Dear all,
I am trying to use the method M3 for including BLQ observation in the
estimation process in NONMEM. I'm using version VI level 1.0 with PsN. I
have tried to implement the coding as presented in Ahn et al (J
Pharmacokinet Pharmacodyn 2008, 35:401-421), using the F_FLAG variable and
a separate PHI1.for file (as in the publication).
I have several questions:
can I lave out the TRANS routine from $SUBROUTINE (this is how it's
presented in the paper)?
I get the message that NUMERICAL is required with LAPLACIAN. Is it okay to
include this here?
I would like to use a combination of additive and proportional error
model, but I'm not sure how to implement this (paper describes either
additive or proportional, not both, and I'm not exactly sure what to do
with SIG and how to incorporate this for VECTRA(1)) I've tried the code
below, but I'm sure there are errors :-)
Finally, with the code below, I get the error message: "ERROR IN CLIK WITH
INDIVIDUAL 1 ID=0.21000100E+06 CONDITIONAL LIKELIHOOD FOR SOME
OBSERVATION ESTIMATED TO BE NEGLIGIBLE" What does this mean?
The NONMEM code and a fraction of the dataset is presented below. Any help
to get this to run would be highly appreciated.
Best
Nele
NONMEM code:
$PROBLEM xyz
$INPUT ID OID STDY PER TRT=DROP GRP DOSE NTIM TIME TAD MDV DV
SEX AGE WT AMT RATE EVID CMT TYPE
$DATA BLQ_dataset_16-Apr-2010.prn
IGNORE=#
$SUBROUTINES ADVAN12 TRANS4 OTHER=../../PHI1.for
$PK
TVCL=THETA(1)
CL=TVCL*EXP(ETA(3))
TVV2=THETA(2)
V2=TVV2*EXP(ETA(2))
TVQ3=THETA(3)
Q3=TVQ3
TVV3=THETA(4)
V3=TVV3
TVQ4=THETA(5)
Q4=TVQ4
TVV4=THETA(6)
V4=TVV4
TVKA=THETA(7)
KA=TVKA*EXP(ETA(1))
TVF1=THETA(8)
F1=TVF1*EXP(ETA(4))
TVLAG=THETA(9)
ALAG1=TVLAG
S2=V2/1000
$ERROR
SIG1=THETA(10)
SIG2=THETA(11)
LOQ%
IPRED=F
DEL=0
IF (IPRED.EQ.0) DEL=0.0001
VECTRA(1)=(LOQ-IPRED)/SIG2
CUMD=FUNCA(VECTRA)
IF(TYPE.EQ.1) THEN
F_FLAG=0
Y=F+THETA(11)*SIG2*ERR(1)+THETA(10)*SIG1*F*ERR(1)
W=F
IRES=DV-IPRED
IWRES=IRES/(W+DEL)
ENDIF
IF(TYPE.EQ.2) THEN
F_FLAG=1
Y=CUMD
ENDIF
;
$THETA
(0,13) ; CL
(0,17) ; V2
(0,50) ; Q3
(0,100) ; V3
(0,100) ;Q4
(0,100) ;V4
(0,2) ;KA
1 FIX ; F1
(0,0.1) ;ALAG1
(0,0.1) ; prop. error
(0,0.1) ; add. error
$OMEGA
0.1 ; IIV_KA
0.1 ; IIV_V2
0.1 ; IIV_CL
0.1 ; IIV_F1
;
$SIGMA
1 FIX ; prop.error
;
$ESTIMATION METHOD=1 LAPLACIAN NUMERICAL MAXEVAL99 PRINT=5 NOABORT
MSFO=msf034
$COV
fraction of the dataset (data modifed):
#ID,OID,STDY,PER,TRT,GRP,DOSE,NTIM,TIME,TAD,MDV,DV,SEX,AGE,WT,AMT,RATE,EVID,CMT,TYPE
210001,1,1,1,9,1,100,0,0,0,1,0,1,28,86,100,0,1,1,1
210001,1,1,1,9,1,100,0,0,0,1,0,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,0.042,0.033,0.033,0,0,1,28,86,0,0,0,2,2
210001,1,1,1,9,1,100,0.083,0.083,0.083,0,55,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,0.133,0.133,0.133,0,136,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,0.167,0.167,0.167,0,239,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,0.25,0.25,0.25,0,359,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,0.2,0.333,0.333,1,0,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,0.333,0.333,0.333,0,417,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,0.5,0.5,0.5,0,533,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,0.75,0.75,0.75,0,453,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,1,1,1,0,386,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,2,2,2,0,172,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,3,3.033,3.033,0,147,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,4,4,4,0,116,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,6,6,6,0,67.9,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,8,8,8,0,49.6,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,12,12,12,0,22.8,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,18,18,18,0,0,1,28,86,0,0,0,2,2
210001,1,1,1,9,1,100,24,24,24,0,0,1,28,86,0,0,0,2,2
210001,1,1,1,9,1,100,48,48,48,0,0,1,28,86,0,0,0,2,2
210001,1,1,1,9,1,100,72,72,72,0,0,1,28,86,0,0,0,2,2
