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Register a new userA note on Influence diagnostics in nonlinear mixed-effects elliptical models
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Added by
Alexandre Patriota
Publication date
2009
fields
Mathematical Statistics
and research's language is
English
Authors
Alexandre G. Patriota
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This paper provides general matrix formulas for computing the score function, the (expected and observed) Fisher information and the $Delta$ matrices (required for the assessment of local influence) for a quite general model which includes the one proposed by Russo et al. (2009). Additionally, we also present an expression for the generalized leverage. The matrix formulation has a considerable advantage, since although the complexity of the postulated model, all general formulas are compact, clear and have nice forms.
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The ability to generate samples of the random effects from their conditional distributions is fundamental for inference in mixed effects models. Random walk Metropolis is widely used to perform such sampling, but this method is known to converge slowly for medium dimensional problems, or when the joint structure of the distributions to sample is spatially heterogeneous. The main contribution consists of an independent Metropolis-Hastings (MH) algorithm based on a multidimensional Gaussian proposal that takes into account the joint conditional distribution of the random effects and does not require any tuning. Indeed, this distribution is automatically obtained thanks to a Laplace approximation of the incomplete data model. Such approximation is shown to be equivalent to linearizing the structural model in the case of continuous data. Numerical experiments based on simulated and real data illustrate the performance of the proposed methods. For fitting nonlinear mixed effects models, the suggested MH algorithm is efficiently combined with a stochastic approximation version of the EM algorithm for maximum likelihood estimation of the global parameters.
The functional linear model is a popular tool to investigate the relationship between a scalar/functional response variable and a scalar/functional covariate. We generalize this model to a functional linear mixed-effects model when repeated measurements are available on multiple subjects. Each subject has an individual intercept and slope function, while shares common population intercept and slope function. This model is flexible in the sense of allowing the slope random effects to change with the time. We propose a penalized spline smoothing method to estimate the population and random slope functions. A REML-based EM algorithm is developed to estimate the variance parameters for the random effects and the data noise. Simulation studies show that our estimation method provides an accurate estimate for the functional linear mixed-effects model with the finite samples. The functional linear mixed-effects model is demonstrated by investigating the effect of the 24-hour nitrogen dioxide on the daily maximum ozone concentrations and also studying the effect of the daily temperature on the annual precipitation.
Linear Mixed Effects (LME) models have been widely applied in clustered data analysis in many areas including marketing research, clinical trials, and biomedical studies. Inference can be conducted using maximum likelihood approach if assuming Normal distributions on the random effects. However, in many applications of economy, business and medicine, it is often essential to impose constraints on the regression parameters after taking their real-world interpretations into account. Therefore, in this paper we extend the classical (unconstrained) LME models to allow for sign constraints on its overall coefficients. We propose to assume a symmetric doubly truncated Normal (SDTN) distribution on the random effects instead of the unconstrained Normal distribution which is often found in classical literature. With the aforementioned change, difficulty has dramatically increased as the exact distribution of the dependent variable becomes analytically intractable. We then develop likelihood-based approaches to estimate the unknown model parameters utilizing the approximation of its exact distribution. Simulation studies have shown that the proposed constrained model not only improves real-world interpretations of results, but also achieves satisfactory performance on model fits as compared to the existing model.
Nonlinear Mixed effects models are hidden variables models that are widely used in many field such as pharmacometrics. In such models, the distribution characteristics of hidden variables can be specified by including several parameters such as covariates or correlations which must be selected. Recent development of pharmacogenomics has brought averaged/high dimensional problems to the field of nonlinear mixed effects modeling for which standard covariates selection techniques like stepwise methods are not well suited. This work proposes to select covariates and correlation parameters using a penalized likelihood approach. The penalized likelihood problem is solved using a stochastic proximal gradient algorithm to avoid inner-outer iterations. Speed of convergence of the proximal gradient algorithm is improved by the use of component-wise adaptive gradient step sizes. The practical implementation and tuning of the proximal gradient algorithm is explored using simulations. Calibration of regularization parameters is performed by minimizing the Bayesian Information Criterion using particle swarm optimization, a zero order optimization procedure. The use of warm restart and parallelization allows to reduce significantly computing time. The performance of the proposed method compared to the traditional grid search strategy is explored using simulated data. Finally, an application to real data from two pharmacokinetics studies is provided, one studying an antifibrinolitic and the other studying an antibiotic.
We present a parameter estimation method for nonlinear mixed effect models based on ordinary differential equations (NLME-ODEs). The method presented here aims at regularizing the estimation problem in presence of model misspecifications, practical identifiability issues and unknown initial conditions. For doing so, we define our estimator as the minimizer of a cost function which incorporates a possible gap between the assumed model at the population level and the specific individual dynamic. The cost function computation leads to formulate and solve optimal control problems at the subject level. This control theory approach allows to bypass the need to know or estimate initial conditions for each subject and it regularizes the estimation problem in presence of poorly identifiable parameters. Comparing to maximum likelihood, we show on simulation examples that our method improves estimation accuracy in possibly partially observed systems with unknown initial conditions or poorly identifiable parameters with or without model error. We conclude this work with a real application on antibody concentration data after vaccination against Ebola virus coming from phase 1 trials. We use the estimated model discrepancy at the subject level to analyze the presence of model misspecification.
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