Hi Hyewon My 2 cents of advice: 1. Note that you need to estimate the baseline hazard. You can then add AUC as a covariate on the baseline hazard, or perhaps the Weibull shape factor. 2. Because of my limited experience, I am not sure of the type of survival distribution you are trying to model, but if it is a Weibull distribution, I would write the code as follows: $PK IF(NEWIND.LE.1) OT=0 ; OT is zero at start for each individual
HAZBASE=THETA(X)*EXP(ETA(X)) ; baseline hazard for RTTE ALPH=THETA(Y) ; weibull shape parameter EFF=HAZBASE*(1-AUC/(EC+AUC) ; Imax model on hazbase (or on ALPH if you want) etc $DES DADT(1) = EFF*ALPH*(EFF*(T-OT+DEL))**(ALPH-1) ; HAZARD CHANGES WITH TIME $ERROR OT=TIME ; so that NONMEM remembers this value to subtract at the next record in $DES etc Hope that helps. Regards, Emmanuel >>> Hyewon Kim 03/24/11 1:18 PM >>> Dear NMuser I am trying to analyze time to repeated event data using NONMEM. The response were obtained till 24 hours after drug administration. Inhibitory Emax model was implemented. I am getting unreasonable parameter estimates which is far beyond what data say. If some body can point out what i am doing wrong, it would be very helpful. Thank you in advance. Hyewon Data set (# of observations =62, # of patients=50 ) C ID TIME CS MDV AUC . 101 0 . 1 1.111 . 101 0.05 0 0 1.111 . 101 2 0 0 1.111 . 102 0 . 1 0 . 102 24 1 0 0 . 103 0 . 1 0.999 . 103 0.75 . 0 0.999 .... Model File $PROB RUN# 101 $INPUT C ID TIME CS MDV AUC ;CS:0=having event,1=censored $DATA .data.csv IGNORE=C $SUBROUTINE ADVAN=6 TOL=6 $MODEL COMP=(HAZARD) $PK LAMD=THETA(1)*EXP(ETA(1)) ;scale factor ALPH=THETA(2) ;shape factor EC=THETA(3) ;AUC when effect is half of its max EFF=1-AUC/(EC+AUC) ;drug effect $DES DEL=1E-6 DADT(1)=LAMD*ALPH*(TIME+DEL)**(ALPH-1)*EXP(-LAMD*(TIME+DEL)**ALPH)*EFF $ERROR DEL2=1E-6 IF(NEWIND.NE.2) OLDCHZ=0 CHZ=A(1)-OLDCHZ OLDCHZ=A(1) SUR=EXP(-CHZ) HAZNOW=LAMD*ALPH*(TIME+DEL2)**(ALPH-1)*EXP(-LAMD*(TIME+DEL2)**ALPH)*EFF IF(CS.EQ.1) Y=SUR ;survival prob of censored IF(CS.EQ.0) Y=SUR*HAZNOW ;pdf of event $THETA (0,10) ;[scale factor] (0,1.0) ;[shaph factor] (0,0.01) ;[AUC at half of Emax] $OMEGA 0.01 ;[p] omega(1,1) $EST METHOD=COND LIKE LAPLACIAN PRINT=5 SIG=3 MAX=9999 MSFO=101.msf $COV PRINT=E $TABLE ID TIME SUR AUC ONEHEADER NOPRINT FILE=101.tab ### UNIVERSITY OF CAPE TOWN This e-mail is subject to the UCT ICT policies and e-mail disclaimer published on our website at http://www.uct.ac.za/about/policies/emaildisclaimer/ or obtainable from +27 21 650 9111. This e-mail is intended only for the person(s) to whom it is addressed. If the e-mail has reached you in error, please notify the author. If you are not the intended recipient of the e-mail you may not use, disclose, copy, redirect or print the content. If this e-mail is not related to the business of UCT it is sent by the sender in the sender's individual capacity. ###
