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RE: OMEGA-Block

From: Grevel, Joachim <Joachim.Grevel>
Date: Tue, 4 Aug 2009 08:21:57 +0100

Dear Hauke,

thanks for including portions of your control stream and output. Leonid =
explained to you the rationale of preferring V1 and V2 over V1 and VSS.
I personally (not a company policy) routinely would use all four etas =
the way you did, but with a full set of covariates. I would also take =
out some of the correlation by allometricallly (by a size covariate) =
scaling all volumes and clearances according to the Holford paradigm =
(see NMusers on 3/4 rule). A further trick to make it all work is to =
logarithmically transform all concentrations as recommended by Mats =
Karlsson.
I go through all this trouble in order to capture "all" between patient =
variability and to prevent it from spilling over into unexplained =
(residual) variability.
I am not bothered too much by warnings and refused covariance steps. I =
verify my pivotal models with bootstraps. When it comes to simulations =
with your final (validated) model you will reap the fruits of your =
labor.

Hope that is of some use to you,

Joachim
_________________________________
AstraZeneca R&D Charnwood
Clin. Pharmacology and DMPK
Bakewell Road
Loughborough, LE11 5RH
Tel: +44 1509 644035
joachim.grevel



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-----Original Message-----
From: owner-nmusers
[mailto:owner-nmusers
Sent: 03 August 2009 17:06
To: nmusers
Subject: Re: [NMusers] OMEGA-Block



Dear NMusers,

thank you for your responses. I parameterized the model by VSS, because =

the estimation of the parameter became much better, in terms of
varability, compared to parameterization by V1 and V2.
This is the excerpt from my control stream and output file:


$PK
   CL = THETA(1) * EXP(ETA(1))
   Q = THETA(2) * EXP(ETA(2))
   V1 = THETA(3)* EXP(ETA(3))
   VSS = THETA(4) * EXP(ETA(4))
   V2=VSS-V1

$OMEGA
   0.1 ; OMCL
   0.5 ;OMQ
$OMEGA BLOCK(2)
   0.05 ;OMV1
  0.01 0.05 ;OMVSS


  OMEGA - COV MATRIX FOR RANDOM EFFECTS - ETAS ********


             ETA1 ETA2 ETA3 ETA4

  ETA1
+ 4.08E-02

  ETA2
+ 0.00E+00 4.56E-01

  ETA3
+ 0.00E+00 0.00E+00 2.62E-01

  ETA4
+ 0.00E+00 0.00E+00 -4.34E-02 7.20E-03


Best regards

Hauke




Am 03.08.2009, 16:37 Uhr, schrieb Grevel, Joachim
<Joachim.Grevel

> Hello Hauke,
>
> as always for these specific questions you need to provide us with the =
 
> relevant portions of your control stream and of your output.
>
> Thanks for participating,
>
> Joachim
> _________________________________
> AstraZeneca R&D Charnwood
> Clin. Pharmacology and DMPK
> Bakewell Road
> Loughborough, LE11 5RH
> Tel: +44 1509 644035
> joachim.grevel
>
>
>
> =
-------------------------------------------------------------------------=
-
> AstraZeneca UK Limited is a company incorporated in England and Wales =

> with registered number: 03674842 and a registered office at 15 =
Stanhope
> Gate, London W1K 1LN.
> Confidentiality Notice: This message is private and may contain
> confidential, proprietary and legally privileged information. If you
> have received this message in error, please notify us and remove it =
from
> your system and note that you must not copy, distribute or take any
> action in reliance on it. Any unauthorised use or disclosure of the
> contents of this message is not permitted and may be unlawful.
> Disclaimer: Email messages may be subject to delays, interception,
> non-delivery and unauthorised alterations. Therefore, information
> expressed in this message is not given or endorsed by AstraZeneca UK
> Limited unless otherwise notified by an authorised representative
> independent of this message. No contractual relationship is created by =
 
> this message by any person unless specifically indicated by agreement =
in
> writing other than email.
> Monitoring: AstraZeneca UK Limited may monitor email traffic data and =

> content for the purposes of the prevention and detection of crime,
> ensuring the security of our computer systems and checking Compliance =

> with our Code of Conduct and Policies.
> -----Original Message-----
> From: owner-nmusers
> [mailto:owner-nmusers
> Sent: 03 August 2009 15:07
> To: nmusers
> Subject: [NMusers] OMEGA-Block
>
>
>
> Dear NMusers,
>
> modelling a 2-compartmet model parameterized by CL, V1, VSS and Q, I =
got
> to a problem with which I don’t know how to deal with: After =
choosing my
> structural and statistic model (combined residual error model) I
> estimated
> the covariance matrix by including an OMEGA-BLOCK(4), which reduced =
the
> OFV by 15. The correlations between the parameters were all estimated =
to
> be minor (< 0.8). But when I model with a BLOCK(2) on VSS and V1, =
which I
> would expect to be positively correlated, the correlation is estimated =
to
> be -0.99. Additionally, the inclusion of BLOCK(2) does not =
significantly
> improve the OFV.
> So does it, after all, still make sense to include the BLOCK(2)?
> Generally, at which step of model-building would you recommend to test =
 
> for
> parameter correlation?
>
> Thanking you in advance,
>
> Hauke
>
> -----------------------------
> Hauke Rühs
>
> Apotheker
> Pharmazeutisches Institut
> - Klinische Pharmazie -
> An der Immenburg 4
>
> 53121 Bonn
>
> Tel: + 49-(0)228 73-5781
> Fax: + 49-(0)228 73-9757
>
> www.klinische-pharmazie.info
>
>
Received on Tue Aug 04 2009 - 03:21:57 EDT

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