NONMEM Users Network Archive

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RE: Unexpected influence of parameter order on estimation results

From: Elassaiss - Schaap, J. - <jeroen.elassaiss>
Date: Fri, 18 Jun 2010 08:51:21 +0200

Hi Sebastien,

While I do not know about the reasons, I have been told about this a
long ago: Vladimir Piotrovskij tought me to keep thetas in pristine
order approx. 7 years ago. The order of etas apparently does not matter.
And I have been coding accordingly ever since. Perhaps it is no issue
anymore after Bob's rewrite of NM7, but I have not tested it. Anyone?

Best whishes,
Jeroen

Modeling & Simulation Expert
Pharmacokinetics, Pharmacodynamics & Pharmacometrics (P3) - DMPK
MSD
PO Box 20 - AP1112
5340 BH Oss
The Netherlands
jeroen.elassaiss
T: +31 (0)412 66 9320
F: +31 (0)412 66 2506
www.msd.com

-----Original Message-----
From: owner-nmusers
On Behalf Of Sebastien.Bihorel
Sent: Friday, 18 June, 2010 4:05
To: nmusers
Subject: [NMusers] Unexpected influence of parameter order on estimation
results

Dear NMusers,

I always thought that the order in which parameters are declared in the
control stream has no impact on the estimation outcomes, but the
following results seem to contradict this.
The PK of drug X was modeled with a linear 3-compartment model using a
proportional residual variability model. Inter-individual variability
was estimated on elimination clearance and central volume of
distribution. The magnitude of residual variability was estimated using
a THETA and a SIGMA fixed to 1 as follows:

$ERROR
IPRED=F
CV=THETA(x)
W=CV*IPRED
Y=IPRED+W*EPS(1)

Two versions of this model were created with slight differences in the
order of declaration of the theta parameters: the theta used to estimate
the RV was basically moved from the third to the last position and the
$PK and the $ERROR blocks were updated accordingly.

Both models were run with NONMEM 6.2.0 on opensuse 11.1 (with the
gfortran compiler). One of the models converged successfully while the
other stopped at an early iteration and returned some estimation
warnings and a 'S matrix singular' message. The strange thing is that
gradients appears identical until the 10th iteration, at which point the
two models take different search paths (see below).

I would be very interested to know the opinion of the group on this
puzzling result.

Thanks

Sebastien
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Received on Fri Jun 18 2010 - 02:51:21 EDT

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