Optimal cross-over designs for nonlinear mixed models using a first-order expansion

We consider the construction of optimal cross-over designs for nonlinear mixed effect models based on the first-order expansion. We show that for AB/BA designs a balanced subject allocation is optimal when the parameters depend on treatments only. For multiple period, multiple sequence designs, uniform designs are optimal among dual balanced designs under the same conditions. As a by-product, the same results hold for multivariate linear mixed models with variances depending on treatments.     

A simulated annealing version of the EM algorithm for non-Gaussian deconvolution

The Expectation–Maximization (EM) algorithm is a very popular technique for maximum likelihood estimation in incomplete data models. When the expectation step cannot be performed in closed form, a stochastic approximation of EM (SAEM) can be used. Under very general conditions, the authors have shown that the attractive stationary points of the SAEM algorithm correspond to the global and local maxima of the observed likelihood. In order to avoid convergence towards a local maxima, a simulated annealing version of SAEM is proposed. An illustrative application to the convolution model for estimating the coefficients of the filter is given.     

Estimation in Truncated GLG Model for Ordered Categorical Spatial Data Using the SAEM Algorithm

In this article, we utilize a scale mixture of Gaussian random field as a tool for modeling spatial ordered categorical data with non-Gaussian latent variables. In fact, we assume a categorical random field is created by truncating a Gaussian Log-Gaussian latent variable model to accommodate heavy tails. Since the traditional likelihood approach for the considered model involves high-dimensional integrations which are computationally intensive, the maximum likelihood estimates are obtained using a stochastic approximation expectation–maximization algorithm. For this purpose, Markov chain Monte Carlo methods are employed to draw from the posterior distribution of latent variables. A numerical example illustrates the methodology.     

PkStaMp Library for Constructing Optimal Population Designs for PK/PD Studies

We discuss a Matlab-based library for constructing optimal sampling schemes for pharmacokinetic (PK) and pharmacodynamic (PD) studies. The software relies on optimal design theory for nonlinear mixed effects models and, in particular, on the first-order optimization algorithm. The library includes a number of popular compartmental PK and combined PK/PD models and can be extended to include more models. An outline of inputs/outputs is provided, some algorithmic details and examples are presented, and future work is discussed.     

A refined parameter estimating approach for HIV dynamic model

HIV dynamic models, a set of ordinary differential equations (ODEs), have provided new understanding of the pathogenesis of HIV infection and the treatment effects of antiviral therapies. However, to estimate parameters for ODEs is very challenging due to the complexity of this nonlinear system. In this article, we propose a comprehensive procedure to deal with this issue. In the proposed procedure, a series of cutting-edge statistical methods and techniques are employed, including nonparametric mixed-effects smoothing-based methods for ODE models and stochastic approximation expectation–maximization (EM) approach for mixed-effects ODE models. A simulation study is performed to validate the proposed approach. An application example from a real HIV clinical trial study is used to illustrate the usefulness of the proposed method.     

A likelihood-based constrained algorithm for multivariate normal mixture models

It is well known that the log-likelihood function for samples coming from normal mixture distributions may present spurious maxima and singularities. For this reason here we reformulate some Hathaways results and we propose two constrained estimation procedures for multivariate normal mixture modelling according to the likelihood approach. Their perfomances are illustrated on the grounds of some numerical simulations based on the EM algorithm. A comparison between multivariate normal mixtures and the hot-deck approach in missing data imputation is also considered.Salvatore Ingrassia: S. Ingrassia carried out the research as part of the project Metodi Statistici e Reti Neuronali per lAnalisi di Dati Complessi (PRIN 2000, resp. G. Lunetta).     

Two-stage Adaptive Designs in Nonlinear Mixed Effects Models: Application to Pharmacokinetics in Children

Nonlinear mixed effects models (NLMEM) are used in pharmacokinetics to analyse concentrations of patients during drug development, particularly for pediatric studies. Approaches based on the Fisher information matrix can be used to optimize their design. Local design needs some a priori parameter values which might be difficult to guess. Therefore, two-stage adaptive designs are useful to provide some flexibility. We implemented in the R function PFIM the Fisher matrix for two-stage designs in NLMEM. We evaluated, with simulations, the impact of one-stage and two-stage designs on the precision of parameter estimation when the true and a priori parameters are different.     

