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:lgibian...@quantpharm.com]
Sent: Thursday, April 16, 2009 2:22 PM
To: Mats Karlsson
Cc: nmusers@globomaxnm.com
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.duff...@otago.ac.nz]
Sent: Thursday, April 16, 2009 10:13 AM
To: Mats Karlsson; drmo...@pri-home.net; nele.pl...@nycomed.com;
nmusers@globomaxnm.com
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.duff...@otago.ac.nz
P: +64 3 479 5044
F: +64 3 479 7034
Design software: www.winpopt.com
