RE: Parameter Estimation in IF Conditioning Statement
Dear All,
First, I would like to thank you all you quick responses. My main interest was
to discuss the estimabiltiy of a parameter that only occurs in the IF
conditioning statement. The part of the code that I provided was simplified and
I never meant to claim that both parts were identical. I really appreciate the
additional insight that has been given though.
I would like to follow-up on some points.
@ Luann: Incorporating the part into the code that you suggested does not
resolve the issue that THRESH=THETA(1) is not estimated. Possibly for the
reason that Leonid pointed out?
@ Leonid: The observed CONC variable is as continuous as a (theoretically)
continuous random variable can be over a range of approximately 20 units and
approximately 500 samples. I agree that in a certain sense all observed
variables are discrete. Which brings me back to my initial questions that
having a statement like ' Y=THETA(1) IF(X.LT.Y)' and having Y not appear
anywhere else in the code causes problems for NONMEN? The reasoning that you
have been given makes sense to me even though I would not have expected it as I
assumed that NONMEM also tries larger variable changes.
@ Nick: Thanks for pointing out the CAVEAT that ODE should be used when using a
time-varying covariate affects parameters in a disease progression model. I
have gone through your slides several times and I consider them as very
helpful. In this case, CONC=WCMIN is constant within a subject and I decided to
use $PRED for reducing the run times. In fact, when using ODE with a time
varying CONC2, the same holds true for the estimability of THETA(1)=THRESH.
Mit freundlichen Grüßen / Kind regards,
Dr. Benjamin Weber
Boehringer Ingelheim Pharma GmbH & Co. KG
Translational Medicine
Tel.: +49 (7351) 54-143520
Fax: +49 (7351) 83-143520
mailto:[email protected]
Boehringer Ingelheim Pharma GmbH & Co. KG, Sitz: Ingelheim am Rhein;
Registergericht Mainz: HR A 22206; Komplementär Boehringer Ingelheim
Deutschland GmbH; Geschäftsführung: Dr. Engelbert Günster (Vorsitzender),
Ursula Fuggis-Hahn, Ralf Gorniak, Michael Klein, Dr. Martin Wanning;
Vorsitzender des Aufsichtsrates: Dr. Joachim Hasenmaier; Sitz: Ingelheim am
Rhein; Registergericht Mainz: HR B 23260
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Quoted reply history
-----Original Message-----
From: Mats Karlsson [mailto:[email protected]]
Sent: Freitag, 20. September 2013 08:12
To: 'Leonid Gibiansky'; Weber,Dr.,Benjamin (TransMed) BIP-DE-B
Cc: [email protected]
Subject: RE: [NMusers] Parameter Estimation in IF Conditioning Statement
Dear Benjamin and Leonid,
Although a steep sigmoidal Emax function often works well to approximate a
step function, the rate of change is quite dependent on the value of the X
variable. Another function (below) has some advantages. For details, see
Henin et al., AAPS J. 2012 Jun;14(2):155-63.
A mechanism-based approach for absorption modeling: the Gastro-Intestinal
Transit Time (GITT) model.
STEP = EXP(X*GAM)/(EXP(X*GAM)+EXP(X50*GAM))
Where X50 (inflection point) would be estimated and GAM (steepness)
typically fixed.
Best regards,
Mats
Mats Karlsson, PhD
Professor of Pharmacometrics
Dept of Pharmaceutical Biosciences
Faculty of Pharmacy
Uppsala University
Box 591
75124 Uppsala
Phone: +46 18 4714105
Fax + 46 18 4714003
www.farmbio.uu.se/research/researchgroups/pharmacometrics/
-----Original Message-----
From: [email protected] [mailto:[email protected]] On
Behalf Of Leonid Gibiansky
Sent: 19 September 2013 21:33
To: [email protected]
Cc: [email protected]
Subject: Re: [NMusers] Parameter Estimation in IF Conditioning Statement
Hi Benjamin
I think the problem was that when nonmem tested small variations of
THETA(1) in the first version, nothing changed in the OF as these variation
have not resulted in the change in the IF conditions (e.g., if your data
contained WCMIN values 1 and 2 and nothing in between, and
THETA(1) was 1.5, changes of THETA(1) to 1.6 or 1.4 were not resulting in
the changes in OF, gradient was zero, and the gradient method was unable to
move the model. When you put theta(1) in the centering, this resulted in
changes of OF. This is not an unusual behavior. Therefore, it is better to
use continuous functions rather than switches. For example, you can code it
as
INT = THETA(4)+(THETA(5)-THETA(4))/(1+(THETA(1)/WCMIN)**GAM)
SLOPE = THETA(3)+INT*CONC+ETA(2)
When GAM is infinity, this is equivalent to your model. You may use large
GAM (or even estimated GAM)
Leonid
--------------------------------------
Leonid Gibiansky, Ph.D.
