# RE: RE: Link different thetas to same omega using mu referencing

From: Rupert Austin <rupert.austin>
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

Loughborough, LE11 3AQ, UK

Tel: +44 (0)1509 222908

From: owner-nmusers
Sent: 13 April 2016 13:26
To: nmusers
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
[mailto:owner-nmusers
Sent: Wednesday, April 13, 2016 7:56 AM
To: Leander, Jacob; nmusers
<mailto:nmusers
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

Office: 610-354-8840, ext. 249

Cell: 610-329-6636

From: owner-nmusers
[mailto: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) =
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, =
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 =

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

Thank You,

ICON plc