Parameter Estimation in IF Conditioning Statement

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.