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Re: Questions about identifiability

From: Amy Cheung <sya.cheung>
Date: Fri, 13 Apr 2007 09:44:47 +0100

Dear Silke,

Before looking into the identifiability question, it is useful to know
what the differential equations and the dosing route are, please?

Kind regards,


S.Y.A. Cheung
Postgraduate Research Student
The Centre for Applied Pharmacokinetic Research (CAPKR)
School of Pharmacy and Pharmaceutical Sciences
University of Manchester
Stopford Building
Oxford Road


On 13/04/07, Silke.Dittberner
> Dear NONMEM users,
> The PK of the compound we are working on can be described by a 2-compartm=
> model with non–linear protein binding in the central and in the periphe=
> compartment, which from a physiological point of view makes complete sens=
> The question we have is whether such model is identifiable having just to=
> plasma concentration (no binding information is available).
> Therefore we want to simulate different kind of datasets and check if NON=
> is able to re-estimate them properly.
> · Our first question was: "Is the structure itself in principle
> identifiable?"
> We simulated a dataset with 100 time points per subject and no
> intra- or inter-individual variability and no residual error. ('ideal' da=
> plenty time points, no random error) Since under these conditions th=
> parameters could be re-estimated (parameter estimates were nearly identic=
> to the original ones, %SE is very small) we concluded that the struct=
> in principle is identifiable.
> · Our second question was: "Are the time points of the given stud=
> sufficient to estimate all parameters assuming 'ideal' data?"
> We simulated the given dataset assuming no intra- or
> inter-individual variability and no residual error. The parameter estimat=
> were again nearly identical to the original ones and %SE is still ver=
> small (below 0.3 %).
> · Our third question was: "Could the parameters still be re-estim=
> if we assume inter- and intra-subject variability for the simulation step=
> We simulated the given dataset assuming IIV, IOV and residual err=
> Under these conditions, the parameter (fixed and random effect) estima=
> are again similar, but not identical to the original ones, %SE increased =
> about 9% (one exception is the SE% of the parameter for the amount =
> peripheral binding sites which were estimated to be 16%). However, when w=
> re-estimate omitting the IIV and IOV, the estimated parameters differ fr=
> the original ones and estimates for the peripheral binding becomes diffic=
> to estimate.
> The questions we have are:
> 1. Are these experiments sufficient to conclude on the model
> identifiability?
> 2. Does it make sense that the fixed effect parameters differ from t=
> original ones when IIV and IOV are omitted in the estimation step in
> constrast to when they are included in the simulation step? Shouldn't the
> structure of the model remain stable?
> 3. How often would you simulate and re-estimate the third experiment=
> 4. Would you vary the initial estimates to check for any potential
> other set of parameters? (If yes how often?)
> 5. One problem is that the complete model with IIV and IOV has quite
> long run times (around 24h), do you think checking the model with just II=
> would be enough?
> 6. Do you have any other proposal to check for the identifiability o=
f a
> model?
> Your help is highly appreciated, thank you in advance,
> Silke
> Silke Dittberner
> PhD student
> Institute of Pharmacy
> University Bonn
> Germany

Received on Fri Apr 13 2007 - 04:44:47 EDT

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