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From: Mats Karlsson <Mats.Karlsson_at_farmbio.uu.se>

Date: Tue, 12 Jan 2016 05:02:23 +0000

Dear Sven

If you don't assume the covariance between THETA(1) and THETA(2) to be zero=

but use the estimated covariance value, you do let the data speak. A probl=

em in this respect is that publications never give such values even if it o=

f course is possible. With online access to model code and output (as with =

the DDMoRe repository (repository.ddmore.eu)) it will be more likely to fin=

d the information.

Best regards,

Mats

Skickat från min iPhone

*> 11 jan 2016 kl. 14:28 skrev Stodtmann, Sven <sven.stodtmann_at_Abbvie.com>:
*

*>
*

*> Dear All,
*

*>
*

*> In order to account for uncertainty in estimated parameters when running =
*

a simulation, a natural approach would be running multiple simulations for =

different parameter vectors which are drawn from the (theoretical, asymptot=

ic) distribution of the estimator (i.e. normal with mean THETA and covarian=

ce according to the NONMEMs $COR output for the THETAs).

*> This approach may in some cases (particularly, when there are a lot of co=
*

variate effects estimated) lead to very broad parameter distributions, even=

assigning some quite high probability of unphysiological values if one did=

n’t have good quality data, strong priors or a very careful parametrizati=

on of the model (e.g. transforming/bounding parameters, which requires/intr=

oduces prior knowledge as well).

*>
*

*> Another problem connected with parameter uncertainty on covariate effects=
*

is the following. Say we model

*> TVCL = THETA(1)
*

*> SEX_EFF = THETA(2)
*

*> CL = TVCL * SEX_EFF**SEX, =
*

(Eq. 1)

*> where male is coded as SEX=0, female as SEX=1.
*

*> In this case, when using the above mentioned technique to account for par=
*

ameter uncertainty, the female population will have a more variable (uncert=

ain) PK, not just different one. If we phrase the problem differently, usin=

g

*> CL = TVCL * SEX_EFF**(1-SEX) , (=
*

Eq. 2)

*> The conclusion would be the other way around (i.e. male PK is more uncert=
*

ain).

*>
*

*> One approach to deal with the second problem could be this:
*

*> In order to remove this (usually unjustified) assumption (the female popu=
*

lation having a less certain PK compared to the male), one could try to mod=

el the same covariate effect as follows:

*> TVCL = THETA(1)
*

*> SQRT_SEX_EFF = THETA(2)
*

*> CL = TVCL * SQRT_SEX_EFF**SEX / SQRT_SEX_EFF**(1-SEX)
*

*> In this case TVCL would already include “half” of the effect (on the =
*

log scale; the “new” TVCL would be TVCL*SQRT(SEX_EFF) in terms of the p=

arameters used in Eq.1).

*> With this approach, both sub-populations, male and female get “some par=
*

t” of the uncertainty effect.

*> Of course it would be even nicer to let the data decide which sub-populat=
*

ion gets how much uncertainty exactly instead of evenly splitting it.

*>
*

*> How do you deal with uncertainty in the estimates of covariate effects wh=
*

en it comes to simulations/predictions?

