Model-Based Conditional Weighted Residuals Analysis for Structural Model Assessment

The AAPS Journal
Moustafa M A IbrahimMats O Karlsson

Abstract

Nonlinear mixed effects models are widely used to describe longitudinal data to improve the efficiency of drug development process or increase the understanding of the studied disease. In such settings, the appropriateness of the modeling assumptions is critical in order to draw correct conclusions and must be carefully assessed for any substantial violations. Here, we propose a new method for structure model assessment, based on assessment of bias in conditional weighted residuals (CWRES). We illustrate this method by assessing prediction bias in two integrated models for glucose homeostasis, the integrated glucose-insulin (IGI) model, and the integrated minimal model (IMM). One dataset was simulated from each model then analyzed with the two models. CWRES outputted from each model fitting were modeled to capture systematic trends in CWRES as well as the magnitude of structural model misspecifications in terms of difference in objective function values (ΔOFVBias). The estimates of CWRES bias were used to calculate the corresponding bias in conditional predictions by the inversion of first-order conditional estimation method's covariance equation. Time, glucose, and insulin concentration predictions were the investigated indepe...Continue Reading

References

May 31, 2001·Journal of Pharmacokinetics and Pharmacodynamics·Y YanoL B Sheiner
Jul 19, 2005·Computer Methods and Programs in Biomedicine·Lars LindbomNiclas Jonsson
Sep 8, 2005·American Journal of Physiology. Endocrinology and Metabolism·Gianna ToffoloClaudio Cobelli
May 25, 2007·Clinical Pharmacology and Therapeutics·R L LalondeR Miller
Jul 7, 2007·Pharmaceutical Research·Andrew C HookerMats O Karlsson
Jan 25, 2008·Computer Methods and Programs in Biomedicine·Emmanuelle CometsFrance Mentré
Jun 26, 2009·Journal of Pharmacokinetics and Pharmacodynamics·Hanna E SilberMats O Karlsson
Dec 15, 2010·Journal of Pharmacokinetics and Pharmacodynamics·Venkata V Pavan Kumar, Stephen B Duffull
Nov 25, 2016·CPT: Pharmacometrics & Systems Pharmacology·T H T NguyenUNKNOWN Model Evaluation Group of the International Society of Pharmacometrics (ISoP) Best Practice Committee
May 8, 2018·CPT: Pharmacometrics & Systems Pharmacology·Moustafa M A IbrahimMats O Karlsson
Jul 4, 2018·The AAPS Journal·Moustafa M A IbrahimMats O Karlsson
Apr 20, 2019·Pharmaceutical Research·Moustafa M A IbrahimMats O Karlsson

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Software Mentioned

NONMEM
NLME
CWRES
PsN
ETAS
qa
FOCE
R

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