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From: Andre Jackson <jacksonan1945_at_gmail.com>

Date: Tue, 6 Oct 2015 07:40:19 -0400

Thanks for the clarification. It cleared up a lot of issues for me.

From: Eleveld, DJ [mailto:d.j.eleveld_at_umcg.nl]

Sent: Tuesday, October 6, 2015 4:30 AM

To: 'Andre Jackson'; nmusers_at_globomaxnm.com

Subject: RE: [NMusers] Phsysiological model

Hi Andre,

Hopefully you can see that

(1) QCO=15.87*(BW)**0.75

calculates very different values for QCO compared to

(2) QCO=15.87*(WT/WTstd)**0.75

unless of course WTstd is 1kg. In that case (WTstd is 1 kg) then they are

exactly the same.

The easiest way to separate these situations is to find out the units of the

15.87. Where does this number come from?

If QCO is cardiac output (i am just guessing here) then the units should be

l/min or something like that. In (1) the 15.87 is the l/min/kg

but in (2) the units of the 15.87 are l/min/70kg. So for (1) a 70 kg person

QCO would be 384 l/min while for (2) a 70 kg persom gives 15.87 l/min.

Hopefully one of these is obviously wrong so you can pick the right one.

If the 15.87 is an estimated parameter (a THETA) then it does not matter (in

a mathematical functional sense) what WTstd you use. It does the change the

units of the THETA you estimate.

Using 1 kg seems mathematically easiest but it makes interpretation a bit

harder. The advantage of using WGTstd=70kg is that the estimated THETA has

an easy interpretation as the predicted QCO for a standard individual. This

makes comparison between studies quite a bit easier.

A simplified example for an imaginary drug:

Imagine studies in children and adults and obese and they all normalize to

their median weights in thier individual studies so for clearance they might

find something like:

(children) CL=0.314*(WT/15kg)**0.75

(adults) CL=1*(WT/70kg)**0.75

(obese) CL=1.498*(WT/120kg)**0.75

Do these look different from each other? Superficially they do. But if you

use the adult equation to calculate the values for children and obese you

get:

(adult formula, predict 15 kg child)CL=1*(15kg/70kg)=0.314

(adult formula, predict 120 kg obese)CL=1*(120kg/70kg)=1.498

So the three formulas (children,adults,obese) are actually exaclty the same

because they predict the same CL values for all weights. This is the

advantage for using WTstd=70kg even if the median weight isnt close to 70

kg.

I agree with Nich Holford about the theoretical scaling exponent for k

values. If you are estimating values where the units are 1/time then the

scaling exponent should be -0.25.

warm regards,

Douglas Eleveld

_____

Van: owner-nmusers_at_globomaxnm.com [mailto:owner-nmusers_at_globomaxnm.com]

Namens Andre Jackson

Verzonden: October 5, 2015 7:18 PM

Aan: nmusers_at_globomaxnm.com

Onderwerp: [NMusers] Phsysiological model

All:

I am attempting to take a Physiological model presented in the literature

and place it into Nonmem with the help of the authors. A point was raised

related to centering parameters which I would appreciate some feedback.

In the published paper, model parameters such as Cardiac output are

allometrically scaled as power models:

QCO=15.87*(BW)**0.75

and gut metabolism as:

K_Gutmet=THETA(2)*(WT)**0.75)

My question is should I use these equations as stated in the publication or

should I center the estimates as e.g.,

QCO=15.87*(WT/WTstd)**0.75

The weights that will be investigated go from 30 kg up to 80 kg.

It would also be very helpful if one can give me an explanation as to why or

why not.

Thanks

Andre

_____

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Received on Tue Oct 06 2015 - 07:40:19 EDT

Date: Tue, 6 Oct 2015 07:40:19 -0400

Thanks for the clarification. It cleared up a lot of issues for me.