210001,1,1,1,9,1,100,96,95.917,95.917,0,0,1,28,86,0,0,0,2,2
210008,8,1,1,9,1,100,0,0,0,1,0,1,21,71,100,0,1,1,1
210008,8,1,1,9,1,100,0,0,0,1,0,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,0.042,0.033,0.033,0,0,1,21,71,0,0,0,2,2
210008,8,1,1,9,1,100,0.083,0.117,0.117,0,110,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,0.133,0.133,0.133,0,82,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,0.167,0.167,0.167,0,344,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,0.2,0.2,0.2,0,397,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,0.25,0.25,0.25,0,599,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,0.333,0.333,0.333,0,370,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,0.5,0.5,0.5,0,368,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,0.75,0.75,0.75,0,318,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,1,1,1,0,258,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,2,2,2,0,279,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,3,3,3,0,170,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,4,4,4,0,131,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,6,6,6,0,70.7,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,8,8,8,0,46.4,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,12,12,12,0,30.3,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,18,18,18,0,25.2,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,24,24,24,0,0,1,21,71,0,0,0,2,2
210008,8,1,1,9,1,100,48,48,48,0,0,1,21,71,0,0,0,2,2
210008,8,1,1,9,1,100,72,72,72,0,0,1,21,71,0,0,0,2,2
210008,8,1,1,9,1,100,96,96,96,0,0,1,21,71,0,0,0,2,2
______________________________________________________________
Dr. Nele Kner
Pharmacometrics -- Modeling and Simulation
Nycomed GmbH
Byk-Gulden-Str. 2
D-78467 Konstanz, Germany
Fon: (+49) 7531 / 84 - 4759
Fax: (+49) 7531 / 84 - 94759
mailto: nele.kaessner
http://www.nycomed.com
County Court: Freiburg, Commercial Register HRB 701257
Chairman Supervisory Board: Charles Depasse
Management Board: Stefan Brinkmann, Dr. Frederik Bendiksen,
Gilbert Rademacher, Dr. Rainer Wiartalla
----------------------------------------------------------------------
Proprietary or confidential information belonging to Nycomed Group may
be contained in this message. If you are not the addressee indicated
in this message, please do not copy or deliver this message to anyone.
In such case, please destroy this message and notify the sender by
reply e-mail. Please advise the sender immediately if you or your
employer do not consent to Internet e-mail for messages of this kind.
Opinions, conclusions and other information in this message that
pertain to the sender's employer and its products and services
represent the opinion of the sender and do not necessarily represent
or reflect the views and opinions of the employer.
BLQ method M3 using F_FLAG
Dear all,
I am trying to use the method M3 for including BLQ observation in the
estimation process in NONMEM. I'm using version VI level 1.0 with PsN. I
have tried to implement the coding as presented in Ahn et al (J
Pharmacokinet Pharmacodyn 2008, 35:401-421), using the F_FLAG variable and
a separate PHI1.for file (as in the publication).
I have several questions:
can I lave out the TRANS routine from $SUBROUTINE (this is how it's
presented in the paper)?
I get the message that NUMERICAL is required with LAPLACIAN. Is it okay to
include this here?
I would like to use a combination of additive and proportional error
model, but I'm not sure how to implement this (paper describes either
additive or proportional, not both, and I'm not exactly sure what to do
with SIG and how to incorporate this for VECTRA(1)) I've tried the code
below, but I'm sure there are errors :-)
Finally, with the code below, I get the error message: "ERROR IN CLIK WITH
INDIVIDUAL 1 ID=0.21000100E+06 CONDITIONAL LIKELIHOOD FOR SOME
OBSERVATION ESTIMATED TO BE NEGLIGIBLE" What does this mean?
