From: Martin Bergstrand <*martin.bergstrand*>

Date: Wed, 7 Apr 2010 19:02:09 +0200

Dear Sebastien and NONMEM users,

It is correct that NONMEM doesn't return any RES or WRES for individuals who

have at least one observation with F_FLAG=1. It is understandable that

NONMEM can't return residuals for the BQL observations (F_FLAG=1) since PRED

is a likelihood in this case and not a prediction (furthermore the

observation is an interval and can neither be used to calculate a residual).

However, I don't understand why it doesn't do so for the observations for

which F_FLAG=0? Can this be considered a bug?

You can of course always get out individual residuals (IRES) and individual

weighted residuals (IWRES) (below this paragraph you can see my definition

of IWRES). What you can do if you really want to get RES and WRES is to run

a MAXEVAL=0 run with your final estimates. The BQL data should in this case

be omitted (or set to a fix value) and all M3 code taken out. Remember in

this case that the IRES and IWRES and other EBE dependent variables will not

be correct following the MAXEVAL=0 run (i.e. use only the PRED, RES and WRES

out of this run and the rest from your original fit with the M3 code). In

case you are using the FOCE estimation method you would preferably want to

look at conditional weighted residuals (CWRES) rather than WRES. However I

have yet not seen any example of a workaround to get these when using the M3

method (Obs! CWRES will not be correctly calculated with the MAXEVAL=0

trick).

$ERROR

IPRED = F

W = THETA(11) ; SD for additive

residual error

; W = THETA(11) * IPRED ; SD for proportional

residual error

; W = SQRT(THEATA(11)**2+THETA(12)**2*IPRED**2) ; SD for combined

residual error

Y = IPRED + W*EPS(1)

IRES = DV - IPRED

IWRES = IRES/W

$SIGMA 1 FIX

If you use Xpose to do your diagnostic plots it can be good to know that

Xpose by default omits all rows with WRES=0 (this is done to omit

information on dosing row from being plotted). You can change this setting

in Xpose by using the command inclZeroWRES=TRUE (you should then enter some

other subset to omit the dose rows e.g. subset="EVID==0").

My favorite type of diagnostics are VPCs (I think I share this with Prof.

Nick Holford). VPCs can easily be adopted to handle the presence of BQL

data. How to do this with PsN and Xpose is explained in a PAGE poster from

2009

(http://www.page-meeting.org/pdf_assets/7002-Poster_PAGE_VPC_090618_final.pd

f).

Best regards,

Martin Bergstrand, MSc, PhD student

-----------------------------------------------

Pharmacometrics Research Group,

Department of Pharmaceutical Biosciences,

Uppsala University

-----------------------------------------------

martin.bergstrand

-----------------------------------------------

Work: +46 18 471 4639

Mobile: +46 709 994 396

Fax: +46 18 471 4003

-----Original Message-----

From: owner-nmusers

Behalf Of Sebastien Bihorel

Sent: den 7 april 2010 17:31

To: nmusers

Subject: [NMusers] RES and WRES output with Beal's M3 method

Dear NONMEM users,

We have noticed some problems with the table outputs of RES and WRES,

when we implemented Beal's M3 method as proposed by Ahn and colleagues

(J Pharmacokinet Pharmacodyn (2008) 35:401-421). While RES and WRES are

correctly calculated and reported for patients without BLOQ records,

these metrics are reported as being 0 for patients with at least one

BLOQ sample, even for the records that were not flagged as BLOQ. This

behavior seems to be common to NONMEM 6 and 7.

Does anybody know about an NONMEM option or a workaround that would

allow the user to access to the actual RES and WRES for the non-BLQ records?

Any feedback would be greatly appreciated.

Sebastien Bihorel

PS: this is the $ERROR block code we used for a simple proportional RV model

$ERROR (ONLY OBSERVATIONS)

;Information needed for BLQF and > BLQF samples

LOQ=5

SIG = THETA(3)

DFLG=0 ;create a dose record flag

IF(AMT.NE.0) DFLG=1

IPRED=F+DFLG

W=IPRED

;Computations for samples with DV > LOQ (BLQF=0)

IF (BLQF.LT.0.25) THEN

F_FLAG=0

FFLG=0

IRES=DV-IPRED

IWRES=IRES/W

Y=IPRED+W*SIG*EPS(1) ;NOTE: Prediction is a concentration

ENDIF

;Computations for samples with DV <= LOQ (BLQF=1)

IF (BLQF.GE.0.25) THEN

F_FLAG=1

FFLG=1

DUM=(LOQ-IPRED)/(W*SIG)

IPRED=PHI(DUM)

Y=IPRED ;NOTE: prediction is a *probability*

ENDIF

Received on Wed Apr 07 2010 - 13:02:09 EDT

Date: Wed, 7 Apr 2010 19:02:09 +0200

Dear Sebastien and NONMEM users,

It is correct that NONMEM doesn't return any RES or WRES for individuals who

have at least one observation with F_FLAG=1. It is understandable that

NONMEM can't return residuals for the BQL observations (F_FLAG=1) since PRED

is a likelihood in this case and not a prediction (furthermore the

observation is an interval and can neither be used to calculate a residual).

