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RE: Subpopulation

From: Ribbing, Jakob <Jakob.Ribbing>
Date: Tue, 12 Aug 2008 19:52:38 +0100

Dear Huali,


The best is to derive one model for all data. If you are pressed with
time it may be sufficient to describe the data in the dose range which
is clinically relevant (if known). Possibly, in this dose range there is
no nonlinerarity. However, splitting the subjects based on the outcome
is not a good idea. The two models you end up with will both be biased
in the parameter estimates since subjects with e.g. high Km (or slow
absorption/high Vmax) will be more abundant in the linear-kinetics
dataset and vice versa for the nonlinear-kinetics dataset*.
Additionally, without a model it is difficult to distinguish an initial
nonlinearity from the absorption process, so that borderline cases may
end up in the wrong dataset.


The nonlinearity may only be relevant for a subpopulation of your study
subjects. This can be investigated in a mixture model, in case a single
distribution of parameter values can not describe your data. Before
making such an attempt, try to understand the possible sources of
nonlinearity in your specific case, so that the model captures this.


I hope this helps!




*I do not know the source of nonlinearity in the specific case, so this
just to exemplify with nonlinear CL.


From: owner-nmusers
On Behalf Of Huali Wu
Sent: 12 August 2008 17:14
To: nmusers
Subject: [NMusers] Subpopulation


Dear NMusers:


I am trying to fit a dataset with 13 dose levels. The highest dose is
about 10 times of the lowest dose. Each patient receive one dose and
were sampled intensively up to 7 days. The results of individual PK
analysis shown linear kinetics for some of the patients and nonlinear
kinetics for the other patients. I have tried to fit all of them
together. But my advisor wants me to fit linear patients and nonlinear
patients separately to get a better look of fitting.


Additionally, all the nonlinear patients are from higher dose levels.
But not all the patients in higher dose levels shown nonlinear kinetics.
So my question is which way is more appropriate in this case? Should I
fit them all together or separately? Could these two types of patients
be considered as subpopulations?


Any comment or suggestion will be highly appreciated.


Best regards,




Received on Tue Aug 12 2008 - 14:52:38 EDT

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