Maximum likelihood estimates in the multivariate normal with patterned mean and covariance via the em algorithm

The maximum likelihood equations for a multivariate normal model with structured mean and structured covariance matrix may not have an explicit solution. In some cases the model's error term may be decomposed as the sum of two independent error terms, each having a patterned covariance matrix, such that if one of the unobservable error terms is artificially treated as "missing data", the EM algorithm can be used to compute the maximum likelihood estimates for the original problem. Some decompositions produce likelihood equations which do not have an explicit solution at each iteration of the EM algorithm, but within-iteration explicit solutions are shown for two general classes of models including covariance component models used for analysis of longitudinal data.     

Testing for autocorrelation and random-effects in nonlinear mixed effects models based on M-estimation

M-estimation (robust estimation) for the parameters in nonlinear mixed effects models using Fisher scoring method is investigated in the article, which shares some of the features of the existing maximum likelihood estimation: consistency and asymptotic normality. Score tests for autocorrelation and random effects based on M-estimation, together with their asymptotic distribution are also studied. The performance of the test statistics are evaluated via simulations and a real data analysis of plasma concentrations data.     

Using auxiliary data for parameter estimation with non-ignorably missing outcomes

We propose a method for estimating parameters in generalized linear models when the outcome variable is missing for some subjects and the missing data mechanism is non-ignorable. We assume throughout that the covariates are fully observed. One possible method for estimating the parameters is maximum likelihood with a non-ignorable missing data model. However, caution must be used when fitting non-ignorable missing data models because certain parameters may be inestimable for some models. Instead of fitting a non-ignorable model, we propose the use of auxiliary information in a likelihood approach to reduce the bias, without having to specify a non-ignorable model. The method is applied to a mental health study.     

Computational aspects of the EM algorithm for spatial econometric models with missing data

Maximum likelihood (ML) estimation with spatial econometric models is a long-standing problem that finds application in several areas of economic importance. The problem is particularly challenging in the presence of missing data, since there is an implied dependence between all units, irrespective of whether they are observed or not. Out of the several approaches adopted for ML estimation in this context, that of LeSage and Pace [Models for spatially dependent missing data. J Real Estate Financ Econ. 2004;29(2):233–254] stands out as one of the most commonly used with spatial econometric models due to its ability to scale with the number of units. Here, we review their algorithm, and consider several similar alternatives that are also suitable for large datasets. We compare the methods through an extensive empirical study and conclude that, while the approximate approaches are suitable for large sampling ratios, for small sampling ratios the only reliable algorithms are those that yield exact ML or restricted ML estimates.     

Confidence intervals and tests on the variance ratio in random models with two variance components

The LM test is modified to test any value of the ratio of two variance components in a mixed effects linear model with two variance components. The test is exact, so it can be used to construct exact confidence intervals on this ratio.Exact Neyman-Pearson (NP) tests on the variance ratio are described.Their powers provide attainable upper bounds on powers of tests on the variance ratio.Efficiencies of LM tests, which include ANOVA tests, and NP tests are compared for unbalanced, random, one-way ANOVA models.Confidence intervals corresponding to LM tests and NP tests are described.     

A new REML (parameter expanded) EM algorithm for linear mixed models

Linear mixed models are regularly applied to animal and plant breeding data to evaluate genetic potential. Residual maximum likelihood (REML) is the preferred method for estimating variance parameters associated with this type of model. Typically an iterative algorithm is required for the estimation of variance parameters. Two algorithms which can be used for this purpose are the expectation‐maximisation (EM) algorithm and the parameter expanded EM (PX‐EM) algorithm. Both, particularly the EM algorithm, can be slow to converge when compared to a Newton‐Raphson type scheme such as the average information (AI) algorithm. The EM and PX‐EM algorithms require specification of the complete data, including the incomplete and missing data. We consider a new incomplete data specification based on a conditional derivation of REML. We illustrate the use of the resulting new algorithm through two examples: a sire model for lamb weight data and a balanced incomplete block soybean variety trial. In the cases where the AI algorithm failed, a REML PX‐EM based on the new incomplete data specification converged in 28% to 30% fewer iterations than the alternative REML PX‐EM specification. For the soybean example a REML EM algorithm using the new specification converged in fewer iterations than the current standard specification of a REML PX‐EM algorithm. The new specification integrates linear mixed models, Henderson's mixed model equations, REML and the REML EM algorithm into a cohesive framework.     

