Dear Nick and Joachim,
thanks a lot for your reply. I corrected the code to TOL=7 and NSIG=2/SIGL=6
as well as to
DADT(5)=BLHAZ*EXP(BETA*DPRG) ; CUMULATIVE HAZARD (instead of my assumption of
HAZ)
but I have still the ERROR message:
CONDITIONAL LIKELIHOOD SET TO NEGATIVE VALUE
WITH INDIVIDUAL 1 (IN INDIVIDUAL RECORD ORDERING), DATA RECORD 1
Do you have any idea what that means?
Is it possible that I have insufficient information to make a TTE analysis?
Best regards,
Friederike
-----Ursprüngliche Nachricht-----
Von: [email protected] [mailto:[email protected]] Im
Auftrag von Nick Holford
Gesendet: Montag, 15. August 2011 11:55
An: nmusers
Betreff: Re: [NMusers] Time to Event Model
Friederike,
I have not tried to understand all the details of your model but the
most obvious problem is the way you obtain the cumulative hazard.
Remove the initialization A_0(5)=BLHAZ. The cumulative hazard starts at
zero.
The hazard in $DES must be the same as the hazard for HAZNOW.
Change
DADT(5)=BETA*DPRG ; HAZARD RATE
to
DADT(5)=BLHAZ*EXP(BETA*DPRG) ; HAZARD RATE
Nick
Quoted reply history
On 15/08/2011 8:55 p.m., Friederike Kanefendt wrote:
>
> Dear NMusers,
>
> I try to model the influence of an intervention on Time-To-Event
> (disease progression) data with NM7 based on the presentation of Nick
> Holford (PAGE 2011).
>
> One problem might be that I have only data from 21 patients with 11
> event data (DV=1) and 10 right censored data (DV=0)...
>
> The treatment influences the hazard rate.
>
> (h(t)=h_0 (t)*exp(BETA*X).
>
> For X I tested disease progression (DPRG) -affected by ON or OFF
> treatment-, free drug concentration (C), or the AUC at steady state
> (AUC_SS).
>
> Unfortunately, the estimation aborted with different ERROR messages:
>
> 1) for Concentration
>
> NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE.
>
> NO. OF REQUIRED SIGNIFICANT DIGITS IN SOLUTION VECTOR
>
> TO DIFFERENTIAL EQUATIONS, 4, MAY BE TOO LARGE.
>
> 0PROGRAM TERMINATED BY OBJ
> --> setting
> TOL to lower values has no influence
>
> 2) for AUC_SS and DPRG
>
> CONDITIONAL LIKELIHOOD SET TO NEGATIVE VALUE
>
> WITH INDIVIDUAL 1 (IN INDIVIDUAL RECORD ORDERING), DATA RECORD 1
>
> Does someone have experience with that kind of error or have any idea
> what could be the problem?
>
> Attached you find my control file and a part of the structure of the
> data set
>
> Thanks in advance.
>
> Best regards,
>
> Friederike
>
> I have a data set with dosing events and dummy observations for the PK
> model as well as one row with event/exclusion
>
> ID TIME AMT DV MDV CLx Vx ...
>
> 1, 0, 50, 0, 1, 30, 2000
>
> 1, 23.83, 0, 0, 1, 30, 2000
>
> 1, 24, 50, 0, 1, 30, 2000
>
> 1, 47.83, 0, 0, 1, 30, 2000
>
> 1, 48, 50, 0, 1, 30, 2000
>
> ...
>
> 1, 8280, 0, 1, 0, 30, 2000 ; progression (event)
>
> 2, 0, 50, 0, 1, 35, 1800
>
> 2, 23.83, 0, 0, 1, 35, 1800
>
> 2, 24, 50, 0, 1, 35, 1800
>
> 2, 47.83, 0, 0, 1, 35, 1800
>
> 2, 48, 50, 0, 1, 35, 1800
>
> ...
>
> 2, 4236, 0, 0, 0, 35, 1800 ; censored
>
> ...
>
> $INPUT ID TIME AMT DV MDV CLx Vx ...