However, I don't understand why it doesn't do so for the observations for

which F_FLAG=0? Can this be considered a bug?

You can of course always get out individual residuals (IRES) and individual

weighted residuals (IWRES) (below this paragraph you can see my definition

of IWRES). What you can do if you really want to get RES and WRES is to run

a MAXEVAL=0 run with your final estimates. The BQL data should in this case

be omitted (or set to a fix value) and all M3 code taken out. Remember in

this case that the IRES and IWRES and other EBE dependent variables will not

be correct following the MAXEVAL=0 run (i.e. use only the PRED, RES and WRES

out of this run and the rest from your original fit with the M3 code). In

case you are using the FOCE estimation method you would preferably want to

look at conditional weighted residuals (CWRES) rather than WRES. However I

have yet not seen any example of a workaround to get these when using the M3

method (Obs! CWRES will not be correctly calculated with the MAXEVAL=0

trick).

$ERROR

IPRED = F

W = THETA(11) ; SD for additive

residual error

; W = THETA(11) * IPRED ; SD for proportional

residual error

; W = SQRT(THEATA(11)**2+THETA(12)**2*IPRED**2) ; SD for combined

residual error

Y = IPRED + W*EPS(1)

IRES = DV - IPRED

IWRES = IRES/W

$SIGMA 1 FIX

If you use Xpose to do your diagnostic plots it can be good to know that

Xpose by default omits all rows with WRES=0 (this is done to omit

information on dosing row from being plotted). You can change this setting

in Xpose by using the command inclZeroWRES=TRUE (you should then enter some

other subset to omit the dose rows e.g. subset="EVID==0").

My favorite type of diagnostics are VPCs (I think I share this with Prof.

Nick Holford). VPCs can easily be adopted to handle the presence of BQL

data. How to do this with PsN and Xpose is explained in a PAGE poster from

2009

(http://www.page-meeting.org/pdf_assets/7002-Poster_PAGE_VPC_090618_final.pd

f).

Best regards,

Martin Bergstrand, MSc, PhD student

-----------------------------------------------

Pharmacometrics Research Group,

Department of Pharmaceutical Biosciences,

Uppsala University

-----------------------------------------------

martin.bergstrand

-----------------------------------------------

Work: +46 18 471 4639

Mobile: +46 709 994 396

Fax: +46 18 471 4003

-----Original Message-----

From: owner-nmusers

Behalf Of Sebastien Bihorel

Sent: den 7 april 2010 17:31

To: nmusers

Subject: [NMusers] RES and WRES output with Beal's M3 method

Dear NONMEM users,

We have noticed some problems with the table outputs of RES and WRES,

when we implemented Beal's M3 method as proposed by Ahn and colleagues

(J Pharmacokinet Pharmacodyn (2008) 35:401-421). While RES and WRES are

correctly calculated and reported for patients without BLOQ records,

these metrics are reported as being 0 for patients with at least one

BLOQ sample, even for the records that were not flagged as BLOQ. This

behavior seems to be common to NONMEM 6 and 7.

Does anybody know about an NONMEM option or a workaround that would

allow the user to access to the actual RES and WRES for the non-BLQ records?

Any feedback would be greatly appreciated.

Sebastien Bihorel

PS: this is the $ERROR block code we used for a simple proportional RV model

$ERROR (ONLY OBSERVATIONS)

;Information needed for BLQF and > BLQF samples

LOQ=5

SIG = THETA(3)

DFLG=0 ;create a dose record flag

IF(AMT.NE.0) DFLG=1

IPRED=F+DFLG

W=IPRED

;Computations for samples with DV > LOQ (BLQF=0)

IF (BLQF.LT.0.25) THEN

F_FLAG=0

FFLG=0

IRES=DV-IPRED

IWRES=IRES/W

Y=IPRED+W*SIG*EPS(1) ;NOTE: Prediction is a concentration

ENDIF

;Computations for samples with DV <= LOQ (BLQF=1)

IF (BLQF.GE.0.25) THEN

F_FLAG=1

FFLG=1

DUM=(LOQ-IPRED)/(W*SIG)

IPRED=PHI(DUM)

Y=IPRED ;NOTE: prediction is a *probability*

ENDIF

Received on Wed Apr 07 2010 - 13:02:09 EDT