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 > >
