From: Batul Parta - batulparta@yahoo.com
Subject: [NMusers] Nonmem model
Date: 12/17/2003 11:51 AM

Dear all,
 
I am having problems getting NM to estimate any
parameters in the following situation. I have data
on bactericidal effects of an antibiotic. The PK is
fixed (one comp.). PD consists of three compartments:
sensitive (comp. 2), non-sensitive (comp. 3), and non-
replicating (comp. 4). PD data are log-transformed in
the data file. My observations are the sum of comps 2
and 4. The nonmem codes are given at the end of this mail.
 
My problem is that NM does not estimate anything but
the two THETAs associated with the error terms. It converges
all right but nothing else is changed from the initial
estimates. In my data file, I have the usual stuff (date,
time, amount) plus a CMT, which is 1 for the dose and 2 for
the first (and only first) PD observation.
 
Beside the model given below, I have tried one with no
log-transformed data as well as one with a hypothetical
compartment which is the sum of compartments 2 and 4. All
have the same problem. Starting with different initial values
doe not help either. 
 
Any suggestions?
 
Best regards and thank you for your help,
 
B. Parta

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From: Leonid Gibiansky - lgibiansky@emmes.com
Subject: Re: [NMusers] Nonmem model
Date: 12/17/2003 12:33 PM

Batul
I think you need initial conditions. As written, A2=A3=A4=0 at
time = 0, is this correct ? Are there any source terms (doses to
compartments 2, 3, or 4)? In not, then zero is the unique solution
of the system for A2, A3, A4. Discrepancy between zero and your 
observations goes into the error term.

What is the intended meaning of:
CMT, which is ... 2 for the first (and only first) PD observation?
I think it will be ignored since you explicitly stated that
VBAC=A(2)+A(4)
IPRD=VBAC

Leonid

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From: Lewis Sheiner - lbs@lewisbsheiner.net
Subject: Re: [NMusers] Nonmem model
Date: 12/17/2003 1:59 PM

 I agree with Leonid: You need a 'dose' of 1 unit into CMT = 2 at
 time 0 so there are some bugs for the drug to kill.
LBS.
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From: Batul Parta - batulparta@yahoo.com
Subject: Re: [NMusers] Nonmem model
Date: 12/19/2003 10:04 AM

Thank you for the suggestions. I entered the first observation as
dose and the model converges, estimating parameters. However, I am
uncertain if the procedure is correct. If the observations are given
as log-transformed data in the data file, what does nonmem add up,
when adding the contents of the 2 compartments? Obviously, one needs
to add the non-transformed DV. Does nonmem read the data file, converts
the log-transformed data in the data file to non-transformed, adds
them, and then transfers back to the log scale?
 
Should I try entering the data as observed (not log-transformed) in the
data file or is there any other way to make nonmem do the correct adding?
 
Once again, thank you for you help! 
 
B. Part
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From: Leonid Gibiansky - lgibiansky@emmes.com
Subject: Re: [NMusers] Nonmem model
Date: 12/19/2003 10:31 AM

NONMEM is not transforming the data. All the computations are done
in the original scale. Log transformation enters the model only here:
IPRED=LOG(IPRD)

Therefore, the dose (the first PD observation in your case) should be
entered in the original scale. All other PD observations should be log-transformed.
Leonid 
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From: GIRARD PASCAL - PASCAL.GIRARD@adm.univ-lyon1.fr
Subject: Re: [NMusers] Nonmem model
Date: 12/20/2003 8:36 AM

All this is a little bit confusing ...

You don't show your $INPUT but I guess (1) you have only one DV which is the log
of your observation and (2) you never observe A(2) and A(4) so (3) your prediction 
is correctly defined as log(A(2)+A(4)) according to the log-transform of your 
DV. NONMEM never does any transformation on the data, unless you use some date
or time format or call the PASS( . ) subroutine,

Bonnes fetes,

Pascal Girard 
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