From: Sadler, Brian <*Brian.Sadler*>

Date: Wed, 13 Apr 2016 12:25:38 +0000

Hi Jacob,

I suggest:

CAT1=0

CAT2=0

CAT3=0

IF(CAT.EQ.1) CAT1=1

IF(CAT.EQ.2) CAT2=1

IF(CAT.EQ.3) CAT3=1

MU_1 = CAT1*THETA(1) + CAT2*THETA(2) + CAT3*THETA(3)

CL = EXP(MU_1+ETA(1))

That way you have only one OMEGA. This could be more flexible when expandin=

g OMEGA for additional IIV in block format.

Cheers... Brian

From: owner-nmusers

Behalf Of Michael Fossler

Sent: Wednesday, April 13, 2016 7:56 AM

To: Leander, Jacob; nmusers

Subject: [NMusers] RE: Link different thetas to same omega using mu referen=

cing

This looks like it would work - it seems to obey the rules around mu-refere=

ncing. You can simplify the $OMEGA by using SAME(3)

Mike

Michael J. Fossler, Pharm. D., Ph. D., F.C.P.

VP, Quantitative Sciences

Trevena, Inc

mfossler

Office: 610-354-8840, ext. 249

Cell: 610-329-6636

From: owner-nmusers

ilto:owner-nmusers

Sent: Wednesday, April 13, 2016 7:01 AM

To: nmusers

Subject: [NMusers] Link different thetas to same omega using mu referencing

Hi

Consider the case where we have a categorical (potentially time-varying) co=

variate named CAT that can take several values (e.g. 0,1,2,3).

Let's say I want to model CL depending on this categorical covariate (where=

parameters are estimated on log-scale).

A simple solution to this would be

IF(CAT.EQ.1) TVCL = THETA(1)

IF(CAT.EQ.2) TVCL = THETA(2)

IF(CAT.EQ.3) TVCL = THETA(3)

I let CL be described by a log-normal distribution with the same omega elem=

ent for all CAT values.

CL = EXP(TVCL + ETA(1))

With an omega statement:

$OMEGA 0.1

I now want to switch to the mu referencing framework in NONMEM. Each theta =

needs to be reference to a MU value, and to force it to be described by the=

same eta I apply the following approach.

MU_1 = THETA(1)

MU_2 = THETA(2)

MU_3 = THETA(3)

IF(CAT.EQ.1) CL = EXP(MU_1 + ETA(1))

IF(CAT.EQ.2) CL = EXP(MU_2 + ETA(2))

IF(CAT.EQ.3) CL = EXP(MU_3 + ETA(3))

With an omega statement:

$OMEGA BLOCK(1) 0.1

$OMEGA BLOCK(1) SAME

$OMEGA BLOCK(1) SAME

where I force the omega element corresponding to ETA1, ETA2 and ETA3 to be=

the same.

Is this a valid approach to obtain what I need?

Or is there a simpler way in the mu-referencing framework to link different=

thetas to the same omega element?

All the best,

Jacob

________________________________

Confidentiality Notice: This message is private and may contain confidentia=

l and proprietary information. If you have received this message in error, =

please notify us and remove it from your system and note that you must not =

copy, distribute or take any action in reliance on it. Any unauthorized use=

or disclosure of the contents of this message is not permitted and may be =

unlawful.

________________________________

Notice: This e-mail message, together with any attachments, contains inform=

ation of Trevena, Inc., 1018 West 8th Avenue, King of Prussia, PA 19406, US=

A. This information may be confidential, proprietary, copyrighted and/or le=

gally privileged.

It is intended solely for use by the individual or entity named on this mes=

sage. If you are not the intended recipient, and have received this message=

in error, please notify us immediately and delete it and any attachments f=

rom your system. <br /><br /> ICON plc made the following annotations.=

------ This e-mail transmission may contain confidential or legally privi=

leged information that is intended only for the individual or entity named =

in the e-mail address. If you are not the intended recipient, you are her=

eby notified that any disclosure, copying, distribution, or reliance upon t=

he contents of this e-mail is strictly prohibited. If you have received t=

his e-mail transmission in error, please reply to the sender, so that ICON =

plc can arrange for proper delivery, and then please delete the message. =

ublin 18 Ireland Registered number: 145835

Received on Wed Apr 13 2016 - 08:25:38 EDT

Date: Wed, 13 Apr 2016 12:25:38 +0000

Hi Jacob,

I suggest:

CAT1=0

CAT2=0

CAT3=0

IF(CAT.EQ.1) CAT1=1

IF(CAT.EQ.2) CAT2=1

IF(CAT.EQ.3) CAT3=1

MU_1 = CAT1*THETA(1) + CAT2*THETA(2) + CAT3*THETA(3)

CL = EXP(MU_1+ETA(1))

That way you have only one OMEGA. This could be more flexible when expandin=

g OMEGA for additional IIV in block format.

