Dataset Information

Nonlinear Mixed-Effects Models for PET Data.

ABSTRACT: OBJECTIVE:The current state-of-the-art for compartment modeling of dynamic PET data can be described as a two-stage approach. In Stage 1, individual estimates of kinetic parameters are obtained by fitting models using standard techniques, such as nonlinear least squares, to each individual's data one subject at a time. Population-level effects, such as the difference between diagnostic groups, are analyzed in Stage 2 using standard statistical methods by treating the individual estimates as if they were observed data. While this approach is generally valid, it is possible to increase efficiency and precision of the analysis, allow more complex models to be fitted, and also to permit parameter-specific investigation by fitting data across subjects simultaneously. We explore the application of nonlinear mixed-effects (NLME) models for estimation and inference in this setting. METHODS:In the NLME framework, subjects are modeled simultaneously through the inclusion of random effects of subjects for each kinetic parameter; meanwhile, population parameters are estimated directly in a joint model. RESULTS:Simulation results indicate that NLME outperforms the two-stage approach in estimating group-level effects and also has improved power to detect differences across groups. We applied our NLME approach to clinical PET data and found effects not detected by the two-stage approach. CONCLUSION:The proposed NLME approach is more accurate and correspondingly more powerful than the two-stage approach in compartment modeling of PET data. SIGNIFICANCE:The NLME method can broaden the methodological scope of PET modeling because of its efficiency and stability.

SUBMITTER: Chen Y

PROVIDER: S-EPMC6436945 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Publications

Nonlinear Mixed-Effects Models for PET Data.

Chen Yakuan Y Goldsmith Jeff J Ogden R Todd RT

IEEE transactions on bio-medical engineering 20180801 3

<h4>Objective</h4>The current state-of-the-art for compartment modeling of dynamic PET data can be described as a two-stage approach. In Stage 1, individual estimates of kinetic parameters are obtained by fitting models using standard techniques, such as nonlinear least squares, to each individual's data one subject at a time. Population-level effects, such as the difference between diagnostic groups, are analyzed in Stage 2 using standard statistical methods by treating the individual estimates ...[more]

PMID: 30072311

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Project description:Background and objectivesModel-informed precision dosing (MIPD) frequently uses nonlinear mixed-effects (NLME) models to predict and optimize therapy outcomes based on patient characteristics and therapeutic drug monitoring data. MIPD is indicated for compounds with narrow therapeutic range and complex pharmacokinetics (PK), such as voriconazole, a broad-spectrum antifungal drug for prevention and treatment of invasive fungal infections. To provide guidance and recommendations for evidence-based application of MIPD for voriconazole, this work aimed to (i) externally evaluate and compare the predictive performance of a published so-called 'hybrid' model for MIPD (an aggregate model comprising features and prior information from six previously published NLME models) versus two 'standard' NLME models of voriconazole, and (ii) investigate strategies and illustrate the clinical impact of Bayesian forecasting for voriconazole.MethodsA workflow for external evaluation and application of MIPD for voriconazole was implemented. Published voriconazole NLME models were externally evaluated using a comprehensive in-house clinical database comprising nine voriconazole studies and prediction-/simulation-based diagnostics. The NLME models were applied using different Bayesian forecasting strategies to assess the influence of prior observations on model predictivity.ResultsThe overall best predictive performance was obtained using the aggregate model. However, all NLME models showed only modest predictive performance, suggesting that (i) important PK processes were not sufficiently implemented in the structural submodels, (ii) sources of interindividual variability were not entirely captured, and (iii) interoccasion variability was not adequately accounted for. Predictive performance substantially improved by including the most recent voriconazole observations in MIPD.ConclusionOur results highlight the potential clinical impact of MIPD for voriconazole and indicate the need for a comprehensive (pre-)clinical database as basis for model development and careful external model evaluation for compounds with complex PK before their successful use in MIPD.

Dataset Information

Nonlinear Mixed-Effects Models for PET Data.

Publications

Nonlinear Mixed-Effects Models for PET Data.

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