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RE: OMEGA BLOCK with mixture model?

From: Mats Karlsson <mats.karlsson>
Date: Sun, 19 Apr 2009 10:09:09 +0200

Hi Leonid,

Pls see below.

Mats Karlsson, PhD
Professor of Pharmacometrics
Dept of Pharmaceutical Biosciences
Uppsala University
Box 591
751 24 Uppsala Sweden
phone: +46 18 4714105
fax: +46 18 471 4003


-----Original Message-----
From: Leonid Gibiansky [mailto:LGibiansky
Sent: Thursday, April 16, 2009 2:22 PM
To: Mats Karlsson
Cc: nmusers
Subject: Re: [NMusers] OMEGA BLOCK with mixture model?

Mats,
Another difference between BLOCK(2) and DIAG(3) is that they provide
different number of ETAs for the individual fit. I am a bit surprised
that one-compartment model with random effects on CL, V, and F is
identifiable (even with diagonal OMEGA). Indeed, for each subject, this
model has 3 free parameters. The only thing that allows to identify them
separately is the distributional assumption. It could be rather week so
I would expect higher variance values with DIAG(3) versus BLOCK(2).

>>Actually parameter estimates are the same for the two runs DIAG3 and
BLOCK2.

How often have you used ETAs on CL, V, and F in the same one-compartment
model (without IV arm)? Is it always stable (or at least as stable as
BLOCK(2))?

>>I've probably used it 5-15 times. I have noted no difference in stability
compared to BLOCK.
I ran a small simulation study (3 conditions X 100 dataset) comparing DIAG3
and BLOCK2. I found no important difference between the two in OFV,
stability or parameter estimates.

Thanks
Leonid

--------------------------------------
Leonid Gibiansky, Ph.D.
President, QuantPharm LLC
web: www.quantpharm.com
e-mail: LGibiansky at quantpharm.com
tel: (301) 767 5566




Mats Karlsson wrote:
> Hi Steve,
>
> For a one-compartment model I think these are differences:
>
> 1) DIAG(3) is more restrictive than BLOCK(2) in the sense that only
positive
> correlation between CL/F and V/F can be estimated
> 2) DIAG(3) is less restrictive than BLOCK(2) in the sense that different
> transformations can be used for F
> 3) DIAG(3) provides an EBE that can be used for diagnostic purposes
(DIAG(3)
> and BLOCK(2) would give the same estimates for the same model so I don't
> understand your comment of var(F) being higher than cov(CL/F,V/F))
> 4) DIAG(3) may facilitate covariate model building (although this is minor
> as you with BLOCK(2) can put the same relationship in in two places)
> 5) If there truly is a mixture in F1, then I think DIAG(3) has a
advantages
> over BLOCK(2) in number of parameters (two fewer) needed to describe the
> variability model
> 6) If some additional assumptions can be reliably made, such as all
> variability in F1 is truly in bioavailability and bioavailability is
> restricted to be between 0 and 1, some additional info may be extracted
from
> the data for example by .
>
> I would not rank any of these as major differences (expect possibly the
> mixture aspect which I've never tried).
>
> For two- or three-compartment models the advantages are that if indeed the
> main covariance structure between CL/F, V1/F, Q/F, V2/F is a joint
positive
> correlation due to variability in bioavailability, fu etc, then a DIAG(5)
is
> more parsimonious than a BLOCK(4).
>
> Mats
>
> Mats Karlsson, PhD
> Professor of Pharmacometrics
> Dept of Pharmaceutical Biosciences
> Uppsala University
> Box 591
> 751 24 Uppsala Sweden
> phone: +46 18 4714105
> fax: +46 18 471 4003
>
>
> -----Original Message-----
> From: Stephen Duffull [mailto:stephen.duffull
> Sent: Thursday, April 16, 2009 10:13 AM
> To: Mats Karlsson; drmould
> nmusers
> Subject: RE: [NMusers] OMEGA BLOCK with mixture model?
>
> Mats
>
>> With oral data only I would normally model with BLOCK(2) on
>> CL/F and V/F or a DIAG(3) on CL/F, V/F and relative F. The
>> latter may have some advantages for diagnostics, covariate
>> model building etc.
>
> I have often seen these two options considered. I am unclear as to the
> advantages of DIAG(3) over BLOCK(2)? In theory it would seem that they
> should be identical. In practice it seems that DIAG(3) is more relaxed
> since it is not required that the variance of relative F if reassigned to
> the covariance of (CL/F, V/F) [under BLOCK(2)] yields a positive definite
> matrix.
>
> I presume an advantage wrt covariate model building would be access to the
> EBEs of F_i. However, given the variance of F_i may exceed the covariance
> of (CL/F, V/F) then I wonder if this is a real advantage or an artefact of
> numerical procedures?
>
> I am keen to learn more about real advantages of application of DIAG(3) as
> an alternative to BLOCK(2).
>
> Steve
> --
> Professor Stephen Duffull
> Chair of Clinical Pharmacy
> School of Pharmacy
> University of Otago
> PO Box 913 Dunedin
> New Zealand
> E: stephen.duffull
> P: +64 3 479 5044
> F: +64 3 479 7034
>
> Design software: www.winpopt.com
>
>
Received on Sun Apr 19 2009 - 04:09:09 EDT

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