| Assessment of type I error rates for the statistical sub-model in NONMEM. | |
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MedLine Citation:
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PMID: 12449498 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The aim of this study was to assess the type I error rate when applying the likelihood ratio (LR) test, for components of the statistical sub-model in NONMEM. Data were simulated from a pharmacokinetic one compartment intravenous bolus model. Two models were fitted to the data, the simulation model and a model containing one additional parameter, and the difference in objective function values between models was calculated. The additional parameter was either (i) a covariate effect on the interindividual variability in CL or V, (ii) a covariate effect on the residual error variability, (iii) a covariance term between CL and V, or (iv) interindividual variability in V. Factors in the simulation conditions (number of individuals and samples per individual, interindividual and residual error magnitude, residual error model) were varied systematically to assess their potential influence on the type I error rate. Different estimation methods within NONMEM were tried. When the first-order conditional estimation method with interaction (FOCE INTER) was used the estimated type I error rates for inclusion of a covariate effect (i) on the interindividual variability, or (ii) on the residual error variability, were in agreement with the type I error rate expected under the assumption that the model approximations made by the estimation method are negligible. When the residual error variability was increased, the type I error rates for (iii) inclusion of covariance between etaCL-etaV were inflated if the underlying residual distribution was lognormal, or if a normal distribution was combined with too little information in the data (too few samples per subject or sampling at uninformative time-points). For inclusion of (iv) etaV, the type I error rates were affected by the underlying residual error distribution; with a normal distribution the estimated type I error rates were close to the expected, while if a non-normal distribution was used the type I errors rates increased with increasing residual variability. When the first-order (FO) estimation method was used the estimated type I error rates were higher than the expected in most situations. For the FOCE INTER method, but not the FO method, the LR test is appropriate when the underlying assumptions of normality of residuals, and of enough information in the data, hold true. Deviations from these assumptions may lead to inflated type I error rates. |
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Authors:
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Ulrika Wählby; M René Bouw; E Niclas Jonsson; Mats O Karlsson |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of pharmacokinetics and pharmacodynamics Volume: 29 ISSN: 1567-567X ISO Abbreviation: J Pharmacokinet Pharmacodyn Publication Date: 2002 Jun |
Date Detail:
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Created Date: 2002-11-25 Completed Date: 2003-04-21 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 101096520 Medline TA: J Pharmacokinet Pharmacodyn Country: England |
Other Details:
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Languages: eng Pagination: 251-69 Citation Subset: IM |
Affiliation:
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Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 751 24 Uppsala, Sweden. Ulrika.Wahlby@farmbio.uu.se |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Analysis of Variance Computer Simulation / statistics & numerical data Humans Injections, Intravenous / statistics & numerical data Likelihood Functions Models, Statistical* Nonlinear Dynamics |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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