APPLICATION OF TWO-LEVEL NEGATIVE EXPONENTIAL MODEL TO CHILDREN'S LEARNING CURVE IN READING

ABSTRACT

This paper attempts to model the development of children's reading skills using the negative exponential curve with mixed effects model. The model describes the nature of growth in children's reading skills and accounts for intra-individual and inter-individual variations. In addition, we propose methods including cross-validation, regression, and graphing to determine an appropriate curve for the data, to find good initial values for parameters, and to select potential covariates. We illustrate with an example that motivated this research: a longitudinal study of academic reading skills from grade 1 to grade 12 in Connecticut public schools.     

Convergence properties of the EM algorithm in constrained parameter spaces

The established general results on convergence properties of the EM algorithm require the sequence of EM parameter estimates to fall in the interior of the parameter space over which the likelihood is being maximized. This paper presents convergence properties of the EM sequence of likelihood values and parameter estimates in constrained parameter spaces for which the sequence of EM parameter estimates may converge to the boundary of the constrained parameter space contained in the interior of the unconstrained parameter space. Examples of the behavior of the EM algorithm applied to such parameter spaces are presented.     

An EM algorithm for fitting a mixture model with symmetric log-concave densities

Abstract

In this article, we revisit the problem of fitting a mixture model under the assumption that the mixture components are symmetric and log-concave. To this end, we first study the nonparametric maximum likelihood estimation (MLE) of a monotone log-concave probability density. To fit the mixture model, we propose a semiparametric EM (SEM) algorithm, which can be adapted to other semiparametric mixture models. In our numerical experiments, we compare our algorithm to that of Balabdaoui and Doss (2018 Balabdaoui, F., and C. R. Doss. 2018. Inference for a two-component mixture of symmetric distributions under log-concavity. Bernoulli 24 (2):1053–71.[Crossref], [Web of Science ®] , [Google Scholar], Inference for a two-component mixture of symmetric distributions under log-concavity. Bernoulli 24 (2):1053–71) and other mixture models both on simulated and real-world datasets.     

Tests and Confidence Intervals for an Extended Variance Component Using the Modified Likelihood Ratio Statistic

Abstract.  The large deviation modified likelihood ratio statistic is studied for testing a variance component equal to a specified value. Formulas are presented in the general balanced case, whereas in the unbalanced case only the one-way random effects model is studied. Simulation studies are presented, showing that the normal approximation to the large deviation modified likelihood ratio statistic gives confidence intervals for variance components with coverage probabilities very close to the nominal confidence coefficient.     

Estimation of Some Nonlinear Panel Data Models With Both Time-Varying and Time-Invariant Explanatory Variables

The so-called “fixed effects” approach to the estimation of panel data models suffers from the limitation that it is not possible to estimate the coefficients on explanatory variables that are time-invariant. This is in contrast to a “random effects” approach, which achieves this by making much stronger assumptions on the relationship between the explanatory variables and the individual-specific effect. In a linear model, it is possible to obtain the best of both worlds by making random effects-type assumptions on the time-invariant explanatory variables while maintaining the flexibility of a fixed effects approach when it comes to the time-varying covariates. This article attempts to do the same for some popular nonlinear models.     

A new estimation procedure for a partially nonlinear model via a mixed‐effects approach

The authors consider the estimation of the parametric component of a partially nonlinear semiparametric regression model whose nonparametric component is viewed as a nuisance parameter. They show how estimation can proceed through a nonlinear mixed‐effects model approach. They prove that under certain regularity conditions, the proposed estimate is consistent and asymptotically Gaussian. They investigate its finite‐sample properties through simulations and illustrate its use with data on the relation between the photosynthetically active radiation and the net ecosystem‐atmosphere exchange of carbon dioxide.     

Using jackknife in nonlinear models - confidence regions for a function of the structural parameter

A method of constructing jackknife confidence regions for a function of the structural parameter of a nonlinear model is investigated. The method is available for nonlinear regression models as well as for models with errors in the variables. Properties are discussed in comparison with traditional methods. This is supported by a simulation study.