Re: OMEGA BLOCK with mixture model?

> -----Original Message----- > > From: Leonid Gibiansky [ mailto: [email protected] ] Sent: Thursday, April 16, 2009 2:22 PM > > To: Mats Karlsson > Cc: [email protected] > 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: [email protected] ] Sent: Thursday, April 16, 2009 10:13 AM > > > > To: Mats Karlsson; [email protected]; [email protected]; > > [email protected] > > 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: [email protected] > > P: +64 3 479 5044 > > F: +64 3 479 7034 > > > > Design software: www.winpopt.com