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

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

 

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

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