uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Shrinkage in Nonlinear Mixed-Effects Population Models: Quantification, Influencing Factors, and Impact
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Show others and affiliations
2012 (English)In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 14, no 4, 927-936 p.Article in journal (Refereed) Published
Abstract [en]

Shrinkage of empirical Bayes estimates (EBEs) of posterior individual parameters in mixed-effects models has been shown to obscure the apparent correlations among random effects and relationships between random effects and covariates. Empirical quantification equations have been widely used for population pharmacokinetic/pharmacodynamic models. The objectives of this manuscript were (1) to compare the empirical equations with theoretically derived equations, (2) to investigate and confirm the influencing factor on shrinkage, and (3) to evaluate the impact of shrinkage on estimation errors of EBEs using Monte Carlo simulations. A mathematical derivation was first provided for the shrinkage in nonlinear mixed effects model. Using a linear mixed model, the simulation results demonstrated that the shrinkage estimated from the empirical equations matched those based on the theoretically derived equations. Simulations with a two-compartment pharmacokinetic model verified that shrinkage has a reversed relationship with the relative ratio of interindividual variability to residual variability. Fewer numbers of observations per subject were associated with higher amount of shrinkage, consistent with findings from previous research. The influence of sampling times appeared to be larger when fewer PK samples were collected for each individual. As expected, sample size has very limited impact on shrinkage of the PK parameters of the two-compartment model. Assessment of estimation error suggested an average 1:1 relationship between shrinkage and median estimation error of EBEs.

Place, publisher, year, edition, pages
2012. Vol. 14, no 4, 927-936 p.
Keyword [en]
empirical Bayes estimate, mixed-effects models, population PK/PD, shrinkage
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-187003DOI: 10.1208/s12248-012-9407-9ISI: 000310367100030OAI: oai:DiVA.org:uu-187003DiVA: diva2:573661
Available from: 2012-12-03 Created: 2012-12-03 Last updated: 2017-12-07Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full text

Authority records BETA

Karlsson, Mats O.

Search in DiVA

By author/editor
Karlsson, Mats O.
By organisation
Department of Pharmaceutical Biosciences
In the same journal
AAPS Journal
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 370 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf