremum of a quadratic form of a Gaussian process. Further, the result implies that the distribution of the modified likelihood ratio statistic is well approximated by a chi-squared distribution. Simulation results show that the approximation has satisfactory precision for the cases considered. We also give a real-data example.     

Adaptive designs for selecting drug combinations based on efficacy–toxicity response

We propose a new adaptive procedure for dose-finding in clinical trials with combination of two drugs when both efficacy and toxicity responses are available. We model the distribution of this bivariate binary endpoint using the bivariate probit model. The analytic formulae for the Fisher information matrix are obtained, that form the basis for derivation of the locally optimal, minimax, Bayesian, and adaptive designs in the framework of optimal design theory.     

Learning the two parameters of the Poisson–Dirichlet distribution with a forensic application

In forensic science, the rare type match problem arises when the matching characteristic from the suspect and the crime scene is not in the reference database; hence, it is difficult to evaluate the likelihood ratio that compares the defense and prosecution hypotheses. A recent solution consists of modeling the ordered population probabilities according to the two-parameter Poisson–Dirichlet distribution, which is a well-known Bayesian nonparametric prior, and plugging the maximum likelihood estimates of the parameters into the likelihood ratio. We demonstrate that this approximation produces a systematic bias that fully Bayesian inference avoids. Motivated by this forensic application, we consider the need to learn the posterior distribution of the parameters that governs the two-parameter Poisson–Dirichlet using two sampling methods: Markov Chain Monte Carlo and approximate Bayesian computation. These methods are evaluated in terms of accuracy and efficiency. Finally, we compare the likelihood ratio that is obtained by our proposal with the existing solution using a database of Y-chromosome haplotypes.     

Optimality of quasi-score in the multivariate mean–variance model with an application to the zero-inflated Poisson model with measurement errors

In a multivariate mean–variance model, the class of linear score (LS) estimators based on an unbiased linear estimating function is introduced. A special member of this class is the (extended) quasi-score (QS) estimator. It is ‘extended’ in the sense that it comprises the parameters describing the distribution of the regressor variables. It is shown that QS is (asymptotically) most efficient within the class of LS estimators. An application is the multivariate measurement error model, where the parameters describing the regressor distribution are nuisance parameters. A special case is the zero-inflated Poisson model with measurement errors, which can be treated within this framework.     

A Bayesian benchmarking of the Scott–Smith model for small areas

When the finite population ‘totals’ are estimated for individual areas, they do not necessarily add up to the known ‘total’ for all areas. Benchmarking (BM) is a technique used to ensure that the totals for all areas match the grand total, which can be obtained from an independent source. BM is desirable to practitioners of survey sampling. BM shifts the small-area estimators to accommodate the constraint. In doing so, it can provide increased precision to the small-area estimators of the finite population means or totals. The Scott–Smith model is used to benchmark the finite population means of small areas. This is a one-way random effects model for a superpopulation, and it is computationally convenient to use a Bayesian approach. We illustrate our method by estimating body mass index using data in the third National Health and Nutrition Examination Survey. Several properties of the benchmarked small-area estimators are obtained using a simulation study.     

A new compound class of log-logistic Weibull–Poisson distribution: model,properties and applications

A new class of distributions called the log-logistic Weibull–Poisson distribution is introduced and its properties are explored. This new distribution represents a more flexible model for lifetime data. Some statistical properties of the proposed distribution including the expansion of the density function, quantile function, hazard and reverse hazard functions, moments, conditional moments, moment generating function, skewness and kurtosis are presented. Mean deviations, Bonferroni and Lorenz curves, Rényi entropy and distribution of the order statistics are derived. Maximum likelihood estimation technique is used to estimate the model parameters. A simulation study is conducted to examine the bias, mean square error of the maximum likelihood estimators and width of the confidence interval for each parameter and finally applications of the model to real data sets are presented to illustrate the usefulness of the proposed distribution.     

Estimation of parameters for a Birnbaum–Saunders regression model with censored data

Little work has been published on the analysis of censored data for the Birnbaum–Saunders distribution (BISA). In this article, we implement the EM algorithm to fit a regression model with censored data when the failure times follow the BISA. Three approaches to implement the E-Step of the EM algorithm are considered. In two of these implementations, the M-Step is attained by an iterative least-squares procedure. The algorithm is exemplified with a single explanatory variable in the model.     

Optimal Latin hypercube designs for the Kullback–Leibler criterion

Space-filling designs are commonly used for selecting the input values of time-consuming computer codes. Computer experiment context implies two constraints on the design. First, the design points should be evenly spread throughout the experimental region. A space-filling criterion (for instance, the maximin distance) is used to build optimal designs. Second, the design should avoid replication when projecting the points onto a subset of input variables (non-collapsing). The Latin hypercube structure is often enforced to ensure good projective properties. In this paper, a space-filling criterion based on the Kullback–Leibler information is used to build a new class of Latin hypercube designs. The new designs are compared with several traditional optimal Latin hypercube designs and appear to perform well.     

Tests for the variance parameter in the Fay–Herriot model

The Fay–Herriot model is a linear mixed model that plays a relevant role in small area estimation (SAE). Under the SAE set-up, tools for selecting an adequate model are required. Applied statisticians are often interested on deciding if it is worthwhile to use a mixed effect model instead of a simpler fixed-effect model. This problem is not standard because under the null hypothesis the random effect variance is on the boundary of the parameter space. The likelihood ratio test and the residual likelihood ratio test are proposed and their finite sample distributions are derived. Finally, we analyse their behaviour under simulated scenarios and we also apply them to real data.