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From: Eleveld, DJ <d.j.eleveld_at_umcg.nl>

Date: Tue, 6 Oct 2015 08:30:03 +0000

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 e=

xactly the same.

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

e 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 (i=

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

he units of the THETA you estimate.

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

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

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

s 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 migh=

t 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 g=

et:

(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 advan=

tage 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 valu=

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

g exponent should be -0.25.

warm regards,

Douglas Eleveld

________________________________

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

ens 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 a=

nd 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 allomet=

rically 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 o=

r why not.

Thanks

Andre

________________________________

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

sseerde(n). Anderen dan de geadresseerde(n) mogen geen gebruik maken van di=

t bericht, het niet openbaar maken of op enige wijze verspreiden of vermeni=

gvuldigen. Het UMCG kan niet aansprakelijk gesteld worden voor een incomple=

te aankomst of vertraging van dit verzonden bericht.

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

s 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 i=

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

delay of this transferred message.

Received on Tue Oct 06 2015 - 04:30:03 EDT

Date: Tue, 6 Oct 2015 08:30:03 +0000

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 e=

xactly the same.

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

e 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 (i=

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

he units of the THETA you estimate.

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

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

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

s 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 migh=

t 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 g=

et:

(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 advan=

tage 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 valu=

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

g exponent should be -0.25.

warm regards,

Douglas Eleveld

________________________________

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

ens 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 a=

nd 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 allomet=

rically 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 o=

r why not.

Thanks

Andre

________________________________

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

sseerde(n). Anderen dan de geadresseerde(n) mogen geen gebruik maken van di=

t bericht, het niet openbaar maken of op enige wijze verspreiden of vermeni=

gvuldigen. Het UMCG kan niet aansprakelijk gesteld worden voor een incomple=

te aankomst of vertraging van dit verzonden bericht.

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

s 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 i=

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

delay of this transferred message.

Received on Tue Oct 06 2015 - 04:30:03 EDT