The NONMEM code and a fraction of the dataset is presented below. Any help
to get this to run would be highly appreciated.
Best
Nele
NONMEM code:
$PROBLEM xyz
$INPUT ID OID STDY PER TRT=DROP GRP DOSE NTIM TIME TAD MDV DV
SEX AGE WT AMT RATE EVID CMT TYPE
$DATA BLQ_dataset_16-Apr-2010.prn
IGNORE=#
$SUBROUTINES ADVAN12 TRANS4 OTHER=../../PHI1.for
$PK
TVCL=THETA(1)
CL=TVCL*EXP(ETA(3))
TVV2=THETA(2)
V2=TVV2*EXP(ETA(2))
TVQ3=THETA(3)
Q3=TVQ3
TVV3=THETA(4)
V3=TVV3
TVQ4=THETA(5)
Q4=TVQ4
TVV4=THETA(6)
V4=TVV4
TVKA=THETA(7)
KA=TVKA*EXP(ETA(1))
TVF1=THETA(8)
F1=TVF1*EXP(ETA(4))
TVLAG=THETA(9)
ALAG1=TVLAG
S2=V2/1000
$ERROR
SIG1=THETA(10)
SIG2=THETA(11)
LOQ=25
IPRED=F
DEL=0
IF (IPRED.EQ.0) DEL=0.0001
VECTRA(1)=(LOQ-IPRED)/SIG2
CUMD=FUNCA(VECTRA)
IF(TYPE.EQ.1) THEN
F_FLAG=0
Y=F+THETA(11)*SIG2*ERR(1)+THETA(10)*SIG1*F*ERR(1)
W=F
IRES=DV-IPRED
IWRES=IRES/(W+DEL)
ENDIF
IF(TYPE.EQ.2) THEN
F_FLAG=1
Y=CUMD
ENDIF
;
$THETA
(0,13) ; CL
(0,17) ; V2
(0,50) ; Q3
(0,100) ; V3
(0,100) ;Q4
(0,100) ;V4
(0,2) ;KA
1 FIX ; F1
(0,0.1) ;ALAG1
(0,0.1) ; prop. error
(0,0.1) ; add. error
$OMEGA
0.1 ; IIV_KA
0.1 ; IIV_V2
0.1 ; IIV_CL
0.1 ; IIV_F1
;
$SIGMA
1 FIX ; prop.error
;
$ESTIMATION METHOD=1 LAPLACIAN NUMERICAL MAXEVAL=9999 PRINT=5 NOABORT
MSFO=msf034
$COV
fraction of the dataset (data modifed):
#ID,OID,STDY,PER,TRT,GRP,DOSE,NTIM,TIME,TAD,MDV,DV,SEX,AGE,WT,AMT,RATE,EVID,CMT,TYPE
210001,1,1,1,9,1,100,0,0,0,1,0,1,28,86,100,0,1,1,1
210001,1,1,1,9,1,100,0,0,0,1,0,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,0.042,0.033,0.033,0,0,1,28,86,0,0,0,2,2
210001,1,1,1,9,1,100,0.083,0.083,0.083,0,55,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,0.133,0.133,0.133,0,136,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,0.167,0.167,0.167,0,239,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,0.25,0.25,0.25,0,359,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,0.2,0.333,0.333,1,0,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,0.333,0.333,0.333,0,417,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,0.5,0.5,0.5,0,533,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,0.75,0.75,0.75,0,453,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,1,1,1,0,386,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,2,2,2,0,172,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,3,3.033,3.033,0,147,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,4,4,4,0,116,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,6,6,6,0,67.9,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,8,8,8,0,49.6,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,12,12,12,0,22.8,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,18,18,18,0,0,1,28,86,0,0,0,2,2
210001,1,1,1,9,1,100,24,24,24,0,0,1,28,86,0,0,0,2,2
210001,1,1,1,9,1,100,48,48,48,0,0,1,28,86,0,0,0,2,2
210001,1,1,1,9,1,100,72,72,72,0,0,1,28,86,0,0,0,2,2
210001,1,1,1,9,1,100,96,95.917,95.917,0,0,1,28,86,0,0,0,2,2
210008,8,1,1,9,1,100,0,0,0,1,0,1,21,71,100,0,1,1,1
210008,8,1,1,9,1,100,0,0,0,1,0,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,0.042,0.033,0.033,0,0,1,21,71,0,0,0,2,2
210008,8,1,1,9,1,100,0.083,0.117,0.117,0,110,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,0.133,0.133,0.133,0,82,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,0.167,0.167,0.167,0,344,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,0.2,0.2,0.2,0,397,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,0.25,0.25,0.25,0,599,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,0.333,0.333,0.333,0,370,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,0.5,0.5,0.5,0,368,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,0.75,0