dear NONMEM community,
The following MESSAGE:
MINIMIZATION SUCCESSFUL
HOWEVER, PROBLEMS OCCURRED WITH THE MINIMIZATION.
REGARD THE RESULTS OF THE ESTIMATION STEP CAREFULLY, AND ACCEPT THEM ONLY
AFTER CHECKING THAT THE COVARIANCE STEP PRODUCES REASONABLE OUTPUT.
...has already been discussed in 2008, and seems to be a computational issue
preventing successful COV (Prof. Nick Holford). I encounter the same problem
with an i.v. Gemcitabine model. COV is successful with GEM and its
metabolite dFdU. However, if I add intracellular triphosphates (dFdCTP),
minimisation is just fine, but no COV. This has persisted after attempts to
simplify model or computation (e.g. fixing ETAs, using just one EPS,
introducing simulated PK-curves (based on PK-estimates) back into the
model). Mass-transport to triphosphate-CMPT is intentionally fixed very low
(low concentrations), and volume-of-distribution of intracellular
triphosphates scaled to V1.
Thanks for support,
kind regards, Markus
--
Markus Joerger MD PhD
Department of Medical Oncology
Rorschacherstr. 95
9007 St. Gallen
[email protected]
[email protected]
phone: +41-765591070
fax: +41-714946368
CONTROL STREAM:
------------------------------
---------------------------------------------------------------------------------------------
$DATA MO5_gem33.CSV IGNORE=C
$SUBROUTINES ADVAN5
$MODEL COMP=(GEM) COMP=(P1) COMP=(dFdU) COMP(dFdCTP)
$PK
TVCL1=THETA(1)
CL1=TVCL1*EXP(ETA(1))
TVV1=THETA(2)
V1=TVV1*EXP(ETA(2))
TVQ1=THETA(3)
Q1=TVQ1*EXP(ETA(3))
TVV2=THETA(4)
V2=TVV2*EXP(ETA(4))
TVCL2=THETA(5)
CL2=TVCL2*EXP(ETA(5))
TVV3=THETA(6)
V3=TVV3*EXP(ETA(6))
TVK40=THETA(7)
K40=TVK40*EXP(ETA(7))
K12=Q1/V1
K21=Q1/V2
K13=CL1/V1
K30=CL2/V3
RF=THETA(8)
K14=0.000001*K13
V4=K14*RF*V1/K13
S1=V1/1000
S3=V3/1000
S4=V4/1000
$ERROR CALLFL=0
IPRE=-3
FLG1=0
FLG3=0
FLG4=0
IF(CMT.EQ.1)FLG1=1
IF(CMT.EQ.3)FLG3=1
IF(CMT.EQ.4)FLG4=1
IF(F.GT.0) IPRE=LOG(F)
Y=LOG(F)+EPS(1)*FLG1+EPS(2)*FLG3+EPS(3)*FLG4
W=LOG(F)
IRES=DV-IPRE
IWRES=IRES/W
$THETA
(0,163) ;CL-gemcitabine.1
(0,11.9) ;V1.2
(0,95.1) ;Q1.3
(0,20) ;V2.4
(0,14.1) ;CL-dFdU.5
(0,28) ;V3.6
(0,0.21) ;K40.7
(0,646) ;RF.8
$OMEGA
0.37 ;CL1.1
0.23 ;V1.2
0.0094 ;Q1.3
0.036 ;V2.4
0.14 ;CL2.5
0.14 ;V3.6
0.27 ;K40.9.7
$SIGMA
0.07 ;IIV-1
0.0355 ;IIV-3
0.757 ;IIV-4
$ESTIMATION PRINT=5 MAXEVAL=3000 METHOD=1
NOABORT POSTHOC SIGDIG=3 MSFO=MSF004BBAB
computational issues preventing COV
Hi Markus
Sometimes you just cannot force $COV to converge using defaults. If you use NONMEM 7, try
$COV UNCONDITIONAL
option
Also, nommem should explain somehow what is wrong (R matrix is singular, parameter is on the boundary, or something similar). If this is the case, then you can try MATRIX=S
Could you provide more details of the output ?
Thanks
Leonid
--------------------------------------
Leonid Gibiansky, Ph.D.
