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From: Rupert Austin <rupert.austin_at_btconnect.com>

Date: Wed, 13 Apr 2016 16:44:28 +0100

I’m not sure that Brian’s suggestion is acceptable due =

to the following constraint I quote from one of the NONMEM manuals:

“Time dependent covariates cannot be part of the MU_ =

equation”

If CAT is time-varying (as suggested by Jacob) then “MU_1 = =

CAT1*THETA(1) + CAT2*THETA(2) + CAT3*THETA(3)” includes time =

dependent covariates. Rather worryingly, I don’t think NONMEM =

will trap this problem since I have fallen foul of it with no resulting =

NONMEM warnings, and I have no idea what the consequences are for the =

resulting NONMEM run and results.

Rupert

Rupert Austin, PhD

Senior Scientist

BAST Inc Limited

Loughborough University Science and Enterprise Park

Charnwood Wing

Holywell Park

Ashby Road

Loughborough, LE11 3AQ, UK

Tel: +44 (0)1509 222908

From: owner-nmusers_at_globomaxnm.com [mailto:owner-nmusers_at_globomaxnm.com] =

On Behalf Of Sadler, Brian

Sent: 13 April 2016 13:26

To: nmusers_at_globomaxnm.com

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

referencing

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 =

expanding OMEGA for additional IIV in block format.

Cheers… Brian

From: owner-nmusers_at_globomaxnm.com <mailto:owner-nmusers_at_globomaxnm.com> =

[mailto:owner-nmusers_at_globomaxnm.com] On Behalf Of Michael Fossler

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

To: Leander, Jacob; nmusers_at_globomaxnm.com =

<mailto:nmusers_at_globomaxnm.com>

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

referencing

This looks like it would work – it seems to obey the rules =

around mu-referencing. 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

<mailto:mfossler_at_trevenainc.com> mfossler_at_trevenainc.com

Office: 610-354-8840, ext. 249

Cell: 610-329-6636

From: owner-nmusers_at_globomaxnm.com <mailto:owner-nmusers_at_globomaxnm.com> =

[mailto:owner-nmusers_at_globomaxnm.com] On Behalf Of Leander, Jacob

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

To: nmusers_at_globomaxnm.com <mailto:nmusers_at_globomaxnm.com>

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

referencing

Hi

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

covariate 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 =

element 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 =

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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 =

information of Trevena, Inc., 1018 West 8th Avenue, King of Prussia, PA =

19406, USA. This information may be confidential, proprietary, =

copyrighted and/or legally privileged.

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

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

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

attachments from your system.

ICON plc made the following annotations.

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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 =

hereby notified that any disclosure, copying, distribution, or reliance =

upon the contents of this e-mail is strictly prohibited. If you have =

received this e-mail transmission in error, please reply to the sender, =

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the message.

Thank You,

ICON plc

South County Business Park

Leopardstown

Dublin 18

Ireland

Registered number: 145835

Received on Wed Apr 13 2016 - 11:44:28 EDT

Date: Wed, 13 Apr 2016 16:44:28 +0100

I’m not sure that Brian’s suggestion is acceptable due =

to the following constraint I quote from one of the NONMEM manuals:

“Time dependent covariates cannot be part of the MU_ =

equation”

If CAT is time-varying (as suggested by Jacob) then “MU_1 = =

CAT1*THETA(1) + CAT2*THETA(2) + CAT3*THETA(3)” includes time =

dependent covariates. Rather worryingly, I don’t think NONMEM =

will trap this problem since I have fallen foul of it with no resulting =

NONMEM warnings, and I have no idea what the consequences are for the =

resulting NONMEM run and results.

Rupert

Rupert Austin, PhD

Senior Scientist

BAST Inc Limited

Loughborough University Science and Enterprise Park

Charnwood Wing

Holywell Park

Ashby Road

Loughborough, LE11 3AQ, UK

Tel: +44 (0)1509 222908

From: owner-nmusers_at_globomaxnm.com [mailto:owner-nmusers_at_globomaxnm.com] =

On Behalf Of Sadler, Brian

Sent: 13 April 2016 13:26

To: nmusers_at_globomaxnm.com

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

referencing

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 =

expanding OMEGA for additional IIV in block format.

Cheers… Brian

From: owner-nmusers_at_globomaxnm.com <mailto:owner-nmusers_at_globomaxnm.com> =

[mailto:owner-nmusers_at_globomaxnm.com] On Behalf Of Michael Fossler

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

To: Leander, Jacob; nmusers_at_globomaxnm.com =

<mailto:nmusers_at_globomaxnm.com>

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

referencing

This looks like it would work – it seems to obey the rules =

around mu-referencing. 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

<mailto:mfossler_at_trevenainc.com> mfossler_at_trevenainc.com

Office: 610-354-8840, ext. 249

Cell: 610-329-6636

From: owner-nmusers_at_globomaxnm.com <mailto:owner-nmusers_at_globomaxnm.com> =

[mailto:owner-nmusers_at_globomaxnm.com] On Behalf Of Leander, Jacob

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

To: nmusers_at_globomaxnm.com <mailto:nmusers_at_globomaxnm.com>

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

referencing

Hi

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

covariate 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 =

element 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 =

confidential 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 =

information of Trevena, Inc., 1018 West 8th Avenue, King of Prussia, PA =

19406, USA. This information may be confidential, proprietary, =

copyrighted and/or legally privileged.

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

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

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

attachments from your system.

ICON plc made the following annotations.

-------------------------------------------------------------------------=

-----

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

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 =

hereby notified that any disclosure, copying, distribution, or reliance =

upon the contents of this e-mail is strictly prohibited. If you have =

received this 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.

Thank You,

ICON plc

South County Business Park

Leopardstown

Dublin 18

Ireland

Registered number: 145835

Received on Wed Apr 13 2016 - 11:44:28 EDT

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