Nonlinear mixed effects modelling for estimation of steady state attainment

Assessment of the time needed to attain steady state is a key pharmacokinetic objective during drug development. Traditional approaches for assessing steady state include ANOVA‐based methods for comparing mean plasma concentration values from each sampling day, with either a difference or equivalence test. However, hypothesis‐testing approaches are ill suited for assessment of steady state. This paper presents a nonlinear mixed effects modelling approach for estimation of steady state attainment, based on fitting a simple nonlinear mixed model to observed trough plasma concentrations. The simple nonlinear mixed model is developed and proposed for use under certain pharmacokinetic assumptions. The nonlinear mixed modelling estimation approach is described and illustrated by application to trough data from a multiple dose trial in healthy subjects. The performance of the nonlinear mixed modelling approach is compared to ANOVA‐based approaches by means of simulation techniques. Copyright © 2005 John Wiley & Sons, Ltd.     

Mixture of linear mixed models using multivariate t distribution

Linear mixed models are widely used when multiple correlated measurements are made on each unit of interest. In many applications, the units may form several distinct clusters, and such heterogeneity can be more appropriately modelled by a finite mixture linear mixed model. The classical estimation approach, in which both the random effects and the error parts are assumed to follow normal distribution, is sensitive to outliers, and failure to accommodate outliers may greatly jeopardize the model estimation and inference. We propose a new mixture linear mixed model using multivariate t distribution. For each mixture component, we assume the response and the random effects jointly follow a multivariate t distribution, to conveniently robustify the estimation procedure. An efficient expectation conditional maximization algorithm is developed for conducting maximum likelihood estimation. The degrees of freedom parameters of the t distributions are chosen data adaptively, for achieving flexible trade-off between estimation robustness and efficiency. Simulation studies and an application on analysing lung growth longitudinal data showcase the efficacy of the proposed approach.     

Estimated estimating equations: semiparametric inference for clustered and longitudinal data

Summary.  We introduce a flexible marginal modelling approach for statistical inference for clustered and longitudinal data under minimal assumptions. This estimated estimating equations approach is semiparametric and the proposed models are fitted by quasi-likelihood regression, where the unknown marginal means are a function of the fixed effects linear predictor with unknown smooth link, and variance–covariance is an unknown smooth function of the marginal means. We propose to estimate the nonparametric link and variance–covariance functions via smoothing methods, whereas the regression parameters are obtained via the estimated estimating equations. These are score equations that contain nonparametric function estimates. The proposed estimated estimating equations approach is motivated by its flexibility and easy implementation. Moreover, if data follow a generalized linear mixed model, with either a specified or an unspecified distribution of random effects and link function, the model proposed emerges as the corresponding marginal (population-average) version and can be used to obtain inference for the fixed effects in the underlying generalized linear mixed model, without the need to specify any other components of this generalized linear mixed model. Among marginal models, the estimated estimating equations approach provides a flexible alternative to modelling with generalized estimating equations. Applications of estimated estimating equations include diagnostics and link selection. The asymptotic distribution of the proposed estimators for the model parameters is derived, enabling statistical inference. Practical illustrations include Poisson modelling of repeated epileptic seizure counts and simulations for clustered binomial responses.     

The Analysis of Designed Experiments and Longitudinal Data by Using Smoothing Splines

In designed experiments and in particular longitudinal studies, the aim may be to assess the effect of a quantitative variable such as time on treatment effects. Modelling treatment effects can be complex in the presence of other sources of variation. Three examples are presented to illustrate an approach to analysis in such cases. The first example is a longitudinal experiment on the growth of cows under a factorial treatment structure where serial correlation and variance heterogeneity complicate the analysis. The second example involves the calibration of optical density and the concentration of a protein DNase in the presence of sampling variation and variance heterogeneity. The final example is a multienvironment agricultural field experiment in which a yield–seeding rate relationship is required for several varieties of lupins. Spatial variation within environments, heterogeneity between environments and variation between varieties all need to be incorporated in the analysis. In this paper, the cubic smoothing spline is used in conjunction with fixed and random effects, random coefficients and variance modelling to provide simultaneous modelling of trends and covariance structure. The key result that allows coherent and flexible empirical model building in complex situations is the linear mixed model representation of the cubic smoothing spline. An extension is proposed in which trend is partitioned into smooth and non-smooth components. Estimation and inference, the analysis of the three examples and a discussion of extensions and unresolved issues are also presented.     

