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Re: OMEGA BLOCK with mixture model?

From: Leonid Gibiansky <LGibiansky>
Date: Sun, 19 Apr 2009 13:16:10 -0400

Hi Mats,
Thanks for sharing your experience: very interesting and unexpected (at
least to me) findings. I always used either CL-V or F-CL OMEGAs, but
never F-CL-V for oral studies. Mechanistically and for covariate model
development, F-CL-V structure looks very attractive.
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 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 - 13:16:10 EDT

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