Cheers... Brian

From: owner-nmusers

Behalf Of Michael Fossler

Sent: Wednesday, April 13, 2016 7:56 AM

To: Leander, Jacob; nmusers

Subject: [NMusers] RE: Link different thetas to same omega using mu referen=

cing

This looks like it would work - it seems to obey the rules around mu-refere=

ncing. You can simplify the $OMEGA by using SAME(3)

Mike

Michael J. Fossler, Pharm. D., Ph. D., F.C.P.

VP, Quantitative Sciences

Trevena, Inc

mfossler

Office: 610-354-8840, ext. 249

Cell: 610-329-6636

From: owner-nmusers

ilto:owner-nmusers

Sent: Wednesday, April 13, 2016 7:01 AM

To: nmusers

Subject: [NMusers] Link different thetas to same omega using mu referencing

Hi

Consider the case where we have a categorical (potentially time-varying) co=

variate named CAT that can take several values (e.g. 0,1,2,3).

Let's say I want to model CL depending on this categorical covariate (where=

parameters are estimated on log-scale).

A simple solution to this would be

IF(CAT.EQ.1) TVCL = THETA(1)

IF(CAT.EQ.2) TVCL = THETA(2)

IF(CAT.EQ.3) TVCL = THETA(3)

I let CL be described by a log-normal distribution with the same omega elem=

ent for all CAT values.

CL = EXP(TVCL + ETA(1))

With an omega statement:

$OMEGA 0.1

I now want to switch to the mu referencing framework in NONMEM. Each theta =

needs to be reference to a MU value, and to force it to be described by the=

same eta I apply the following approach.

MU_1 = THETA(1)

MU_2 = THETA(2)

MU_3 = THETA(3)

IF(CAT.EQ.1) CL = EXP(MU_1 + ETA(1))

IF(CAT.EQ.2) CL = EXP(MU_2 + ETA(2))

IF(CAT.EQ.3) CL = EXP(MU_3 + ETA(3))

With an omega statement:

$OMEGA BLOCK(1) 0.1

$OMEGA BLOCK(1) SAME

$OMEGA BLOCK(1) SAME

where I force the omega element corresponding to ETA1, ETA2 and ETA3 to be=

the same.

Is this a valid approach to obtain what I need?

Or is there a simpler way in the mu-referencing framework to link different=

thetas to the same omega element?

All the best,

Jacob

________________________________

Confidentiality Notice: This message is private and may contain confidentia=

l and proprietary information. If you have received this message in error, =

please notify us and remove it from your system and note that you must not =

copy, distribute or take any action in reliance on it. Any unauthorized use=

or disclosure of the contents of this message is not permitted and may be =

unlawful.

________________________________

Notice: This e-mail message, together with any attachments, contains inform=

ation of Trevena, Inc., 1018 West 8th Avenue, King of Prussia, PA 19406, US=

A. This information may be confidential, proprietary, copyrighted and/or le=

gally privileged.

It is intended solely for use by the individual or entity named on this mes=

sage. If you are not the intended recipient, and have received this message=

in error, please notify us immediately and delete it and any attachments f=

rom your system. <br /><br /> ICON plc made the following annotations.=

------ This e-mail transmission may contain confidential or legally privi=

leged information that is intended only for the individual or entity named =

in the e-mail address. If you are not the intended recipient, you are her=

eby notified that any disclosure, copying, distribution, or reliance upon t=

he contents of this e-mail is strictly prohibited. If you have received t=

his e-mail transmission in error, please reply to the sender, so that ICON =

plc can arrange for proper delivery, and then please delete the message. =

ublin 18 Ireland Registered number: 145835

Received on Wed Apr 13 2016 - 08:25:38 EDT