Max–min optimal discriminating designs for several statistical models

In the literature, different optimality criteria have been considered for model identification. Most of the proposals assume the normal distribution for the response variable and thus they provide optimality criteria for discriminating between regression models. In this paper, a max–min approach is followed to discriminate among competing statistical models (i.e., probability distribution families). More specifically, k different statistical models (plausible for the data) are embedded in a more general model, which includes them as particular cases. The proposed optimal design maximizes the minimum KL-efficiency to discriminate between each rival model and the extended one. An equivalence theorem is proved and an algorithm is derived from it, which is useful to compute max–min KL-efficiency designs. Finally, the algorithm is run on two illustrative examples.     

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.     

Optimum mixture designs for the log-logistic dose–response model with mixture of two similar compounds

The article studies the log-logistic class of dose–response bioassay models in the binomial set-up. The dose is identified by the potency adjusted mixing proportions of two similar compounds. Models for both absence and presence of interaction between the compounds have been considered. The aim is to investigate the D- and D_s-optimal mixture designs for the estimation of the full set of parameters or for the estimation of potency for a best guess of the parameter values. We also indicate how to find the optimal design to estimate the mixing proportions at which the probability of success attains a given value in the absence of the interaction effect.     

A pool-adjacent-violators-algorithm approach to detect infinite parameter estimates in one-regressor dose–response models with asymptotes

Binary response models are often applied in dose–response settings where the number of dose levels is limited. Commonly, one can find cases where the maximum likelihood estimation process for these models produces infinite values for at least one of the parameters, often corresponding to the ‘separated data’ issue. Algorithms for detecting such data have been proposed, but are usually incorporated directly into in the parameter estimation. Additionally, they do not consider the use of asymptotes in the model formulation. In order to study this phenomenon in greater detail, we define the class of specifiably degenerate functions where this can occur (including the popular logistic and Weibull models) that allows for asymptotes in the dose–response specification. We demonstrate for this class that the well-known pool-adjacent-violators algorithm can efficiently pre-screen for non-estimable data. A simulation study demonstrates the frequency with which this problem can occur for various response models and conditions.     

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.     

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 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.     

Generation of d–optimal designs in a finite design space

This paper presents some considerations about the numerical procedures for generating D–optimal design in a finite design space. The influence of starting procedures and the finite set of points on the design efficiency is considered. Some modifications of the existing procedures for D–optimal designs generation are described. It is shown that for large number of factors the sequential procedures are more appropriate than the nonsequential ones     

Time-varying coefficient models with ARMA–GARCH structures for longitudinal data analysis

Time-varying coefficient models with autoregressive and moving-average–generalized autoregressive conditional heteroscedasticity structure are proposed for examining the time-varying effects of risk factors in longitudinal studies. Compared with existing models in the literature, the proposed models give explicit patterns for the time-varying coefficients. Maximum likelihood and marginal likelihood (based on a Laplace approximation) are used to estimate the parameters in the proposed models. Simulation studies are conducted to evaluate the performance of these two estimation methods, which is measured in terms of the Kullback–Leibler divergence and the root mean square error. The marginal likelihood approach leads to the more accurate parameter estimates, although it is more computationally intensive. The proposed models are applied to the Framingham Heart Study to investigate the time-varying effects of covariates on coronary heart disease incidence. The Bayesian information criterion is used for specifying the time series structures of the coefficients of the risk factors.     

Estimating improvement in prediction with matched case–control designs

When an existing risk prediction model is not sufficiently predictive, additional variables are sought for inclusion in the model. This paper addresses study designs to evaluate the improvement in prediction performance that is gained by adding a new predictor to a risk prediction model. We consider studies that measure the new predictor in a case–control subset of the study cohort, a practice that is common in biomarker research. We ask if matching controls to cases in regards to baseline predictors improves efficiency. A variety of measures of prediction performance are studied. We find through simulation studies that matching improves the efficiency with which most measures are estimated, but can reduce efficiency for some. Efficiency gains are less when more controls per case are included in the study. A method that models the distribution of the new predictor in controls appears to improve estimation efficiency considerably.     

A double Metropolis–Hastings sampler for spatial models with intractable normalizing constants

The problem of simulating from distributions with intractable normalizing constants has received much attention in recent literature. In this article, we propose an asymptotic algorithm, the so-called double Metropolis–Hastings (MH) sampler, for tackling this problem. Unlike other auxiliary variable algorithms, the double MH sampler removes the need for exact sampling, the auxiliary variables being generated using MH kernels, and thus can be applied to a wide range of problems for which exact sampling is not available. For the problems for which exact sampling is available, it can typically produce the same accurate results as the exchange algorithm, but using much less CPU time. The new method is illustrated by various spatial models.     

A Mann–Whitney scan statistic for continuous data

ABSTRACT

A new method is proposed for identifying clusters in continuous data indexed by time or by space. The scan statistic we introduce is derived from the well-known Mann–Whitney statistic. It is completely non parametric as it relies only on the ranks of the marks. This scan test seems to be very powerful against any clustering alternative. These results have applications in various fields, such as the study of climate data or socioeconomic data.     

Phase type stress–strength models with reliability applications

The stress–strength model has attracted a great deal of attention in reliability analysis, and it has been studied under various modeling assumptions. In this article, the stress–strength reliability is studied for both single unit and multicomponent systems when stress and strength distributions are of phase type. Phase-type distributions, besides their analytical tractability, are a versatile tool for modeling a wide range of real life systems/processes. In particular, matrix-based expressions are obtained for the stress–strength reliability, and mean residual strength for an operating system. The results are illustrated for Erlang-type stress–strength distributions for a single unit system and a system having a general coherent structure. An example on the comparison of two multi-state units in stress–strength ordering is also presented.     

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.     

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.     

Orthogonal main-effect plans in row–column designs for two-level factorial experiments

Row–column designs for two-level factorial experiments are constructed to estimate all the main effects. We give the interactions for row and column blockings. Based on these blockings, independent treatment combinations are proposed to establish the whole design so that practitioners can easily apply it to their experiments. Some examples are given for illustrations. The estimation of two-factor interactions in these designs is discussed.