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From: Nick Holford <n.holford>
Date: Tue, 22 Jul 2008 21:30:25 +1200


Its not clear to me if you did a VPC (visual predictive check) using
just the final estimates of the parameters) or tried to do a posterior
predictive check (PPC) including uncertainty on the parameter estimates
in the simulation.

I dont have any experience with PPC but I dont think its helpful for
model evaluation. Its more of a tool for understanding uncertainties of
predictions for future studies.

I assume you dont have complications like informative dropout processes
to complicate the simulation so if you did a VPC and the median of the
predictions doesnt match the median of the observations then your model
needs more work.

Some negative concs are OK but 'impossibly high values' point to
problems with your model.

So I think you can safely say the VPC has worked very well -- it has
told you that you need to think more about your model. You might find
some ideas in these references:

1. Tod M, Jullien V, Pons G. Facilitation of drug evaluation in
children by population methods and modelling. Clin Pharmacokinet.
2. Anderson BJ, Holford NH. Mechanism-Based Concepts of Size and
Maturity in Pharmacokinetics. Annu Rev Pharmacol Toxicol. 2008;48:303-32.


Paul Matthew Westwood wrote:
> Hello all,
> I wonder if someone can give me some tips on PPC.
> I am working on a midazolam dataset with a pediatric population, and have decided to use PPC as a model validation technique. The dataset I am modelling has up to 43 patients, at different ages, different weights, different times of dosing and sampling, and different doses. I simulated 100 datasets using NONMEM VI, fixing all parameters to the final estimates from the model. The simulated datasets produced had a large proportion of negative concentrations, and also a few impossibly large concentration values. Also the median, 5th and 95th percentiles were not very promising, and the resulting graphs not very clean.
> Firstly, can I use PPC with any degree of confidence with a dataset such as this, and if so, do I omit the negative concentration values from the analysis?
> Thanks in advance for any help given.
> Paul Westwood,
> PhD Student,
> QUB,
> Belfast.

Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand

Received on Tue Jul 22 2008 - 05:30:25 EDT

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