From: Leander, Jacob <*Jacob.Leander*>

Date: Thu, 14 Apr 2016 07:52:08 +0000

Thanks. You’re right. With my solution the eta is not constant for an individual, instead it will vary for each value of the categorical covariate, meaning that it is similar to IOV. With your solution we restrict only one eta per individual not matter of the covariate value.

To exemplify this discussion one can think of two different oral formulations with different absorption rate that are given in sequence. The question is then if we would expect that a person who has “higher than normal” absorption rate for the first formulation also would have a “higher than normal” absorption rate for the second formulation. If the answer to that question is yes then one should impose the restriction that you described.

//Jacob

From: Emmanuel Chigutsa [mailto:echigutsa

Sent: den 13 april 2016 22:47

To: Leander, Jacob <Jacob.Leander

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

Hi Jacob,

Yes, THETA(4) would represent the typical value (before exponentiation). In summary, writing your covariate code after the definition of MU should circumvent the time-varying problem. If you want everything on a log scale you could try:

OCL=MU_1+ETA(1)

CL=EXP(OCL+CLCOV)

The issue with trying to use different etas for the different thetas as you had was that only the variance (omega) was constrained to be same, but not necessarily the same eta for each ID.

Mannie

________________________________

From: "Leander, Jacob" <Jacob.Leander

To: Emmanuel Chigutsa <echigutsa

Sent: Wednesday, April 13, 2016 2:00 PM

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

Thanks for the answers.

Just as Rupert pointed out it is not possible to model time-dependent covariates in the MU expression. I am not sure what is happening if you do but since the NONMEM manual explicitly tell you to avoid it you should not do it.

It seems that Mannies code instead uses a THETA(4) to model the “mean” value and then use CLCOV to change the value for different covariates. Or what does THETA(4) mean in your code Mannie? Remember that the problems was to impose same omega element for different thetas depending on time-varying covariate and also estimate all the parameters on a log scale.

//Jacob

From: owner-nmusers

Sent: den 13 april 2016 19:01

To: rupert.austin

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

I think the following code should work:

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

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

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

MU_1 = THETA(4)

CL = EXP(MU_1+ETA(1))*(1+CLCOV)

$OMEGA BLOCK(1) 0.1

Mannie

________________________________

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Received on Thu Apr 14 2016 - 03:52:08 EDT

Date: Thu, 14 Apr 2016 07:52:08 +0000

Thanks. You’re right. With my solution the eta is not constant for an individual, instead it will vary for each value of the categorical covariate, meaning that it is similar to IOV. With your solution we restrict only one eta per individual not matter of the covariate value.

To exemplify this discussion one can think of two different oral formulations with different absorption rate that are given in sequence. The question is then if we would expect that a person who has “higher than normal” absorption rate for the first formulation also would have a “higher than normal” absorption rate for the second formulation. If the answer to that question is yes then one should impose the restriction that you described.

//Jacob

From: Emmanuel Chigutsa [mailto:echigutsa

Sent: den 13 april 2016 22:47

To: Leander, Jacob <Jacob.Leander

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

Hi Jacob,

Yes, THETA(4) would represent the typical value (before exponentiation). In summary, writing your covariate code after the definition of MU should circumvent the time-varying problem. If you want everything on a log scale you could try:

OCL=MU_1+ETA(1)

CL=EXP(OCL+CLCOV)

The issue with trying to use different etas for the different thetas as you had was that only the variance (omega) was constrained to be same, but not necessarily the same eta for each ID.

Mannie

________________________________

From: "Leander, Jacob" <Jacob.Leander

To: Emmanuel Chigutsa <echigutsa

Sent: Wednesday, April 13, 2016 2:00 PM

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

Thanks for the answers.

Just as Rupert pointed out it is not possible to model time-dependent covariates in the MU expression. I am not sure what is happening if you do but since the NONMEM manual explicitly tell you to avoid it you should not do it.

It seems that Mannies code instead uses a THETA(4) to model the “mean” value and then use CLCOV to change the value for different covariates. Or what does THETA(4) mean in your code Mannie? Remember that the problems was to impose same omega element for different thetas depending on time-varying covariate and also estimate all the parameters on a log scale.

//Jacob

From: owner-nmusers

Sent: den 13 april 2016 19:01

To: rupert.austin

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

I think the following code should work:

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

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

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

MU_1 = THETA(4)

CL = EXP(MU_1+ETA(1))*(1+CLCOV)

$OMEGA BLOCK(1) 0.1

Mannie

________________________________

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.

Received on Thu Apr 14 2016 - 03:52:08 EDT