President, QuantPharm LLC
web: www.quantpharm.com
e-mail: LGibiansky at quantpharm.com
tel: (301) 767 5566
markus joerger wrote:
> dear NONMEM community,
>
> The following MESSAGE:
>
> MINIMIZATION SUCCESSFUL
> HOWEVER, PROBLEMS OCCURRED WITH THE MINIMIZATION.
> REGARD THE RESULTS OF THE ESTIMATION STEP CAREFULLY, AND ACCEPT THEM ONLY
> AFTER CHECKING THAT THE COVARIANCE STEP PRODUCES REASONABLE OUTPUT.
>
> ...has already been discussed in 2008, and seems to be a computational issue preventing successful COV (Prof. Nick Holford). I encounter the same problem with an i.v. Gemcitabine model. COV is successful with GEM and its metabolite dFdU. However, if I add intracellular triphosphates (dFdCTP), minimisation is just fine, but no COV. This has persisted after attempts to simplify model or computation (e.g. fixing ETAs, using just one EPS, introducing simulated PK-curves (based on PK-estimates) back into the model). Mass-transport to triphosphate-CMPT is intentionally fixed very low (low concentrations), and volume-of-distribution of intracellular triphosphates scaled to V1.
>
> Thanks for support,
>
> kind regards, Markus
>
> --
> Markus Joerger MD PhD
> Department of Medical Oncology
> Rorschacherstr. 95
> 9007 St. Gallen
> [email protected] <mailto:[email protected]>
> [email protected] <mailto:[email protected]>
> phone: +41-765591070
> fax: +41-714946368
>
> CONTROL STREAM:
> ------------------------------
> ---------------------------------------------------------------------------------------------
>
> $DATA MO5_gem33.CSV IGNORE=C $SUBROUTINES ADVAN5
>
> $MODEL COMP=(GEM) COMP=(P1) COMP=(dFdU) COMP(dFdCTP)
>
> $PK
>
> TVCL1=THETA(1)
> CL1=TVCL1*EXP(ETA(1))
>
> TVV1=THETA(2)
> V1=TVV1*EXP(ETA(2))
>
> TVQ1=THETA(3)
> Q1=TVQ1*EXP(ETA(3))
>
> TVV2=THETA(4)
> V2=TVV2*EXP(ETA(4))
>
> TVCL2=THETA(5)
> CL2=TVCL2*EXP(ETA(5))
>
> TVV3=THETA(6)
> V3=TVV3*EXP(ETA(6))
>
> TVK40=THETA(7)
> K40=TVK40*EXP(ETA(7))
>
> K12=Q1/V1
> K21=Q1/V2
> K13=CL1/V1
> K30=CL2/V3
>
> RF=THETA(8)
>
> K14=0.000001*K13
> V4=K14*RF*V1/K13
>
> S1=V1/1000
> S3=V3/1000
> S4=V4/1000
>
> $ERROR CALLFL=0
> IPRE=-3
> FLG1=0
> FLG3=0
> FLG4=0
> IF(CMT.EQ.1)FLG1=1
> IF(CMT.EQ.3)FLG3=1
> IF(CMT.EQ.4)FLG4=1
> IF(F.GT.0) IPRE=LOG(F)
> Y=LOG(F)+EPS(1)*FLG1+EPS(2)*FLG3+EPS(3)*FLG4
> W=LOG(F)
> IRES=DV-IPRE
> IWRES=IRES/W
>
> $THETA
> (0,163) ;CL-gemcitabine.1
> (0,11.9) ;V1.2
> (0,95.1) ;Q1.3
> (0,20) ;V2.4
> (0,14.1) ;CL-dFdU.5
> (0,28) ;V3.6
> (0,0.21) ;K40.7
> (0,646) ;RF.8
>
> $OMEGA
> 0.37 ;CL1.1
> 0.23 ;V1.2
> 0.0094 ;Q1.3
> 0.036 ;V2.4
> 0.14 ;CL2.5
> 0.14 ;V3.6
> 0.27 ;K40.9.7
>
> $SIGMA
> 0.07 ;IIV-1
> 0.0355 ;IIV-3
>
> 0.757 ;IIV-4
>
> $ESTIMATION PRINT=5 MAXEVAL=3000 METHOD=1
> NOABORT POSTHOC SIGDIG=3 MSFO=MSF004BBAB
Hi Markus,
This message occurs according to the introduction to NM6 guide: "This
may happen when e.g. the final gradient vector is too large". This means
that there is the possibility of some inaccurate covariance matrix, see
also my post in the 2008 discussion that you mentioned
( http://cognigencorp.com/nonmem/current/2008-November/1235.html). So if
in your case the error estimates are in the neigbourhood of expected it
should be no problem.
