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Re: OMEGA-Block

From: Ethan Wu <ethan.wu75>
Date: Tue, 4 Aug 2009 07:03:52 -0700 (PDT)

ce where this statment comes from: "A further trick to make it all work is =
to logarithmically transform all concentrations as recommended by Mats Karl=
sson." thanks ________________________________ From: "Gre=
vel, Joachim" <Joachim.Grevel

Block Dear Hauke, thanks for including portions of your control s=
tream and output. Leonid explained to you the rationale of preferring V1 an=
d V2 over V1 and VSS. I personally (not a company policy) routinely woul=
d use all four etas the way you did, but with a full set of covariates. I w=
ould also take out some of the correlation by allometricallly (by a size co=
variate) scaling all volumes and clearances according to the Holford paradi=
gm (see NMusers on 3/4 rule). A further trick to make it all work is to log=
arithmically transform all concentrations as recommended by Mats Karlsson. =

variability and to prevent it from spilling over into unexplained (residual=
) variability. I am not bothered too much by warnings and refused covaria=
nce steps. I verify my pivotal models with bootstraps. When it comes to sim=
ulations 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 DM=
PK Bakewell Road Loughborough, LE11 5RH Tel: +44 1509 644035 joachi=
m.grevel
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ntent for the purposes of the prevention and detection of crime, ensuring t=
he security of our computer systems and checking Compliance with our Code o=
f Conduct and Policies. -----Original Message----- From: owner-nmusers
globomaxnm.com [mailto:owner-nmusers
ühs Sent: 03 August 2009 17:06 To: nmusers
t: Re: [NMusers] OMEGA-Block Dear NMusers, thank you for yo=
ur responses. I parameterized the model by VSS, because  the estima=
tion of the parameter became much better, in terms of  varability, =
compared to parameterization by V1 and V2. This is the excerpt from my co=
ntrol stream and output file: $PK   CL = THETA(1) * EXP(ET=
A(1))   Q = THETA(2) * EXP(ETA(2))   V1 = THETA(3)* EXP(E=
TA(3))   VSS = THETA(4) * EXP(ETA(4))   V2=VSS-V1 $O=
MEGA   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 =

        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, 1=
6:37 Uhr, schrieb Grevel, Joachim  <Joachim.Grevel
: > Hello Hauke, > > as always for these specific questions you ne=
ed to provide us with the  > relevant portions of your control stre=
am 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
-------------------------------------------------------------------- > As=
traZeneca UK Limited is a company incorporated in England and Wales  =

e  > Gate, London W1K 1LN. > Confidentiality Notice: This message=
 is private and may contain  > confidential, proprietary and legall=
y privileged information. If you  > have received this message in e=
rror, please notify us and remove it from  > your system and note t=
hat you must not copy, distribute or take any  > action in reliance=
 on it. Any unauthorised use or disclosure of the  > contents of th=
is message is not permitted and may be unlawful. > Disclaimer: Email mess=
ages may be subject to delays, interception,  > non-delivery and un=
authorised alterations. Therefore, information  > expressed in this=
 message is not given or endorsed by AstraZeneca UK  > Limited unle=
ss otherwise notified by an authorised representative  > independen=
t of this message. No contractual relationship is created by  > thi=
s 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 p=
revention and detection of crime,  > ensuring the security of our c=
omputer systems and checking Compliance  > with our Code of Conduct=
 and Policies. > -----Original Message----- > From: owner-nmusers
maxnm.com > [mailto:owner-nmusers
hs > Sent: 03 August 2009 15:07 > To: nmusers
ject: [NMusers] OMEGA-Block > > > > Dear NMusers, > > modelling=
 a 2-compartmet model parameterized by CL, V1, VSS and Q, I got > to a pr=
oblem with which I don’t know how to deal with: After choosing my=

  > estimated > the covariance matrix by including an OMEGA-BLOCK(4), w=
hich reduced the > OFV by 15. The correlations between the parameters wer=
e all estimated to > be minor (< 0.8). But when I model with a BLOCK(2) o=
n VSS and V1, which I > would expect to be positively correlated, the cor=
relation 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 m=
odel-building would you recommend to test  > for > parameter corr=
elation? > > Thanking you in advance, > > Hauke > > -----------=
------------------ > Hauke Rühs > > Apotheker > Pharmazeutisch=
es Institut > - Klinische Pharmazie - > An der Immenburg 4 > > 5312=
1 Bonn > > Tel: + 49-(0)228 73-5781 > Fax: + 49-(0)228 73-9757 > =
> www.klinische-pharmazie.info > >
Received on Tue Aug 04 2009 - 10:03:52 EDT

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