From: Martin Bergstrand <*martin.bergstrand*>

Date: Fri, 5 Mar 2010 10:14:48 +0100

Dear Andreas,

Your interpretation is the same as mine (correct or not). My guessing is =

that you are actually never all that interested in precisely estimating =

BSV in this type of analysis. The approach nevertheless has advantages =

in assessing the overall between subject variability and average =

response. One advantage is that you could also include measurements of =

average response where the SD is unknown.

One thing worth considering will be if it is geometric means or =

arithmetic means that you are dealing with. The example in Elodies =

example assumes arithmetic means but geometric means could easily be =

handled with Y = AV * EXP(SEAV*EPS(1)).

Best regards,

Martin Bergstrand, MSc, PhD student

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

Pharmacometrics Research Group,

Department of Pharmaceutical Biosciences,

Uppsala University

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

<mailto:martin.bergstrand

martin.bergstrand

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

Work: +46 18 471 4639

Mobile: +46 709 994 396

From: owner-nmusers

On Behalf Of alindauer-research

Sent: den 4 mars 2010 16:21

To: Elodie Plan

Cc: nmusers

Subject: RE: [NMusers] Meta-analysis with Nonmem

Hi Elodie, Martin and Mats,

Thanks for your suggestion, a very interesting approach. So, THETA1 =

would give me an estimate of the global between patient variability, =

expressed as SD, across all studies and OMEGA1 would be an estimate of =

the between study variability (BSV) of this SD. OMEGA2 would be the BSV =

of the average response. Is this interpretation correct? I suppose the =

number of studies has to be quite large to get precise estimates of the =

BSV.

Best regards, Andreas.

Ferrer

Andreas Lindauer

Pharmacokineticist

Pharmacokinetics and Metabolism

R&D Center. Ferrer Internacional S.A.

Juan de Sada 32, 08028 Barcelona

alindauer-research

www.ferrergrupo.com

Recicla

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"Elodie Plan" <elodie.plan

04/03/2010 14:33

Para

<alindauer-research

cc

Asunto

RE: [NMusers] Meta-analysis with Nonmem

Dear Andreas,

An approach you may consider is to model both the standard deviation and =

the average as dependent variables:

SD=THETA(1)*EXP(ETA(1))

AV=(THETA(2)+DOSE*THETA(3))*EXP(ETA(2))

SESD=SD/(2*(N-1)**.5)

SEAV=SD/N**.5

IF(FLAG.EQ.0) THEN

Y = SD+SESD*EPS(1)

ELSE

Y = AV+SEAV*EPS(1)

ENDIF

$SIGMA 1 FIX

Your dataset would treat study as individuals, include N the number of =

individuals in the study arm and incorporate a flag, so would look like: =

STUD=ID DV N FLAG DOSE

1 SD1 N1 0 D1

1 AV1 N1 1 D1

1 SD2 N2 0 D2

1 AV2 N2 1 D2

…

Note: this is only valid when there was only 1 endpoint per subject.

Hope this helps.

Best regards,

Elodie, Martin and Mats

Elodie L. Plan, PharmD, MSc, PhD student

********************************************

Uppsala Pharmacometrics Research Group,

Department of Pharmaceutical Biosciences,

P.O. Box 591, SE-751 24 Uppsala, SWEDEN

Office +46 18-471 4385, Fax +46 18-471 4003

From: owner-nmusers

On Behalf Of alindauer-research

Sent: Friday, February 26, 2010 10:26 AM

To: nmusers

Subject: Re: [NMusers] Meta-analysis with Nonmem

Thank you Leonid and Dirk for your replies. They were very helpful.

Leonid, what would you think about the following:

Y=IPRED+SE*EPS(1)+ETA(1)

With SIGMA fixed to 1 and OMEGA being the inter-study =

standard-deviation? What would be the interpretation of SIGMA if it were =

not fixed to 1?

You wrote:

*>>Y=IPRED+SE*EXP(ETA(1))*EPS(1)), etc.
*

Wouldn't this be somehow transformed by NONMEM because of the =

linearization process? Similarly to why we cannot use the exponential =

residual error model directly in NONMEM, but have to do the =

transform-both-sides approach.

Dirk, good idea. However, estimation of the simulated datasets might =

become very time consuming when you combine data from several large =

studies. And, as you said:

*>> If the number of subjects in a study is small, it might be useful to =
*

repeat the simulation and produce different combined datasets.

I would even go further and say, that it is absolutly necessary to =

repeat the simulation-reestimation procedure many times in order to get =

"stable" results.

Best regards, Andreas.

Ferrer

Andreas Lindauer

Pharmacokineticist

Pharmacokinetics and Metabolism

R&D Center. Ferrer Internacional S.A.

Juan de Sada 32, 08028 Barcelona

<mailto:alindauer-research

alindauer-research

<http://www.ferrergrupo.com/> www.ferrergrupo.com

Recicla

¿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.

