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Diagnosing Model Diagnostics
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2007 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6519, Vol. 82, 17-20 p.Article in journal (Refereed) Published
Abstract [en]

Conclusions from clinical trial results that are derived from model-based analyses rely on the model adequately describing the underlying system. The traditionally used diagnostics intended to provide information about model adequacy have seldom discussed shortcomings. Without an understanding of the properties of these diagnostics, development and use of new diagnostics, and additional information pertaining to the diagnostics, there is risk that adequate models will be rejected and inadequate models accepted. Thus, a diagnosis of available diagnostics is desirable.

Place, publisher, year, edition, pages
2007. Vol. 82, 17-20 p.
Keyword [en]
Clinical Trials as Topic/*methods/statistics & numerical data, Computer Graphics, Computer Simulation, Data Interpretation; Statistical, Humans, Models; Biological, Models; Statistical, Nonlinear Dynamics, Regression Analysis, Reproducibility of Results, Research Design
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-97516DOI: 10.1038/sj.clpt.6100241PubMedID: 17571070OAI: oai:DiVA.org:uu-97516DiVA: diva2:172495
Available from: 2008-09-12 Created: 2008-09-12 Last updated: 2010-04-27Bibliographically approved
In thesis
1. Improved pharmacometric model building techniques
Open this publication in new window or tab >>Improved pharmacometric model building techniques
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Pharmacometric modelling is an increasingly used method for analysing the outcome from clinical trials in drug development. The model building process is complex and involves testing, evaluating and diagnosing a range of plausible models aiming to make an adequate inference from the observed data and predictions for future studies and therapy.

The aim of this thesis was to advance the approaches used in pharmacometrics by introducing improved models and methods for application in essential parts of model building procedure: (i) structural model development, (ii) stochastic model development and (iii) model diagnostics.

As a contribution to the structural model development, a novel flexible structural model for drug absorption, a transit compartment model, was introduced and evaluated. This model is capable of describing various drug absorption profiles and yet simple enough to be estimable from data available from a typical trial. As a contribution to the stochastic model development, three novel methods for parameter distribution estimation were developed and evaluated; a default NONMEM nonparametric method, an extended grid method and a semiparametric method with estimated shape parameters. All these methods are useful in circumstances when standard assumptions of parameter distributions in the population do not hold. The new methods provide less biased parameter estimates, better description of variability and better simulation properties of the model. As a contribution to model diagnostics, the most commonly used diagnostics were evaluated for their usefulness. In particular, diagnostics based on individual parameter estimates were systematically investigated and circumstances which are likely to misguide modelers towards making erroneous decisions in model development, relating to choice of structural, covariate and stochastic model components were identified.

In conclusion, novel approaches, insights and models have been provided to the pharmacometrics community.

Implementation of these advances to make model building more efficient and robust has been facilitated by development of diagnostic tools and automated routines.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 98 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 80Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 80
Model building, Absorption model, Transit compartment model, Nonparametric method, Extended grid method, Semiparametric, Distribution transformation, Shrinkage, Model diagnostics
urn:nbn:se:uu:diva-9272 (URN)978-91-554-7275-7 (ISBN)
Public defence
2008-10-03, Room B41, BMC, Uppsala, 09:15
Available from: 2008-09-12 Created: 2008-09-12Bibliographically approved

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