At the same time this may hint about where in your model some
instability is located. Which parameter is associated with a large final
gradient and why does it have such a small error?
Another option is to rescale your parameters (see
http://www.cognigencorp.com/nonmem/current/2008-January/0772.html) as I
notice a more than 1000-fold ratio between your thetas 7 and 8, even
more between theta8 and omega3. See the discussion in
http://www.page-meeting.org/pdf_assets/4964-Elassaiss-Schaap%20-%20Equat
ions%20variability%20reporting%20PK-PD%20-%20Final.pdf for additional
benefits of log-transforming thetas.
Best regards,
Jeroen
Quoted reply history
-----Original Message-----
From: owner-nmusers
On Behalf Of Leonid Gibiansky
Sent: Sunday, 14 February, 2010 14:52
To: markus joerger
Cc: NONMEM
Subject: Re: [NMusers] computational issues preventing COV
Hi Markus
Sometimes you just cannot force $COV to converge using defaults. If you
use NONMEM 7, try $COV UNCONDITIONAL option Also, nommem should explain
somehow what is wrong (R matrix is singular, parameter is on the
boundary, or something similar). If this is the case, then you can try
MATRIX=S
Could you provide more details of the output ?
Thanks
Leonid
--------------------------------------
Leonid Gibiansky, Ph.D.
President, QuantPharm LLC
web: www.quantpharm.com
e-mail: LGibiansky at quantpharm.com
tel: (301) 767 5566
markus joerger wrote:
> dear NONMEM community,
>
> The following MESSAGE:
>
> MINIMIZATION SUCCESSFUL
> HOWEVER, PROBLEMS OCCURRED WITH THE MINIMIZATION.
> REGARD THE RESULTS OF THE ESTIMATION STEP CAREFULLY, AND ACCEPT THEM
> ONLY AFTER CHECKING THAT THE COVARIANCE STEP PRODUCES REASONABLE
OUTPUT.
>
> ...has already been discussed in 2008, and seems to be a computational
> issue preventing successful COV (Prof. Nick Holford). I encounter the
> same problem with an i.v. Gemcitabine model. COV is successful with
> GEM and its metabolite dFdU. However, if I add intracellular
> triphosphates (dFdCTP), minimisation is just fine, but no COV. This
> has persisted after attempts to simplify model or computation (e.g.
> fixing ETAs, using just one EPS, introducing simulated PK-curves
> (based on PK-estimates) back into the model). Mass-transport to
> triphosphate-CMPT is intentionally fixed very low (low
> concentrations), and volume-of-distribution of intracellular
triphosphates scaled to V1.
