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: owner-nmus...@globomaxnm.com [mailto:owner-nmus...@globomaxnm.com] On Behalf Of Leonid Gibiansky Sent: 19 September 2013 21:33 To: benjamin.we...@boehringer-ingelheim.com Cc: nmusers@globomaxnm.com 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, benjamin.we...@boehringer-ingelheim.com 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:benjamin.we...@boehringer-ingelheim.com > > 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. >
