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)=h0(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]
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
Dear Frederike,
The error message points you in the right direction. Please, see page 11 of
61 of the Introduction to NONMEM7:
SIGL<=TOL
NSIG<=SIGL/3
You have TOL=4 in $SUB
And you have: $ESTIMATION SIG=3 SIGL=9
You have to resolve this by either increasing TOL to 10 or decreasing NSIG
and SIGL
I have not checked your code in detail, but this would be my first choice
for improvement.
Good luck!
Joachim
Joachim Grevel, PhD
Scientific Director
BAST Inc Limited
BioCity Nottingham
Pennyfoot Street
Nottingham, NG1 1GF
Tel: +44 (0)115 8120497
Quoted reply history
From: [email protected] [mailto:[email protected]] On
Behalf Of Friederike Kanefendt
Sent: 15 August 2011 09:56
To: [email protected]
Subject: [NMusers] Time to Event Model
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)=h0(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]