Re: BLQ method M3 using F_FLAG

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>>