Search for optimal designs in a three stagenested random model

In this paper we define a class of unbalanced designs, denoted by C_k,s,t, for estimating the components of variance in a k-stage nested random effects linear model. This class contains many of the designs proposed in the literature for nested components of variance models. We focus on the three-state model and discuss the determination of locally optimal designs within this class using a systematic computer search. For large sample sizes we show that approximate optimal designs may be obtained using a limit argument combined with numerical optimization. A comparison of our designs with previously published designs suggests that, in many cases, our designs result in substantial gains in efficiency.     

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.     

Identifiable finite mixtures of location models for clustering mixed-mode data

For clustering mixed categorical and continuous data, Lawrence and Krzanowski (1996) proposed a finite mixture model in which component densities conform to the location model. In the graphical models literature the location model is known as the homogeneous Conditional Gaussian model. In this paper it is shown that their model is not identifiable without imposing additional restrictions. Specifically, for g groups and m locations, (g!)m–1 distinct sets of parameter values (not including permutations of the group mixing parameters) produce the same likelihood function. Excessive shrinkage of parameter estimates in a simulation experiment reported by Lawrence and Krzanowski (1996) is shown to be an artifact of the model's non-identifiability. Identifiable finite mixture models can be obtained by imposing restrictions on the conditional means of the continuous variables. These new identified models are assessed in simulation experiments. The conditional mean structure of the continuous variables in the restricted location mixture models is similar to that in the underlying variable mixture models proposed by Everitt (1988), but the restricted location mixture models are more computationally tractable.     

Multilevel models for repeated binary outcomes: attitudes and voting over the electoral cycle

Models for fitting longitudinal binary responses are explored by using a panel study of voting intentions. A standard multilevel repeated measures logistic model is shown to be inadequate owing to a substantial proportion of respondents who maintain a constant response over time. A multivariate binary response model is shown to be a better fit to the data.     

Comparing two measures of creatinine clearance: an application of errors-in-variables and bootstrap techniques

Two indices of creatinine clearance (an index of kidney function) are compared on a group of cancer patients who underwent chemotherapy with a potentially nephrotoxic drug. The standard index, measured creatinine clearance MCC, is cumbersome to use, whereas the more convenient alternative, estimated creatinine clearance ECC, has not yet been conclusively evaluated on cancer patients. We conclude that under certain clinical conditions ECC and MCC are identically calibrated for males, but not for females, and we obtain estimated true and false positive rates for assessing the use of ECC instead of MCC as a diagnostic tool. We use a model that is formally equivalent to an errors-in-variables model with (unbalanced) repeated observations and correlated measurement errors. The bootstrap is used to obtain standard errors and confidence limits.     

Influence of human immunodeficiency virus infection on neurological impairment: an analysis of longitudinal binary data with informative drop-out

A study to investigate the human immunodeficiency virus (HIV) status on the course of neurological impairment, conducted by the HIV Center at Columbia University, followed a cohort of HIV positive and negative gay men for 5 years and assessed the presence or absence of neurological impairment every 6 months. Almost half of the subjects dropped out before the end of the study for reasons that might have been related to the missing neurological data. We propose likelihood-based methods for analysing such binary longitudinal data under informative and non-informative drop-out. A transition model is assumed for the binary response, and several models for the drop-out processes are considered which are functions of the response variable (neurological impairment). The likelihood ratio test is used to compare models with informative and non-informative drop-out mechanisms. Using simulations, we investigate the percentage bias and mean-squared error (MSE) of the parameter estimates in the transition model under various assumptions for the drop-out. We find evidence for informative drop-out in the study, and we illustrate that the bias and MSE for the parameters of the transition model are not directly related to the observed drop-out or missing data rates. The effect of HIV status on the neurological impairment is found to be statistically significant under each of the models considered for the drop-out, although the regression coefficient may be biased in certain cases. The presence and relative magnitude of the bias depend on factors such as the probability of drop-out conditional on the presence of neurological impairment and the prevalence of neurological impairment in the population under study.     

Venezuelan Rainfall Data Analysed by Using a Bayesian Space–time Model

We consider a set of data from 80 stations in the Venezuelan state of Guárico consisting of accumulated monthly rainfall in a time span of 16 years. The problem of modelling rainfall accumulated over fixed periods of time and recorded at meteorological stations at different sites is studied by using a model based on the assumption that the data follow a truncated and transformed multivariate normal distribution. The spatial correlation is modelled by using an exponentially decreasing correlation function and an interpolating surface for the means. Missing data and dry periods are handled within a Markov chain Monte Carlo framework using latent variables. We estimate the amount of rainfall as well as the probability of a dry period by using the predictive density of the data. We considered a model based on a full second-degree polynomial over the spatial co-ordinates as well as the first two Fourier harmonics to describe the variability during the year. Predictive inferences on the data show very realistic results, capturing the typical rainfall variability in time and space for that region. Important extensions of the model are also discussed.     

The Effect of Drop-Out on the Efficiency of Longitudinal Experiments

It is shown that drop-out often reduces the efficiency of longitudinal experiments considerably. In the framework of linear mixed models, a general, computationally simple method is provided, for designing longitudinal studies when drop-out is to be expected, such that there is little risk of large losses of efficiency due to the missing data. All the results are extensively illustrated using data from a randomized experiment with rats.     

Likelihood Factorizations for Mixed Discrete and Continuous Variables

Some general remarks are made about likelihood factorizations, distinguishing parameter-based factorizations and concentration-graph factorizations. Two parametric families of distributions for mixed discrete and continuous variables are discussed. Conditions on graphs are given for the circumstances under which their joint analysis can be split into separate analyses, each involving a reduced set of component variables and parameters. The result shows marked differences between the two families although both involve the same necessary condition on prime graphs. This condition is both necessary and sufficient for simplified estimation in Gaussian and for discrete log linear models.     

Semiparametric Additive Accelerated Life Models

In this paper we investigate the asymptotic properties of estimators obtained for the semiparametric additive accelerated life model proposed by Bagdonavicius & Nikulin (1995). This model generalizes the well known additive hazards model of survival analysis and is close to the general transformation model (see Dabrowska & Doksum, 1988). Asymptotic properties of the estimator of the regression parameter and the estimator of the reliability function are given in the case of right censoring for discretized data and a numerical example illustrates these results.