From: Sebastien Bihorel <*Sebastien.Bihorel*>

Date: Thu, 13 May 2010 12:05:48 -0400

Dear R-users,

I have recently observed a very puzzling difference of behavior between

NM 6.2.0 and NM 7.1.2, while trying to reproduce the simulation examples

described in Martin Bergstrand's paper 'Handling data below the limit of

quantification in mixed effect models' (AAPS Journal 2009, 11-2). My

model corresponds to Martins' model B (2-cmt linear model with single IV

dosing) and implement my interpretation of the residual variability

described in his equation 3 (see code below). When I run the code in

NONMEM 7.1.2,, all the PRED values are reported as NaN and RES values

either as NaN or 0. NM6 returns non-NaN values for PRED and RES, but

there does not seem to be any differences in simulated DV.

Did anybody experienced the same differences? In my case, could they be

explained by an improper implementation of the RV model?

As a side note, I would also be interested to know if a reference in the

literature would describe the properties of this particular RUV model.

Thank you

Sebastien Bihorel

--------

$PROBLEM base-2cmt-sim

$DATA basedata.csv IGNORE=

$INPUT ID TIME AMT RATE CMT EVID DV MDV STDY

$THETA

(0.,5.) ;1- clearance

(0.,20.) ;2- central compartment volume

(0.,5.) ;3- distribution clearance

(0.,100.) ;4- peripheral compartment volume

(0.,0.1) ;5- 'additive' log RV

(0.,0.1) ;6- 'second' log RV term

$OMEGA

0.3 ;1- IIV in clearance

0.3 ;2- IIV in central compartment volume

0.3 ;3- IIV in distribution clearance

0.3 ;4- IIV in peripheral compartment volume

$SIGMA

1 FIX ;1- 'additive' log RV

1 FIX ;2- 'second' log RV term

$SUBROUTINES ADVAN3 TRANS4

$PK

; Model parameter assignment

TVCL=THETA(1)

TVV1=THETA(2)

TVQ =THETA(3)

TVV2=THETA(4)

ECL=EXP(ETA(1))

EV1=EXP(ETA(2))

EQ =EXP(ETA(3))

EV2=EXP(ETA(4))

; PREDPP required variables

F1=1.0 ; bioavailability in central compartment

CL=TVCL*ECL ; elimination clearance

V1=TVV1*EV1 ; volume of the central compartment

Q =TVQ*EQ ; inter-compartment distribution clearance

V2=TVV2*EV2 ; volume of the peripheral compartment

S1=V1

$ERROR

;set up Dose flag

DFLG=0

IF(AMT.GT.0)DFLG=1

IPRED=LOG(F+DFLG)

W1=THETA(5)*EPS(1)

W2=THETA(6)*EPS(2)

W=SQRT(W1*W1+(W2*(1-F/(0.5+F)))**2)

Y=IPRED+W

$SIM (123456) ONLYSIM

$TABLE ID TIME AMT RATE CMT EVID DV MDV STDY W NOPRINT ONEHEADER

FILE=base-2cmt-sim.tbl

Received on Thu May 13 2010 - 12:05:48 EDT

Date: Thu, 13 May 2010 12:05:48 -0400

Dear R-users,

I have recently observed a very puzzling difference of behavior between

NM 6.2.0 and NM 7.1.2, while trying to reproduce the simulation examples

described in Martin Bergstrand's paper 'Handling data below the limit of

quantification in mixed effect models' (AAPS Journal 2009, 11-2). My

model corresponds to Martins' model B (2-cmt linear model with single IV

dosing) and implement my interpretation of the residual variability

described in his equation 3 (see code below). When I run the code in

NONMEM 7.1.2,, all the PRED values are reported as NaN and RES values

either as NaN or 0. NM6 returns non-NaN values for PRED and RES, but

there does not seem to be any differences in simulated DV.

Did anybody experienced the same differences? In my case, could they be

explained by an improper implementation of the RV model?

As a side note, I would also be interested to know if a reference in the

literature would describe the properties of this particular RUV model.

Thank you

Sebastien Bihorel

--------

$PROBLEM base-2cmt-sim

$DATA basedata.csv IGNORE=

$INPUT ID TIME AMT RATE CMT EVID DV MDV STDY

$THETA

(0.,5.) ;1- clearance

(0.,20.) ;2- central compartment volume

(0.,5.) ;3- distribution clearance

(0.,100.) ;4- peripheral compartment volume

(0.,0.1) ;5- 'additive' log RV

(0.,0.1) ;6- 'second' log RV term

$OMEGA

0.3 ;1- IIV in clearance

0.3 ;2- IIV in central compartment volume

0.3 ;3- IIV in distribution clearance

0.3 ;4- IIV in peripheral compartment volume

$SIGMA

1 FIX ;1- 'additive' log RV

1 FIX ;2- 'second' log RV term

$SUBROUTINES ADVAN3 TRANS4

$PK

; Model parameter assignment

TVCL=THETA(1)

TVV1=THETA(2)

TVQ =THETA(3)

TVV2=THETA(4)

ECL=EXP(ETA(1))

EV1=EXP(ETA(2))

EQ =EXP(ETA(3))

EV2=EXP(ETA(4))

; PREDPP required variables

F1=1.0 ; bioavailability in central compartment

CL=TVCL*ECL ; elimination clearance

V1=TVV1*EV1 ; volume of the central compartment

Q =TVQ*EQ ; inter-compartment distribution clearance

V2=TVV2*EV2 ; volume of the peripheral compartment

S1=V1

$ERROR

;set up Dose flag

DFLG=0

IF(AMT.GT.0)DFLG=1

IPRED=LOG(F+DFLG)

W1=THETA(5)*EPS(1)

W2=THETA(6)*EPS(2)

W=SQRT(W1*W1+(W2*(1-F/(0.5+F)))**2)

Y=IPRED+W

$SIM (123456) ONLYSIM

$TABLE ID TIME AMT RATE CMT EVID DV MDV STDY W NOPRINT ONEHEADER

FILE=base-2cmt-sim.tbl

- application/vnd.ms-excel attachment: basedata.csv