.75,0.75,0,318,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,1,1,1,0,258,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,2,2,2,0,279,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,3,3,3,0,170,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,4,4,4,0,131,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,6,6,6,0,70.7,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,8,8,8,0,46.4,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,12,12,12,0,30.3,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,18,18,18,0,25.2,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,24,24,24,0,0,1,21,71,0,0,0,2,2
210008,8,1,1,9,1,100,48,48,48,0,0,1,21,71,0,0,0,2,2
210008,8,1,1,9,1,100,72,72,72,0,0,1,21,71,0,0,0,2,2
210008,8,1,1,9,1,100,96,96,96,0,0,1,21,71,0,0,0,2,2
______________________________________________________________
Dr. Nele Käßner
Pharmacometrics -- Modeling and Simulation
Nycomed GmbH
Byk-Gulden-Str. 2
D-78467 Konstanz, Germany
Fon: (+49) 7531 / 84 - 4759
Fax: (+49) 7531 / 84 - 94759
mailto: [email protected]
http://www.nycomed.com
County Court: Freiburg, Commercial Register HRB 701257
Chairman Supervisory Board: Charles Depasse
Management Board: Stefan Brinkmann, Dr. Frederik Bendiksen,
Gilbert Rademacher, Dr. Rainer Wiartalla
----------------------------------------------------------------------
Proprietary or confidential information belonging to Nycomed Group may
be contained in this message. If you are not the addressee indicated
in this message, please do not copy or deliver this message to anyone.
In such case, please destroy this message and notify the sender by
reply e-mail. Please advise the sender immediately if you or your
employer do not consent to Internet e-mail for messages of this kind.
Opinions, conclusions and other information in this message that
pertain to the sender's employer and its products and services
represent the opinion of the sender and do not necessarily represent
or reflect the views and opinions of the employer.
Hi Nele,
I will try to help you with some of your problems.
1) There is absolutely no problem leaving out TRANS. I never use TRANS.
However, then you have to manually reparameterize CL- and V-terms into
rate constants (ADVAN12 internally uses rate constants). E.g put this in
your $PK block:
K=CL/V2
K23=Q3/V2
K32=Q3/V3
K24=Q4/V2
K42=Q4/V4
KA=KA
3) Combined error model
(part of a code that apparently worked for me, since I use NM7 I could
directly use the PHI function):
SDADD = THETA(..1) ; the standard deviation of the additive part
CVPROP = THETA(..2) ; the CV of the proportional part
$ERROR
;M3-Method
LOQ=0.3
IPRED = F
IRES = DV-IPRED
W = SQRT(SDADD**2+CVPROP**2*IPRED**2)
DEL = 0
IF(W.EQ.0) DEL = 1
IWRES = IRES/(W+DEL)
DUM=(LOQ-IPRED)/(W+DEL) ; substitute DUM for VECTRA(1)
CUMD=PHI(DUM) ; substitute PHI for FUNCA and
DUM for VECTRA
IF (BQL.EQ.0) THEN ; TYPE.EQ.1 in your code
F_FLAG=0
Y = IPRED+ERR(1)*W
ELSE
F_FLAG=1
Y=CUMD
ENDIF
$SIGMA 1 FIX
$ESTIMATION SIG=3 PRINT=1 METHOD=1 INTER LAPLACIAN MAXEVAL=9999 NOABORT
MSFO=msfo.msf
;;;;;
As to bullets 2 and 4, I have no idea sorry.
You may also have a look at the following publication: Bergstrand &
Karlsson. Handling Data Below the Limit of Quantification in Mixed Effect
Models. The AAPS Journal 2009;11:311-380
Good luck, Andreas.
Andreas Lindauer
Pharmacokineticist
Pharmacokinetics and Metabolism
R&D Center. Ferrer Internacional S.A.
Juan de Sada 32, 08028 Barcelona
Fax +34 93 411 2764
[email protected]
www.ferrergrupo.com
¿Necesita imprimir este mensaje? Protejamos el medio ambiente.
Li cal imprimir aquest missatge? Protegim el medi ambient.
Do you need to print this message? Let's protect the environment.
Este mensaje, y en su caso, cualquier fichero anexo al mismo, puede
contener información confidencial, siendo para uso exclusivo del
destinatario, quedando prohibida su divulgación, copia o distribución a
terceros sin la autorización expresa del remitente. Si Vd. ha recibido
este mensaje erróneamente, se ruega lo notifique al remitente y proceda a
su borrado. Gracias por su colaboración.
This message and its annexed files may contain confidential information
which is exclusively for the use of the addressee. It is strictly
forbidden to distribute copies to third parties without the explicit
permission of the sender. If you receive this message by mistake, please
notify it to the sender and make sure to delete it. Thank you for your
kind cooperation.
[email protected]
Enviado por: [email protected]
20/04/2010 16:42
Para
[email protected]
cc
Asunto
[NMusers] BLQ method M3 using F_FLAG
Dear all,
I am trying to use the method M3 for including BLQ observation in the
estimation process in NONMEM. I'm using version VI level 1.0 with PsN. I
have tried to implement the coding as presented in Ahn et al (J
Pharmacokinet Pharmacodyn 2008, 35:401-421), using the F_FLAG variable and
a separate PHI1.for file (as in the publication).
I have several questions:
can I lave out the TRANS routine from $SUBROUTINE (this is how it's
presented in the paper)?
I get the message that NUMERICAL is required with LAPLACIAN. Is it okay to
include this here?
I would like to use a combination of additive and proportional error
model, but I'm not sure how to implement this (paper describes either
additive or proportional, not both, and I'm not exactly sure what to do
with SIG and how to incorporate this for VECTRA(1)) I've tried the code
below, but I'm sure there are errors :-)
Finally, with the code below, I get the error message: "ERROR IN CLIK WITH
INDIVIDUAL 1 ID=0.21000100E+06 CONDITIONAL LIKELIHOOD FOR SOME
OBSERVATION ESTIMATED TO BE NEGLIGIBLE" What does this mean?
The NONMEM code and a fraction of the dataset is presented below. Any help
to get this to run would be highly appreciated.
Best
Nele
NONMEM code:
$PROBLEM xyz
$INPUT ID OID STDY PER TRT=DROP GRP DOSE NTIM TIME TAD MDV DV
SEX AGE WT AMT RATE EVID CMT TYPE
$DATA BLQ_dataset_16-Apr-2010.prn
IGNORE=#
$SUBROUTINES ADVAN12 TRANS4 OTHER=../../PHI1.for
$PK
TVCL=THETA(1)
CL=TVCL*EXP(ETA(3))
TVV2=THETA(2)
V2=TVV2*EXP(ETA(2))
TVQ3=THETA(3)
Q3=TVQ3
TVV3=THETA(4)
V3=TVV3
TVQ4=THETA(5)
Q4=TVQ4
TVV4=THETA(6)
V4=TVV4
TVKA=THETA(7)
KA=TVKA*EXP(ETA(1))
TVF1=THETA(8)
F1=TVF1*EXP(ETA(4))
TVLAG=THETA(9)
ALAG1=TVLAG
S2=V2/1000
$ERROR
SIG1=THETA(10)
SIG2=THETA(11)
LOQ=25
IPRED=F
DEL=0
IF (IPRED.EQ.0) DEL=0.0001
VECTRA(1)=(LOQ-IPRED)/SIG2
CUMD=FUNCA(VECTRA)
IF(TYPE.EQ.1) THEN
F_FLAG=0
Y=F+THETA(11)*SIG2*ERR(1)+THETA(10)*SIG1*F*ERR(1)
W=F
IRES=DV-IPRED
IWRES=IRES/(W+DEL)
ENDIF
IF(TYPE.EQ.2) THEN
F_FLAG=1
Y=CUMD
ENDIF
;
$THETA
(0,13) ; CL
(0,17) ; V2
(0,50) ; Q3
(0,100) ; V3
(0,100) ;Q4
(0,100) ;V4
(0,2) ;KA
1 FIX ; F1
(0,0.1) ;ALAG1
(0,0.1) ; prop. error
(0,0.1) ; add. error
$OMEGA
0.1 ; IIV_KA
0.1 ; IIV_V2
0.1 ; IIV_CL
0.1 ; IIV_F1
;
$SIGMA
1 FIX ; prop.error
;
$ESTIMATION METHOD=1 LAPLACIAN NUMERICAL MAXEVAL=9999 PRINT=5 NOABORT
MSFO=msf034
$COV
fraction of the dataset (data modifed):
#ID,OID,STDY,PER,TRT,GRP,DOSE,NTIM,TIME,TAD,MDV,DV,SEX,AGE,WT,AMT,RATE,EVID,CMT,TYPE
210001,1,1,1,9,1,100,0,0,0,1,0,1,28,86,100,0,1,1,1
210001,1,1,1,9,1,100,0,0,0,1,0,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,0.042,0.033,0.033,0,0,1,28,86,0,0,0,2,2
210001,1,1,1,9,1,100,0.083,0.083,0.083,0,55,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,0.133,0.133,0.133,0,136,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,0.167,0.167,0.167,0,239,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,0.25,0.25,0.25,0,359,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,0.2,0.333,0.333,1,0,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,0.333,0.333,0.333,0,417,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,0.5,0.5,0.5,0,533,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,0.75,0.75,0.75,0,453,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,1,1,1,0,386,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,2,2,2,0,172,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,3,3.033,3.033,0,147,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,4,4,4,0,116,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,6,6,6,0,67.9,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,8,8,8,0,49.6,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,12,12,12,0,22.8,1,28,86,0,0,0,2,1
210001,1,1,1,9,1,100,18,18,18,0,0,1,28,86,0,0,0,2,2
210001,1,1,1,9,1,100,24,24,24,0,0,1,28,86,0,0,0,2,2
210001,1,1,1,9,1,100,48,48,48,0,0,1,28,86,0,0,0,2,2
210001,1,1,1,9,1,100,72,72,72,0,0,1,28,86,0,0,0,2,2
210001,1,1,1,9,1,100,96,95.917,95.917,0,0,1,28,86,0,0,0,2,2
210008,8,1,1,9,1,100,0,0,0,1,0,1,21,71,100,0,1,1,1
210008,8,1,1,9,1,100,0,0,0,1,0,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,0.042,0.033,0.033,0,0,1,21,71,0,0,0,2,2
210008,8,1,1,9,1,100,0.083,0.117,0.117,0,110,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,0.133,0.133,0.133,0,82,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,0.167,0.167,0.167,0,344,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,0.2,0.2,0.2,0,397,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,0.25,0.25,0.25,0,599,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,0.333,0.333,0.333,0,370,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,0.5,0.5,0.5,0,368,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,0.75,0.75,0.75,0,318,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,1,1,1,0,258,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,2,2,2,0,279,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,3,3,3,0,170,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,4,4,4,0,131,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,6,6,6,0,70.7,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,8,8,8,0,46.4,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,12,12,12,0,30.3,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,18,18,18,0,25.2,1,21,71,0,0,0,2,1
210008,8,1,1,9,1,100,24,24,24,0,0,1,21,71,0,0,0,2,2
210008,8,1,1,9,1,100,48,48,48,0,0,1,21,71,0,0,0,2,2
210008,8,1,1,9,1,100,72,72,72,0,0,1,21,71,0,0,0,2,2
210008,8,1,1,9,1,100,96,96,96,0,0,1,21,71,0,0,0,2,2
______________________________________________________________
Dr. Nele Käßner
Pharmacometrics -- Modeling and Simulation
Nycomed GmbH
Byk-Gulden-Str. 2
D-78467 Konstanz, Germany
Fon: (+49) 7531 / 84 - 4759
Fax: (+49) 7531 / 84 - 94759
mailto: [email protected]
http://www.nycomed.com
County Court: Freiburg, Commercial Register HRB 701257
Chairman Supervisory Board: Charles Depasse
Management Board: Stefan Brinkmann, Dr. Frederik Bendiksen,
Gilbert Rademacher, Dr. Rainer Wiartalla
----------------------------------------------------------------------
Proprietary or confidential information belonging to Nycomed Group may
be contained in this message. If you are not the addressee indicated
in this message, please do not copy or deliver this message to anyone.
In such case, please destroy this message and notify the sender by
reply e-mail. Please advise the sender immediately if you or your
employer do not consent to Internet e-mail for messages of this kind.
Opinions, conclusions and other information in this message that
pertain to the sender's employer and its products and services
represent the opinion of the sender and do not necessarily represent
or reflect the views and opinions of the employer.
----------------------------------------------------------------------
<<image/gif>>
<<image/gif>>