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.