>
> Thanks for support,
>
> kind regards, Markus
>
>
> --
> Markus Joerger MD PhD
> Department of Medical Oncology
> Rorschacherstr. 95
> 9007 St. Gallen
> markus.joerger
> markus.joerger
> phone: +41-765591070
> fax: +41-714946368
>
>
> CONTROL STREAM:
> ------------------------------
> ----------------------------------------------------------------------
> -----------------------
>
> $DATA MO5_gem33.CSV IGNORE=C
> $SUBROUTINES ADVAN5
> $MODEL COMP=(GEM) COMP=(P1) COMP=(dFdU) COMP(dFdCTP)
>
> $PK
>
> TVCL1=THETA(1)
> CL1=TVCL1*EXP(ETA(1))
>
> TVV1=THETA(2)
> V1=TVV1*EXP(ETA(2))
>
> TVQ1=THETA(3)
> Q1=TVQ1*EXP(ETA(3))
>
> TVV2=THETA(4)
> V2=TVV2*EXP(ETA(4))
>
> TVCL2=THETA(5)
> CL2=TVCL2*EXP(ETA(5))
>
> TVV3=THETA(6)
> V3=TVV3*EXP(ETA(6))
>
> TVK40=THETA(7)
> K40=TVK40*EXP(ETA(7))
>
> K12=Q1/V1
> K21=Q1/V2
> K13=CL1/V1
> K30=CL2/V3
>
> RF=THETA(8)
>
> K14=0.000001*K13
> V4=K14*RF*V1/K13
>
> S1=V1/1000
> S3=V3/1000
> S4=V4/1000
>
> $ERROR CALLFL=0
> IPRE=-3
> FLG1=0
> FLG3=0
> FLG4=0
> IF(CMT.EQ.1)FLG1=1
> IF(CMT.EQ.3)FLG3=1
> IF(CMT.EQ.4)FLG4=1
> IF(F.GT.0) IPRE=LOG(F)
> Y=LOG(F)+EPS(1)*FLG1+EPS(2)*FLG3+EPS(3)*FLG4
> W=LOG(F)
> IRES=DV-IPRE
> IWRES=IRES/W
>
> $THETA
> (0,163) ;CL-gemcitabine.1
> (0,11.9) ;V1.2
> (0,95.1) ;Q1.3
> (0,20) ;V2.4
> (0,14.1) ;CL-dFdU.5
> (0,28) ;V3.6
> (0,0.21) ;K40.7
> (0,646) ;RF.8
>
> $OMEGA
> 0.37 ;CL1.1
> 0.23 ;V1.2
> 0.0094 ;Q1.3
> 0.036 ;V2.4
> 0.14 ;CL2.5
> 0.14 ;V3.6
> 0.27 ;K40.9.7
>
> $SIGMA
> 0.07 ;IIV-1
> 0.0355 ;IIV-3
> 0.757 ;IIV-4
>
> $ESTIMATION PRINT=5 MAXEVAL000 METHOD=1
> NOABORT POSTHOC SIGDIG=3 MSFO=MSF004BBAB
This message and any attachments are solely for the intended recipient. If you are not the intended recipient, disclosure, copying, use or distribution of the information included in this message is prohibited --- Please immediately and permanently delete.
Hi Markus,
This message occurs according to the introduction to NM6 guide: "This
may happen when e.g. the final gradient vector is too large". This means
that there is the possibility of some inaccurate covariance matrix, see
also my post in the 2008 discussion that you mentioned
( http://cognigencorp.com/nonmem/current/2008-November/1235.html). So if
in your case the error estimates are in the neigbourhood of expected it
should be no problem.
At the same time this may hint about where in your model some
instability is located. Which parameter is associated with a large final
gradient and why does it have such a small error?
Another option is to rescale your parameters (see
http://www.cognigencorp.com/nonmem/current/2008-January/0772.html) as I
notice a more than 1000-fold ratio between your thetas 7 and 8, even
more between theta8 and omega3. See the discussion in
http://www.page-meeting.org/pdf_assets/4964-Elassaiss-Schaap%20-%20Equat
ions%20variability%20reporting%20PK-PD%20-%20Final.pdf for additional
benefits of log-transforming thetas.
Best regards,
Jeroen
Quoted reply history
-----Original Message-----
From: [email protected] [mailto:[email protected]]
On Behalf Of Leonid Gibiansky
Sent: Sunday, 14 February, 2010 14:52
To: markus joerger
Cc: NONMEM
Subject: Re: [NMusers] computational issues preventing COV
Hi Markus
Sometimes you just cannot force $COV to converge using defaults. If you
use NONMEM 7, try $COV UNCONDITIONAL option Also, nommem should explain
somehow what is wrong (R matrix is singular, parameter is on the
boundary, or something similar). If this is the case, then you can try
MATRIX=S
Could you provide more details of the output ?
Thanks
Leonid
--------------------------------------
Leonid Gibiansky, Ph.D.
President, QuantPharm LLC
web: www.quantpharm.com
e-mail: LGibiansky at quantpharm.com
tel: (301) 767 5566
markus joerger wrote:
> dear NONMEM community,
>
> The following MESSAGE:
>
> MINIMIZATION SUCCESSFUL
> HOWEVER, PROBLEMS OCCURRED WITH THE MINIMIZATION.