A simultaneous variable selection methodology for linear mixed models

Selecting an appropriate structure for a linear mixed model serves as an appealing problem in a number of applications such as in the modelling of longitudinal or clustered data. In this paper, we propose a variable selection procedure for simultaneously selecting and estimating the fixed and random effects. More specifically, a profile log-likelihood function, along with an adaptive penalty, is utilized for sparse selection. The Newton-Raphson optimization algorithm is performed to complete the parameter estimation. By jointly selecting the fixed and random effects, the proposed approach increases selection accuracy compared with two-stage procedures, and the usage of the profile log-likelihood can improve computational efficiency in one-stage procedures. We prove that the proposed procedure enjoys the model selection consistency. A simulation study and a real data application are conducted for demonstrating the effectiveness of the proposed method.     

A semi‐parametric approach to fitting a nonlinear mixed PK/PD model with an effect compartment using SAS

Modelling of the relationship between concentration (PK) and response (PD) plays an important role in drug development. The modelling becomes complicated when the drug concentration and response measurements are not taken simultaneously and/or hysteresis occurs between the response and the concentration. A model‐based approach fits a joint pharmacokinetic (PK) and concentration–response (PK/PD) model, including an effect compartment if necessary, to concentration and response data. However, this approach relies on the PK data being well described by a common PK model. We propose an algorithm for a semi‐parametric approach to fitting nonlinear mixed PK/PD models including an effect compartment using linear interpolation and extrapolation for concentration data. This approach is independent of the PK model, and the algorithm can easily be implemented using SAS PROC NLMIXED. Practical issues in programming and computing are also discussed. The properties of this approach are examined using simulations. This approach is used to analyse data from a study of the PK/PD relationship between insulin and glucose levels. Copyright © 2005 John Wiley & Sons, Ltd.     

Iterative weighted estimation based on variance modelling in linear regression models

ABSTRACT

The estimation of variance function plays an extremely important role in statistical inference of the regression models. In this paper we propose a variance modelling method for constructing the variance structure via combining the exponential polynomial modelling method and the kernel smoothing technique. A simple estimation method for the parameters in heteroscedastic linear regression models is developed when the covariance matrix is unknown diagonal and the variance function is a positive function of the mean. The consistency and asymptotic normality of the resulting estimators are established under some mild assumptions. In particular, a simple version of bootstrap test is adapted to test misspecification of the variance function. Some Monte Carlo simulation studies are carried out to examine the finite sample performance of the proposed methods. Finally, the methodologies are illustrated by the ozone concentration dataset.     

Serial correlation or random subject effects

In longitudinal data analysis with random subject effects, there is often within subject serial correlation and possibly unequally spaced observations. This serial correlation can be partially confounded with the random between subject effects. In real data, it is often not clear whether there is serial correlation, random subject effects or both. Using inference based on the likelihood function, it is not always possible to identify the correct model, especially in small samples. However, it is important that some effort be made to attempt to find a good model rather than just making assumptions. This often means trying models with random coefficients, with serial correlation, and with both. Model selection criteria such as likelihood ratio tests and Akaike's Information Criterion (AIC) can be used. The problem of modelling serial correlation with unequally spaced observations is addressed. A real data example is presented where there is an apparent heterogeneity of variances, possible serial correlation and between subject random effects. In this example, it turns out that the random subject effects explains both the serial correlation and the variance heterogeneity.     

Fast EM-type implementations for mixed effects models

The mixed effects model, in its various forms, is a common model in applied statistics. A useful strategy for fitting this model implements EM-type algorithms by treating the random effects as missing data. Such implementations, however, can be painfully slow when the variances of the random effects are small relative to the residual variance. In this paper, we apply the 'working parameter' approach to derive alternative EM-type implementations for fitting mixed effects models, which we show empirically can be hundreds of times faster than the common EM-type implementations. In our limited simulations, they also compare well with the routines in S-PLUS® and Stata® in terms of both speed and reliability. The central idea of the working parameter approach is to search for efficient data augmentation schemes for implementing the EM algorithm by minimizing the augmented information over the working parameter, and in the mixed effects setting this leads to a transfer of the mixed effects variances into the regression slope parameters. We also describe a variation for computing the restricted maximum likelihood estimate and an adaptive algorithm that takes advantage of both the standard and the alternative EM-type implementations.     