>
> $DATA data.csv
>
> $SUBROUTINE ADVAN6 TOL=4
>
> $MODEL
>
> NCOMP=5
>
> COMP=(DEPOT)
>
> COMP=(CENTRAL)
>
> COMP=(PERI)
>
> COMP=(MET)
>
> COMP=(HAZ)
>
> $THETA (0,0.5) ; 1 TH_BLHAZ - Baseline Hazard
>
> $THETA (0.01) ; 2 TH_BETA - Factor
>
> $THETA (5) ; 3 TH_EFFECT
>
> $THETA (0,5) ; 4 TH_INTRI
>
> $THETA (0,0.5) ; 5 TH_SLOPE
>
> $OMEGA 0 FIX ; 1 ETA_HAZ
>
> $OMEGA 0.1 ; 2 ETA_BETA
>
> $OMEGA 0.1 ; 3 ETA_EFFECT
>
> $OMEGA 0.1 ; 4 ETA_INTRI
>
> $OMEGA 0.1 ; 5 ETA_SLOPE
>
> $PK
>
> ;HAZARD
>
> TVBLHAZ = THETA(1)
>
> BLHAZ = TVBLHAZ*EXP(ETA(1))
>
> TVBETA = THETA(2)
>
> BETA = TVBETA*EXP(ETA(2))
>
> ;SYMPTOMATIC TREATMENT EFFECT
>
> EFFECT = THETA(3)*EXP(ETA(3)) ; TREATMENT EFFECT FACTOR
>
> ;DISEASE PROGRESS
>
> INTRI = THETA(4)*EXP(ETA(4)) ; INTERCEPT OF DISEASE PROGRESSION
>
> SLOPE = THETA(5)*EXP(ETA(5)) ; SLOPE OF DISEASE PROGRESSION
>
> ;PHARMACOKINETIC
>
> ...
>
> ;EXPOSURE OF TOTAL DRUG AT STEADY-STATE
>
> AUC_SS = DOSE/CLx+DOSE/CLM
>
> A_0(5)=BLHAZ
>
> $DES
>
> ...
>
> C=A(2)/V1+A(4)/VM
>
> IF(C.GE.50) THEN ; EFFECTIVE CONCENTRATION
>
> TREA = 1
>
> ELSE
>
> TREA = 0
>
> ENDIF
>
> INTRC = INTRI-EFFECT*TREA
>
> DPRG = INTRC+SLOPE*T
>
> DADT(5)=BETA*DPRG ; HAZARD RATE
>
> ;DADT(5)=BETA*C
>
> ;DADT(5)=BETA*AUC_SS
>
> $ERROR
>
> CUB = A(2)/V1+A(4)/VM
>
> CUMHAZ = A(5) ; CUMULATIVE HAZARD
>
> ;EFFECTIVE CONCENTRATION
>
> IF(CUB.GE.50) THEN ; CONC EFFECTIVE
>
> TREAT = 1
>
> ELSE
>
> TREAT = 0
>
> ENDIF
>
> INTR = INTRI-EFFECT*TREAT ; INTERCEPT OF DISEASE PROGRESSION
>
> DISPRG = INTR+SLOPE*TIME
>
> SURV = EXP(-CUMHAZ) ; SURVIVAL FUNCTION -
> probability not to have an event
>
> IF(DV.EQ.1) THEN ; EVENT
>
> HAZNOW = BLHAZ*EXP(BETA*DISPRG) ; HAZARD RATE AT THAT TIME
>
> Y = HAZNOW*SURV ; PDF - PROBABILITY
> DENSITY FUNCTION
>
> ELSE ;
> CENSORED
>
> Y = SURV
>
> ENDIF
>
> $ESTIMATION SIG=3 SIGL=9 MAXEVAL=9990 METHOD=COND LAPLACE LIKE PRINT=1
>
> $COVARIANCE PRINT=E
>
> $TABLE ID TIME BLHAZ SURV HAZNOW CUMHAZ NOPRINT ONEHEADER NOAPPEND
> FILE=PATAB
>
> Friederike Kanefendt
>
> - PhD-Student -
>
> University of Bonn, Germany
>
> -Clinical Pharmacy-
>
> Phone: +49 (0)228 73-5781
>
> Fax: +49(0) 228 73-9757
>
> [email protected]
>
--
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: [email protected]
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford