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BLQ method M3 using F_FLAG

From: nele.kaessner
Date: Tue, 20 Apr 2010 16:42:27 +0200

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 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






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Received on Tue Apr 20 2010 - 10:42:27 EDT

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