Embedding latent class regression and latent class distal outcome models into cluster-weighted latent class analysis: a detailed simulation experiment

Usually in latent class (LC) analysis, external predictors are taken to be cluster conditional probability predictors (LC models with external predictors), and/or score conditional probability predictors (LC regression models). In such cases, their distribution is not of interest. Class-specific distribution is of interest in the distal outcome model, when the distribution of the external variables is assumed to depend on LC membership. In this paper, we consider a more general formulation, that embeds both the LC regression and the distal outcome models, as is typically done in cluster-weighted modelling. This allows us to investigate (1) whether the distribution of the external variables differs across classes, (2) whether there are significant direct effects of the external variables on the indicators, by modelling jointly the relationship between the external and the latent variables. We show the advantages of the proposed modelling approach through a set of artificial examples, an extensive simulation study and an empirical application about psychological contracts among employees and employers in Belgium and the Netherlands.     

Mixture modelling as an exploratory framework for genotype-trait associations

We propose a mixture modelling framework for both identifying and exploring the nature of genotype-trait associations. This framework extends the classical mixed effects modelling approach for this setting by incorporating a Gaussian mixture distribution for random genotype effects. The primary advantages of this paradigm over existing approaches include that the mixture modelling framework addresses the degrees-of-freedom challenge that is inherent in application of the usual fixed effects analysis of covariance, relaxes the restrictive single normal distribution assumption of the classical mixed effects models and offers an exploratory framework for discovery of underlying structure across multiple genetic loci. An application to data arising from a study of antiretroviral-associated dyslipidaemia in human immunodeficiency virus infection is presented. Extensive simulations studies are also implemented to investigate the performance of this approach.     

Generalized additive models with unknown link function including variable selection

The generalized additive model is a well established and strong tool that allows modelling smooth effects of predictors on the response. However, if the link function, which is typically chosen as the canonical link, is misspecified, estimates can be biased. A procedure is proposed that simultaneously estimates the form of the link function and the unknown form of the predictor functions including selection of predictors. The procedure is based on boosting methodology, which obtains estimates by using a sequence of weak learners. It strongly dominates fitting procedures that are unable to modify a given link function if the true link function deviates from the fixed function. The performance of the procedure is shown in simulation studies and illustrated by real world examples.     

Spatial measurement error in infectious disease models

Individual-level models (ILMs) for infectious disease can be used to model disease spread between individuals while taking into account important covariates. One important covariate in determining the risk of infection transfer can be spatial location. At the same time, measurement error is a concern in many areas of statistical analysis, and infectious disease modelling is no exception. In this paper, we are concerned with the issue of measurement error in the recorded location of individuals when using a simple spatial ILM to model the spread of disease within a population. An ILM that incorporates spatial location random effects is introduced within a hierarchical Bayesian framework. This model is tested upon both simulated data and data from the UK 2001 foot-and-mouth disease epidemic. The ability of the model to successfully identify both the spatial infection kernel and the basic reproduction number (R ₀) of the disease is tested.     

Evaluation of Bayesian multiple stage estimation under spatial CAR model variants

In this study, an evaluation of Bayesian hierarchical models is made based on simulation scenarios to compare single-stage and multi-stage Bayesian estimations. Simulated datasets of lung cancer disease counts for men aged 65 and older across 44 wards in the London Health Authority were analysed using a range of spatially structured random effect components. The goals of this study are to determine which of these single-stage models perform best given a certain simulating model, how estimation methods (single- vs. multi-stage) compare in yielding posterior estimates of fixed effects in the presence of spatially structured random effects, and finally which of two spatial prior models – the Leroux or ICAR model, perform best in a multi-stage context under different assumptions concerning spatial correlation. Among the fitted single-stage models without covariates, we found that when there is low amount of variability in the distribution of disease counts, the BYM model is relatively robust to misspecification in terms of DIC, while the Leroux model is the least robust to misspecification. When these models were fit to data generated from models with covariates, we found that when there was one set of covariates – either spatially correlated or non-spatially correlated, changing the values of the fixed coefficients affected the ability of either the Leroux or ICAR model to fit the data well in terms of DIC. When there were multiple sets of spatially correlated covariates in the simulating model, however, we could not distinguish the goodness of fit to the data between these single-stage models. We found that the multi-stage modelling process via the Leroux and ICAR models generally reduced the variance of the posterior estimated fixed effects for data generated from models with covariates and a UH term compared to analogous single-stage models. Finally, we found the multi-stage Leroux model compares favourably to the multi-stage ICAR model in terms of DIC. We conclude that the mutli-stage Leroux model should be seriously considered in applications of Bayesian disease mapping when an investigator desires to fit a model with both fixed effects and spatially structured random effects to Poisson count data.     