> REGARD THE RESULTS OF THE ESTIMATION STEP CAREFULLY, AND ACCEPT THEM
> ONLY AFTER CHECKING THAT THE COVARIANCE STEP PRODUCES REASONABLE
OUTPUT.
>
> ...has already been discussed in 2008, and seems to be a computational
> issue preventing successful COV (Prof. Nick Holford). I encounter the
> same problem with an i.v. Gemcitabine model. COV is successful with
> GEM and its metabolite dFdU. However, if I add intracellular
> triphosphates (dFdCTP), minimisation is just fine, but no COV. This
> has persisted after attempts to simplify model or computation (e.g.
> fixing ETAs, using just one EPS, introducing simulated PK-curves
> (based on PK-estimates) back into the model). Mass-transport to
> triphosphate-CMPT is intentionally fixed very low (low
> concentrations), and volume-of-distribution of intracellular
triphosphates scaled to V1.
>
> Thanks for support,
>
> kind regards, Markus
>
>
> --
> Markus Joerger MD PhD
> Department of Medical Oncology
> Rorschacherstr. 95
> 9007 St. Gallen
> [email protected] <mailto:[email protected]>
> [email protected] <mailto:[email protected]>
> phone: +41-765591070
> fax: +41-714946368
>
>
> CONTROL STREAM:
> ------------------------------
> ----------------------------------------------------------------------
> -----------------------
>
> $DATA MO5_gem33.CSV IGNORE=C
> $SUBROUTINES ADVAN5
> $MODEL COMP=(GEM) COMP=(P1) COMP=(dFdU) COMP(dFdCTP)
>
> $PK
>
> TVCL1=THETA(1)
> CL1=TVCL1*EXP(ETA(1))
>
> TVV1=THETA(2)
> V1=TVV1*EXP(ETA(2))
>
> TVQ1=THETA(3)
> Q1=TVQ1*EXP(ETA(3))
>
> TVV2=THETA(4)
> V2=TVV2*EXP(ETA(4))
>
> TVCL2=THETA(5)
> CL2=TVCL2*EXP(ETA(5))
>
> TVV3=THETA(6)
> V3=TVV3*EXP(ETA(6))
>
> TVK40=THETA(7)
> K40=TVK40*EXP(ETA(7))
>
> K12=Q1/V1
> K21=Q1/V2
> K13=CL1/V1
> K30=CL2/V3
>
> RF=THETA(8)
>
> K14=0.000001*K13
> V4=K14*RF*V1/K13
>
> S1=V1/1000
> S3=V3/1000
> S4=V4/1000
>
> $ERROR CALLFL=0
> IPRE=-3
> FLG1=0
> FLG3=0
> FLG4=0
> IF(CMT.EQ.1)FLG1=1
> IF(CMT.EQ.3)FLG3=1
> IF(CMT.EQ.4)FLG4=1
> IF(F.GT.0) IPRE=LOG(F)
> Y=LOG(F)+EPS(1)*FLG1+EPS(2)*FLG3+EPS(3)*FLG4
> W=LOG(F)
> IRES=DV-IPRE
> IWRES=IRES/W
>
> $THETA
> (0,163) ;CL-gemcitabine.1
> (0,11.9) ;V1.2
> (0,95.1) ;Q1.3
> (0,20) ;V2.4
> (0,14.1) ;CL-dFdU.5
> (0,28) ;V3.6
> (0,0.21) ;K40.7
> (0,646) ;RF.8
>
> $OMEGA
> 0.37 ;CL1.1
> 0.23 ;V1.2
> 0.0094 ;Q1.3
> 0.036 ;V2.4
> 0.14 ;CL2.5
> 0.14 ;V3.6
> 0.27 ;K40.9.7
>
> $SIGMA
> 0.07 ;IIV-1
> 0.0355 ;IIV-3
> 0.757 ;IIV-4
>
> $ESTIMATION PRINT=5 MAXEVAL=3000 METHOD=1
> NOABORT POSTHOC SIGDIG=3 MSFO=MSF004BBAB
This message and any attachments are solely for the intended recipient. If you
are not the intended recipient, disclosure, copying, use or distribution of the
information included in this message is prohibited --- Please immediately and
permanently delete.