Search

Abstract: Pharmacokinetic/pharmacodynamic data are often analysed using nonlinear mixed-effect models, and model evaluation should be an important part of the analysis. Recently, normalised prediction distribution errors (npde) have been proposed as a model evaluation tool. In this paper, we describe an add-on package for the open source statistical package R, designed to compute npde. npde take into account the full predictive distribution of each individual observation and handle multiple observations within subjects. Under the null hypothesis that the model under scrutiny describes the validation dataset, npde should follow the standard normal distribution. Simulations need to be performed before hand, using for example the software used for model estimation. We illustrate the use of the package with two simulated datasets, one under the true model and one with different parameter values, to show how npde can be used to evaluate models. Model estimation and data simulation were performed using NONMEM version 5.1. [Copyright &y& Elsevier]

Joint modeling of longitudinal and time-to-event data has gained attention over recent years with extensive developments including nonlinear models for longitudinal outcomes and flexible time-to-event models for survival outcomes, possibly involving competing risks. However, in popular software such as R, the function used to describe the biomarker dynamic is mainly linear in the parameters, and the survival submodel relies on pre-implemented functions (exponential, Weibull,...). The objective of this work is to extend the code from the saemix package (version 3.1 on CRAN) to fit parametric joint models where longitudinal submodels are not necessary linear in their parameters, with full user control over the model function. We used the saemix package, designed to fit nonlinear mixed-effects models (NLMEM) through the Stochastic Approximation Expectation Maximization (SAEM) algorithm, and extended the main functions to joint model estimation. To compute standard errors (SE) of parameter estimates, we implemented a recently developed stochastic algorithm. A simulation study was proposed to assess (i) the performances of parameter estimation, (ii) the SE computation and (iii) the type I error when testing independence between the two submodels. Four joint models were considered in the simulation study, combining a linear or nonlinear mixed-effects model for the longitudinal submodel, with a single terminal event or a competing risk model. For all simulation scenarios, parameters were precisely and accurately estimated with low bias and uncertainty. For complex joint models (with NLMEM), increasing the number of chains of the algorithm was necessary to reduce bias, but earlier censoring in the competing risk scenario still challenged the estimation. The empirical SE of parameters obtained over all simulations were very close to those computed with the stochastic algorithm. For more complex joint models (involving NLMEM), some estimates of random effects variances had higher uncertainty and their SE were moderately under-estimated. Finally, type I error was controlled for each joint model. saemix is a flexible open-source package and we adapted it to fit complex parametric joint models that may not be estimated using standard tools. Code and examples to help users get started are freely available on Github. • Extension of the code of saemix package initially designed for nonlinear mixed-effects models to the case of joint models. • Integration of a recently developed stochastic algorithm having interesting properties for standard error estimation. • Good performances for parameter and standard error estimations. • New flexible tool allowing users to fit very specific joint models by defining a personalized likelihood function. [ABSTRACT FROM AUTHOR]

Background and Objective Nonlinear mixed-effect models (NLMEMs) are increasingly used for the analysis of longitudinal studies during drug development. When designing these studies, the expected Fisher information matrix (FIM) can be used instead of performing time-consuming clinical trial simulations. The function PFIM is the first tool for design evaluation and optimization that has been developed in R. In this article, we present an extended version, PFIM 4.0, which includes several new features. Methods Compared with version 3.0, PFIM 4.0 includes a more complete pharmacokinetic/pharmacodynamic library of models and accommodates models including additional random effects for inter-occasion variability as well as discrete covariates. A new input method has been added to specify user-defined models through an R function. Optimization can be performed assuming some fixed parameters or some fixed sampling times. New outputs have been added regarding the FIM such as eigenvalues, conditional numbers, and the option of saving the matrix obtained after evaluation or optimization. Previously obtained results, which are summarized in a FIM, can be taken into account in evaluation or optimization of one-group protocols. This feature enables the use of PFIM for adaptive designs. The Bayesian individual FIM has been implemented, taking into account a priori distribution of random effects. Designs for maximum a posteriori Bayesian estimation of individual parameters can now be evaluated or optimized and the predicted shrinkage is also reported. It is also possible to visualize the graphs of the model and the sensitivity functions without performing evaluation or optimization. Results The usefulness of these approaches and the simplicity of use of PFIM 4.0 are illustrated by two examples: (i) an example of designing a population pharmacokinetic study accounting for previous results, which highlights the advantage of adaptive designs; (ii) an example of Bayesian individual design optimization for a pharmacodynamic study, showing that the Bayesian individual FIM can be a useful tool in therapeutic drug monitoring, allowing efficient prediction of estimation precision and shrinkage for individual parameters. Conclusion PFIM 4.0 is a useful tool for design evaluation and optimization of longitudinal studies in pharmacometrics and is freely available at http://www.pfim.biostat.fr . [ABSTRACT FROM AUTHOR]