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RE: Calculating shrinkage when some etas are zero

From: Ribbing, Jakob <Jakob.Ribbing>
Date: Fri, 21 Aug 2009 14:12:11 +0100

Hi Douglas,

 

This has been a concern for me as well, although I do not know if this =
ever happens(?). For the automatic (generic scripts) exclusion of etas =
that I use for eta-diagnostics, I tend to exclude a group (e.g. each =
dose or dose-study combination) if all subjects have eta=0 in that =
group. This would for example exclude IOV-eta3 from a study that only =
hade two occasions, or the placebo group(s) for etas on drug effect. I =
feel safe with that exclusion for my diagnostics. If I had to make the =
choice between excluding all etas that are exactly equal to zero or none =
at all, I would more trust diagnostics after exclusion.

 

Jakob

 

________________________________

From: Eleveld, DJ [mailto:d.j.eleveld
Sent: 21 August 2009 13:57
To: Ribbing, Jakob; Pyry Všlitalo; nmusers
Subject: RE: [NMusers] Calculating shrinkage when some etas are zero

 

Hi Pyry and Jacob,

 

If you exclude zero etas then what happens to infomative individuals who =
just happen to have the population typical values?

This approch would exclude these individuals when trying to indicate how =
informative an estimation is about a parameter.

I know this is unlikely, but it is possible.

 

The etas just tell what value is estimated, its not the whole story =
about how infomative an estimation is. I dont think you can do

this without considering how 'certian' you are of each of those eta =
values.

 

Douglas Eleveld

 

________________________________

Van: owner-nmusers
Verzonden: vr 21-8-2009 12:26
Aan: Pyry Všlitalo; nmusers
Onderwerp: RE: [NMusers] Calculating shrinkage when some etas are zero

Hi Pyry,

 

Yes, when calculating shrinkage or looking at eta-diagnostic plots it is =
often better to exclude etas from subjects that has no information on =
that parameter at all. For a PK model we would not include subjects that =
were only administered placebo (if PK is exogenous compound). In the =
same manner placebo subjects are not informative on the drug-effects =
parameters of a (PK-)PD model. These subjects have informative etas for =
the placebo-part of the PD model, but not on the drug-effects (etas on =
Emax, ED50, etc.). For any eta-diagnostics you can removed these etas =
based on design (placebo subject, IV dosing, et c) or the =
empirical-Bayes estimate of eta being zero.

 

Cheers

 

Jakob

 

________________________________

From: owner-nmusers
On Behalf Of Pyry Všlitalo
Sent: 21 August 2009 10:45
To: nmusers
Subject: [NMusers] Calculating shrinkage when some etas are zero

 

Hi all,

I saw this snippet of information on PsN-general mailing list.

Kajsa Harling wrote in PsN-general:
"I talked to the experts here about shrinkage. Apparently, sometimes an
individual's eta may be exactly 0 (no effect, placebo, you probably
understand this better than I do). These zeros should not be included in
the shrinkage calculation, but now they are (erroneously) in PsN."

This led me to wonder about the calculation of shrinkage. I decided to =
post here on nmusers, because my question mainly relates to NONMEM. I =
could not find previous discussions about this topic exactly.

As I understand, if a parameter with BSV is not used by some =
individuals, the etas for these individuals will be set to zero. An =
example would be a dataset with IV and oral dosing data. If oral =
absorption rate constant KA with BSV is estimated for this data, then =
all eta(KA) values for IV dosing group will be zero.

The shrinkage of etas is calculated as
1-sd(etas)/omega
If the etas that equal exactly zero would have to be removed from this =
equation then it would mean that NONMEM estimates the omega based on =
only those individuals who need it for the parameter in question, e.g. =
the omega(KA) would be estimated only based on the oral dosing group. Is =
this a correct interpretation for the rationale to leave out zero etas?

I guess the inclusion of zero etas into shrinkage calculations =
significantly increases the estimate of shrinkage because the zero etas =
always reduce the sd(etas). As a practical example, suppose a dataset of =
20 patients with oral and 20 patients with IV administration. Suppose =
NONMEM estimates an omega of 0.4 for BSV of KA. Suppose the sd(etas) for =
oral group is 0.3 and thus sd(etas) for all patients is 0.3/sqrt(2) =
since the etas in IV group for KA are zero.
Thus, as far as I know, PsN would currently calculate a shrinkage of =
1-(0.3/sqrt(2))/0.4=0.47.
Would it be more appropriate to manually calculate a shrinkage of =
1-0.3/0.4=0.25 instead?

All comments much appreciated.

Kind regards,
Pyry



Kajsa Harling wrote:

Dear Ethan,

I have also been away for a while, thank you for your patience.

I talked to the experts here about shrinkage. Apparently, sometimes an
individual's eta may be exactly 0 (no effect, placebo, you probably
understand this better than I do). These zeros should not be included in
the shrinkage calculation, but now they are (erroneously) in PsN.

Does this explain the discrepancy?

Then, the heading shrinkage_wres is incorrect, it should say
shrinkage_iwres (or eps) they say.

Comments are fine as long as they do not have commas in them. But this
is fixed in the latest release.

Best regards,
Kajsa

________________________________

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Received on Fri Aug 21 2009 - 09:12:11 EDT

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