To move or not to move to find a new job: spatial duration time model with dynamic covariate effects

The aim of this paper is to show the flexibility and capacity of penalized spline smoothing as estimation routine for modelling duration time data. We analyse the unemployment behaviour in Germany between 2000 and 2004 using a massive database from the German Federal Employment Agency. To investigate dynamic covariate effects and differences between competing job markets depending on the distance between former and recent working place, a functional duration time model with competing risks is used. It is build upon a competing hazard function where some of the smooth covariate effects are allowed to vary with unemployment duration. The focus of our analysis is on contrasting the spatial, economic and individual covariate effects of the competing job markets and on analysing their general influence on the unemployed's re-employment probabilities. As a result of our analyses, we reveal differences concerning gender, age and education. We also discover an effect between the newly formed and the old West German states. Moreover, the spatial pattern between the considered job markets differs.     

Dynamic generalized linear models with application to environmental epidemiology

Summary. We propose modelling short-term pollutant exposure effects on health by using dynamic generalized linear models. The time series of count data are modelled by a Poisson distribution having mean driven by a latent Markov process; estimation is performed by the extended Kalman filter and smoother. This modelling strategy allows us to take into account possible overdispersion and time-varying effects of the covariates. These ideas are illustrated by reanalysing data on the relationship between daily non-accidental deaths and air pollution in the city of Birmingham, Alabama.     

A Distribution-free Approach in Statistical Modelling with Repeated Measurements and Missing Values

Mixed effect models, which contain both fixed effects and random effects, are frequently used in dealing with correlated data arising from repeated measurements (made on the same statistical units). In mixed effect models, the distributions of the random effects need to be specified and they are often assumed to be normal. The analysis of correlated data from repeated measurements can also be done with GEE by assuming any type of correlation as initial input. Both mixed effect models and GEE are approaches requiring distribution specifications (likelihood, score function). In this article, we consider a distribution-free least square approach under a general setting with missing value allowed. This approach does not require the specifications of the distributions and initial correlation input. Consistency and asymptotic normality of the estimation are discussed.     

Assessing the performance of variational methods for mixed logistic regression models

We present a variational estimation method for the mixed logistic regression model. The method is based on a lower bound approximation of the logistic function [Jaakkola, J.S. and Jordan, M.I., 2000, Bayesian parameter estimation via variational methods. Statistics & Computing, 10, 25–37.]. Based on the approximation, an EM algorithm can be derived that results in a considerable simplification of the maximization problem in that it does not require the numerical evaluation of integrals over the random effects. We assess the performance of the variational method for the mixed logistic regression model in a simulation study and an empirical data example, and compare it to Laplace's method. The results indicate that the variational method is a viable choice for estimating the fixed effects of the mixed logistic regression model under the condition that the number of outcomes within each cluster is sufficiently high.     

Latent Variable Models for Mixed Discrete and Continuous Outcomes

We propose a latent variable model for mixed discrete and continuous outcomes. The model accommodates any mixture of outcomes from an exponential family and allows for arbitrary covariate effects, as well as direct modelling of covariates on the latent variable. An EM algorithm is proposed for parameter estimation and estimates of the latent variables are produced as a by-product of the analysis. A generalized likelihood ratio test can be used to test the significance of covariates affecting the latent outcomes. This method is applied to birth defects data, where the outcomes of interest are continuous measures of size and binary indicators of minor physical anomalies. Infants who were exposed in utero to anticonvulsant medications are compared with controls.     

Statistical analysis of performance indicators in UK higher education

Summary.  Attempts to measure the quality with which institutions such as hospitals and universities carry out their public mandates have gained in frequency and sophistication over the last decade. We examine methods for creating performance indicators in multilevel or hierarchical settings (e.g. students nested within universities) based on a dichotomous outcome variable (e.g. drop-out from the higher education system). The profiling methods that we study involve the indirect measurement of quality, by comparing institutional outputs after adjusting for inputs, rather than directly attempting to measure the quality of the processes unfolding inside the institutions. In the context of an extended case-study of the creation of performance indicators for universities in the UK higher education system, we demonstrate the large sample functional equivalence between a method based on indirect standardization and an approach based on fixed effects hierarchical modelling, offer simulation results on the performance of the standardization method in null and non-null settings, examine the sensitivity of this method to the inadvertent omission of relevant adjustment variables, explore random-effects reformulations and characterize settings in which they are preferable to fixed effects hierarchical modelling in this type of quality assessment and discuss extensions to longitudinal quality modelling and the overall pros and cons of institutional profiling. Our results are couched in the language of higher education but apply with equal force to other settings with dichotomous response variables, such as the examination of observed and expected rates of mortality (or other adverse outcomes) in investigations of the quality of health care or the study of retention rates in the workplace.