President, QuantPharm LLC
web: www.quantpharm.com
e-mail: LGibiansky at quantpharm.com
tel: (301) 767 5566
On 9/19/2013 2:31 PM, [email protected] wrote:
> Dear NONMEM users,
>
> My goal was to add a drug effect to a disease progression model in a
> way that the drug effect is different when a certain threshold
> concentration is exceeded (similarly to modeling a 'hockey-stick' when
> performing covariate analysis). First, I did it in the following way
> (partial simplified code)
>
> $PRED
>
> THRESH = THETA(1) ;threshold concentration
>
> INT = THETA(2)+ ETA(1)
>
> IF(WCMIN.LE.THRESH) SLOPE = THETA(3)+THETA(4)*CONC+ETA(2)
>
> IF(WCMIN.GT.THRESH) SLOPE = THETA(3)+THETA(5)*CONC+ETA(2)
>
> IPRED=INT+SLOPE*TIME
>
> and NONMEM did not manage to estimate THRESH=THETA(1) (i.e., the
> initial estimate did not change during minimization and the gradient
> was zero throughout). I tried this for several different initial
estimates.
>
> I then centered the observed CONC on THRESH and run the following
> model because colleagues mentioned that they have successfully run a
> 'hockey-stick' estimating the threshold parameter (partial simplified
> code)
>
> IF(WCMIN.LE.THRESH) SLOPE = THETA(3)+THETA(4)*(CONC-THRESH)+ETA(2)
>
> IF(WCMIN.GT.THRESH) SLOPE = THETA(3)+THETA(5)*(CONC- THRESH)+ETA(2)
>
> This time, NONMEM provided very reasonable estimates for all model
> parameters and the covariance step was successful.
>
> I wonder now if the centering of the variable (and hence something
> particular to the data set) caused the difference in estimability of
> the threshold parameter or whether NONMEN cannot estimate parameters
> that only occur in the conditioning part of the IF statement (Note
> that after centering THRESH also appears in another part of the code).
>
> Could somebody please provide some insight on this? I have searched in
> the NONMEM user group but could not find anything.
>
> Mit freundlichen Grüßen / Kind regards, Dr. Benjamin Weber
>
> Boehringer Ingelheim Pharma GmbH & Co. KG Translational Medicine
> Tel.: +49 (7351) 54-143520
> Fax: +49 (7351) 83-143520
> mailto:[email protected]
>
> Boehringer Ingelheim Pharma GmbH & Co. KG, Sitz: Ingelheim am Rhein;
> Registergericht Mainz: HR A 22206; Komplementär Boehringer Ingelheim
> Deutschland GmbH; Geschäftsführung: Dr. Engelbert Günster
> (Vorsitzender), Ursula Fuggis-Hahn, Ralf Gorniak, Michael Klein, Dr.
> Martin Wanning; Vorsitzender des Aufsichtsrates: Dr. Joachim
> Hasenmaier;
> Sitz: Ingelheim am Rhein; Registergericht Mainz: HR B 23260
>
> Diese E-Mail ist vertraulich zu behandeln. Sie kann besonderem
> rechtlichem Schutz unterliegen. Wenn Sie nicht der richtige Adressat
> sind, senden Sie bitte diese E-Mail an den Absender zurück, löschen
> die eingegangene E-Mail und geben den Inhalt der E-Mail nicht weiter.
> Jegliche unbefugte Bearbeitung, Nutzung, Vervielfältigung oder
> Verbreitung ist verboten. / This e-mail is confidential and may also
> be legally privileged. If you are not the intended recipient please
> reply to sender, delete the e-mail and do not disclose its contents to
> any person. Any unauthorized review, use, disclosure, copying or
> distribution is strictly prohibited.
>