*>
*

*> Kind Regards,
*

*> _________________________________________________________________________=
*

_______________________________________________

*> SVEN STODTMANN, PHD
*

*> Pharmacometrician
*

*>
*

*> AbbVie Deutschland GmbH & Co KG
*

*> Clinical Pharmacology and Pharmacometrics
*

*> Knollstrasse 50
*

*> 67065 Ludwigshafen am Rhein, Germany
*

*> OFFICE +49 621-589-1940
*

*> EMAIL sven.stodtmann_at_Abbvie.com
*

*>
*

*> abbvie.com
*

*> _________________________________________________________________________=
*

_______________________________________________

*>
*

*> ________________________________
*

*>
*

*> Sitz der Gesellschaft: Wiesbaden - Registergericht: AG Wiesbaden HRA 9790
*

*> Persönlich haftende Gesellschafterin: AbbVie Komplementär GmbH
*

*> Sitz der persönlich haftenden Gesellschafterin: Wiesbaden - Registerger=
*

icht: AG Wiesbaden HRB 26371

*> Geschäftsführer: Dr. Patrick Horber, Thomas Scheidmeir, Dr. Stefan Si=
*

mianer, William J. Chase

*> Vorsitzende des Aufsichtsrats: Dr. Azita Saleki-Gerhardt
*

*>
*

*> This communication may contain information that is proprietary, confident=
*

ial, or exempt from disclosure. If you are not the intended recipient, plea=

se note that any other dissemination, distribution, use or copying of this =

communication is strictly prohibited. Anyone who receives this message in e=

rror should notify the sender immediately by telephone or by return e-mail =

and delete it from his or her computer.

*>
*

*> Diese Kommunikation kann Informationen enthalten, die geheim, vertraulich=
*

oder hinsichtlich der Offenlegung beschränkt sind. Wenn Sie nicht der be=

absichtigte Empfänger sind, nehmen Sie bitte zur Kenntnis, dass jede Weit=

ergabe, Verteilung, Verwendung oder Vervielfältigung dieser. Kommunikatio=

n strikt untersagt ist. Jeder, der diese Nachricht fehlerhaft erhält, sol=

lte den Sender unverzüglich telefonisch oder durch Rücksendung der E-Ma=

il benachrichtigen und diese von seinem oder ihrem Computer löschen.

Received on Tue Jan 12 2016 - 00:02:23 EST

Date: Tue, 12 Jan 2016 05:02:23 +0000

Dear Sven

If you don't assume the covariance between THETA(1) and THETA(2) to be zero=

but use the estimated covariance value, you do let the data speak. A probl=

em in this respect is that publications never give such values even if it o=

f course is possible. With online access to model code and output (as with =

the DDMoRe repository (repository.ddmore.eu)) it will be more likely to fin=

d the information.

Best regards,

Mats

Skickat från min iPhone

a simulation, a natural approach would be running multiple simulations for =

different parameter vectors which are drawn from the (theoretical, asymptot=

ic) distribution of the estimator (i.e. normal with mean THETA and covarian=

ce according to the NONMEMs $COR output for the THETAs).

variate effects estimated) lead to very broad parameter distributions, even=

assigning some quite high probability of unphysiological values if one did=

n’t have good quality data, strong priors or a very careful parametrizati=

on of the model (e.g. transforming/bounding parameters, which requires/intr=

oduces prior knowledge as well).

is the following. Say we model

(Eq. 1)

ameter uncertainty, the female population will have a more variable (uncert=

ain) PK, not just different one. If we phrase the problem differently, usin=

g

Eq. 2)

ain).

lation having a less certain PK compared to the male), one could try to mod=

el the same covariate effect as follows:

log scale; the “new” TVCL would be TVCL*SQRT(SEX_EFF) in terms of the p=

arameters used in Eq.1).

t” of the uncertainty effect.

ion gets how much uncertainty exactly instead of evenly splitting it.

en it comes to simulations/predictions?

_______________________________________________

_______________________________________________

icht: AG Wiesbaden HRB 26371

mianer, William J. Chase

ial, or exempt from disclosure. If you are not the intended recipient, plea=

se note that any other dissemination, distribution, use or copying of this =

communication is strictly prohibited. Anyone who receives this message in e=

rror should notify the sender immediately by telephone or by return e-mail =

and delete it from his or her computer.

oder hinsichtlich der Offenlegung beschränkt sind. Wenn Sie nicht der be=

absichtigte Empfänger sind, nehmen Sie bitte zur Kenntnis, dass jede Weit=

ergabe, Verteilung, Verwendung oder Vervielfältigung dieser. Kommunikatio=

n strikt untersagt ist. Jeder, der diese Nachricht fehlerhaft erhält, sol=

lte den Sender unverzüglich telefonisch oder durch Rücksendung der E-Ma=

il benachrichtigen und diese von seinem oder ihrem Computer löschen.

Received on Tue Jan 12 2016 - 00:02:23 EST

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