Re: Time-to-event analysis with $DES
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
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