Received on Fri Mar 05 2010 - 04:14:48 EST

Date: Fri, 5 Mar 2010 10:14:48 +0100

Dear Andreas,

Your interpretation is the same as mine (correct or not). My guessing is =

that you are actually never all that interested in precisely estimating =

BSV in this type of analysis. The approach nevertheless has advantages =

in assessing the overall between subject variability and average =

response. One advantage is that you could also include measurements of =

average response where the SD is unknown.

One thing worth considering will be if it is geometric means or =

arithmetic means that you are dealing with. The example in Elodies =

example assumes arithmetic means but geometric means could easily be =

handled with Y = AV * EXP(SEAV*EPS(1)).

Best regards,

Martin Bergstrand, MSc, PhD student

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

Pharmacometrics Research Group,

Department of Pharmaceutical Biosciences,

Uppsala University

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

<mailto:martin.bergstrand

martin.bergstrand

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

Work: +46 18 471 4639

Mobile: +46 709 994 396

From: owner-nmusers

On Behalf Of alindauer-research

Sent: den 4 mars 2010 16:21

To: Elodie Plan

Cc: nmusers

Subject: RE: [NMusers] Meta-analysis with Nonmem

Hi Elodie, Martin and Mats,

Thanks for your suggestion, a very interesting approach. So, THETA1 =

would give me an estimate of the global between patient variability, =

expressed as SD, across all studies and OMEGA1 would be an estimate of =

the between study variability (BSV) of this SD. OMEGA2 would be the BSV =

of the average response. Is this interpretation correct? I suppose the =

number of studies has to be quite large to get precise estimates of the =

BSV.

Best regards, Andreas.

Ferrer

Andreas Lindauer

Pharmacokineticist

Pharmacokinetics and Metabolism

R&D Center. Ferrer Internacional S.A.

Juan de Sada 32, 08028 Barcelona

alindauer-research

www.ferrergrupo.com

Recicla

¿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.

"Elodie Plan" <elodie.plan

04/03/2010 14:33

Para

<alindauer-research

cc

Asunto

RE: [NMusers] Meta-analysis with Nonmem

Dear Andreas,

An approach you may consider is to model both the standard deviation and =

the average as dependent variables:

SD=THETA(1)*EXP(ETA(1))

AV=(THETA(2)+DOSE*THETA(3))*EXP(ETA(2))

SESD=SD/(2*(N-1)**.5)

SEAV=SD/N**.5

IF(FLAG.EQ.0) THEN

Y = SD+SESD*EPS(1)

ELSE

Y = AV+SEAV*EPS(1)

ENDIF

$SIGMA 1 FIX

Your dataset would treat study as individuals, include N the number of =

individuals in the study arm and incorporate a flag, so would look like: =

STUD=ID DV N FLAG DOSE

1 SD1 N1 0 D1

1 AV1 N1 1 D1

1 SD2 N2 0 D2

1 AV2 N2 1 D2

…

Note: this is only valid when there was only 1 endpoint per subject.

Hope this helps.

Best regards,

Elodie, Martin and Mats

Elodie L. Plan, PharmD, MSc, PhD student

********************************************

Uppsala Pharmacometrics Research Group,

Department of Pharmaceutical Biosciences,

P.O. Box 591, SE-751 24 Uppsala, SWEDEN

Office +46 18-471 4385, Fax +46 18-471 4003

From: owner-nmusers

On Behalf Of alindauer-research

Sent: Friday, February 26, 2010 10:26 AM

To: nmusers

Subject: Re: [NMusers] Meta-analysis with Nonmem

Thank you Leonid and Dirk for your replies. They were very helpful.

Leonid, what would you think about the following:

Y=IPRED+SE*EPS(1)+ETA(1)

With SIGMA fixed to 1 and OMEGA being the inter-study =

standard-deviation? What would be the interpretation of SIGMA if it were =

not fixed to 1?

You wrote:

Wouldn't this be somehow transformed by NONMEM because of the =

linearization process? Similarly to why we cannot use the exponential =

residual error model directly in NONMEM, but have to do the =

transform-both-sides approach.

Dirk, good idea. However, estimation of the simulated datasets might =

become very time consuming when you combine data from several large =

studies. And, as you said:

repeat the simulation and produce different combined datasets.

I would even go further and say, that it is absolutly necessary to =

repeat the simulation-reestimation procedure many times in order to get =

"stable" results.

Best regards, Andreas.

Ferrer

Andreas Lindauer

Pharmacokineticist

Pharmacokinetics and Metabolism

R&D Center. Ferrer Internacional S.A.

Juan de Sada 32, 08028 Barcelona

<mailto:alindauer-research

alindauer-research

<http://www.ferrergrupo.com/> www.ferrergrupo.com

Recicla

¿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.

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