Dear all, Thank you for your thoughtful advice. It helps a lot.
Hyewon. On Thu, Mar 24, 2011 at 1:53 AM, Nick Holford <n.holf...@auckland.ac.nz>wrote: > Hyewon, > > Sorry -- I just realized that EFF is not the drug effect but 1-drug effect > so that it has a value of 1 when AUC is zero. Please ignore my remarks about > EFF being zero when AUC is zero in my comments below and consider this code > to describe the effect of AUC on hazard: > > HAZNOW=LAMD*ALPH*(TIME+DEL2)**(ALPH-1)*(1-BETAE*AUC/(EC+AUC)) > > I think it is a very strong assumption that the drug will reduce the hazard > to zero at infinite AUC which you can test by estimating a parameter (such > as BETAE). If BETAE is significantly less than 1 then this means the > assumption is not supported. > > Nick > > On 24/03/2011 8:17 a.m., Nick Holford wrote: > > Hyewon, > > The most obvious problem with your code is in $DES. You must use the > variable T not the variable TIME when referring to a time varying hazard. > TIME is the time on each data record. It does not change in $DES. T is the > time from the last data record upto the current data record and changes > within $DES. > > You are predicting the likelihood of an event at the exact time of the > event observation record with multiple events per subject. As you seem to > realize you need to compute the cumulative hazard (CUMHAZ) either from > TIME=0 or from the TIME of the last non-censored event for each subject. > > In my opinion the following code is clearer and less dependent on your data > structure than the method you are using which works only if your data has > just event records after the TIME=0 record. > > IF (MDV.EQ.0.AND.CS.EQ.0) THEN > OLDCHZ=A(1) ; cum haz upto time of this event > ELSE > OLDCHZ=OLDCHZ ; need to do this if OLDCHZ is a random variable > ENDIF > > Your hazard model looks rather complicated. It seems to be based on the > product of a Weibull baseline hazard > LAMD*ALPH*(TIME+DEL2)**(ALPH-1) > then something odd involving the Weibull parameters > *EXP(-LAMD*(TIME+DEL2)**ALPH) > and then forces the hazard to be zero if AUC is zero. > *EFF > Is this really what you want? Do you know the hazard of event is zero if > AUC is zero? Or is the last right parenthesis in the wrong place? > > I would suggest something like this where LAMD and ALPH are the two > parameters of the Weibull baseline hazard (when AUC is zero) and BETAE is a > parameter describing the effect of the drug on the overall hazard. > > HAZNOW=LAMD*ALPH*(TIME+DEL2)**(ALPH-1)*EXP(BETAE*EFF) > > You may also find it easier to develop the model if you do not try to > estimate a random effect on LAMD until you have got reasonable estimates for > the other parameters. > > You may find it helpful to look at this presentation showing how to code > time to event models in NM-TRAN: > http://pkpdrx.com/holford/docs/time-to-event-analysis.pdf > > Best wishes, > > Nick > > On 24/03/2011 3:25 a.m., Hyewon Kim wrote: > > 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 > > > -- > Nick Holford, Professor Clinical Pharmacology > Dept Pharmacology & Clinical Pharmacology > University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand > tel:+64(9)923-6730 fax:+64(9)373-7090 mobile:+64(21)46 23 53 > email: > n.holf...@auckland.ac.nzhttp://www.fmhs.auckland.ac.nz/sms/pharmacology/holford > > > -- > Nick Holford, Professor Clinical Pharmacology > Dept Pharmacology & Clinical Pharmacology > University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand > tel:+64(9)923-6730 fax:+64(9)373-7090 mobile:+64(21)46 23 53 > email: > n.holf...@auckland.ac.nzhttp://www.fmhs.auckland.ac.nz/sms/pharmacology/holford > >