From: Eleveld, DJ [mailto:d.j.eleveld_at_umcg.nl]

Sent: Tuesday, October 6, 2015 4:30 AM

To: 'Andre Jackson'; nmusers_at_globomaxnm.com

Subject: RE: [NMusers] Phsysiological model

Hi Andre,

Hopefully you can see that

(1) QCO=15.87*(BW)**0.75

calculates very different values for QCO compared to

(2) QCO=15.87*(WT/WTstd)**0.75

unless of course WTstd is 1kg. In that case (WTstd is 1 kg) then they are

exactly the same.

The easiest way to separate these situations is to find out the units of the

15.87. Where does this number come from?

If QCO is cardiac output (i am just guessing here) then the units should be

l/min or something like that. In (1) the 15.87 is the l/min/kg

but in (2) the units of the 15.87 are l/min/70kg. So for (1) a 70 kg person

QCO would be 384 l/min while for (2) a 70 kg persom gives 15.87 l/min.

Hopefully one of these is obviously wrong so you can pick the right one.

If the 15.87 is an estimated parameter (a THETA) then it does not matter (in

a mathematical functional sense) what WTstd you use. It does the change the

units of the THETA you estimate.

Using 1 kg seems mathematically easiest but it makes interpretation a bit

harder. The advantage of using WGTstd=70kg is that the estimated THETA has

an easy interpretation as the predicted QCO for a standard individual. This

makes comparison between studies quite a bit easier.

A simplified example for an imaginary drug:

Imagine studies in children and adults and obese and they all normalize to

their median weights in thier individual studies so for clearance they might

find something like:

(children) CL=0.314*(WT/15kg)**0.75

(adults) CL=1*(WT/70kg)**0.75

(obese) CL=1.498*(WT/120kg)**0.75

Do these look different from each other? Superficially they do. But if you

use the adult equation to calculate the values for children and obese you

get:

(adult formula, predict 15 kg child)CL=1*(15kg/70kg)=0.314

(adult formula, predict 120 kg obese)CL=1*(120kg/70kg)=1.498

So the three formulas (children,adults,obese) are actually exaclty the same

because they predict the same CL values for all weights. This is the

advantage for using WTstd=70kg even if the median weight isnt close to 70

kg.

I agree with Nich Holford about the theoretical scaling exponent for k

values. If you are estimating values where the units are 1/time then the

scaling exponent should be -0.25.

warm regards,

Douglas Eleveld

_____

Van: owner-nmusers_at_globomaxnm.com [mailto:owner-nmusers_at_globomaxnm.com]

Namens Andre Jackson

Verzonden: October 5, 2015 7:18 PM

Aan: nmusers_at_globomaxnm.com

Onderwerp: [NMusers] Phsysiological model

All:

I am attempting to take a Physiological model presented in the literature

and place it into Nonmem with the help of the authors. A point was raised

related to centering parameters which I would appreciate some feedback.

In the published paper, model parameters such as Cardiac output are

allometrically scaled as power models:

QCO=15.87*(BW)**0.75

and gut metabolism as:

K_Gutmet=THETA(2)*(WT)**0.75)

My question is should I use these equations as stated in the publication or

should I center the estimates as e.g.,

QCO=15.87*(WT/WTstd)**0.75

The weights that will be investigated go from 30 kg up to 80 kg.

It would also be very helpful if one can give me an explanation as to why or

why not.

Thanks

Andre

_____

De inhoud van dit bericht is vertrouwelijk en alleen bestemd voor de

geadresseerde(n). Anderen dan de geadresseerde(n) mogen geen gebruik maken

van dit bericht, het niet openbaar maken of op enige wijze verspreiden of

vermenigvuldigen. Het UMCG kan niet aansprakelijk gesteld worden voor een

incomplete aankomst of vertraging van dit verzonden bericht.

The contents of this message are confidential and only intended for the eyes

of the addressee(s). Others than the addressee(s) are not allowed to use

this message, to make it public or to distribute or multiply this message in

any way. The UMCG cannot be held responsible for incomplete reception or

delay of this transferred message.

Received on Tue Oct 06 2015 - 07:40:19 EDT