NONMEM Users Network Archive

Hosted by Cognigen

Re: Linear VS LTBS

From: Indranil Bhattacharya <ibhattacharya>
Date: Fri, 21 Aug 2009 07:52:49 -0400

Hi Joachim, thanks for your suggestions/comments.

When using LTBS I had used a different error model and the error block is
shown below
$ERROR
IPRED = -5
IF (F.GT.0) IPRED = LOG(F) ;log transforming predicition
IRES=DV-IPRED
W=1
IWRES=IRES/W ;Uniform Weighting
Y = IPRED + ERR(1)

I also performed bootsrap on both LTBS and non-LTBS models and the non-LTBS
CI were much more tighter and the precision was greater than non-LTBS.
I think the problem plausibly is with the fact that when fitting the
non-transformed data I have used the proportional + additive model while
using LTBS the exponential model (which converts to additional model due to
LTBS) was used. The extra additive component also may be more important in
the non-LTBS model as for some subjects the concentrations were right on
LOQ.

I tried the dual error model for LTBS but does not provide a CV%. So I am
currently running a bootstrap to get the CI when using the dual error model
with LTBS.

Neil

On Fri, Aug 21, 2009 at 3:01 AM, Grevel, Joachim <
Joachim.Grevel

> Hi Neil,
>
> 1. When data are log-transformed the $ERROR block has to change: additive
> error becomes true exponential error which cannot be achieved without
> log-transformation (Nick, correct me if I am wrong).
>
> 2. Error cannot "go away". You claim your structural model (THs) remained
> unchanged. Therefore the "amount" of error will remain the same as well. If
> you reduce BSV you may have to "pay" for it with increased residual
> variability.
>
> 3. Confidence intervals of ETAs based on standard errors produced during
> the covariance step are unreliable (many threads in NMusers). Do bootstrap
> to obtain more reliable C.I..
>
> These are my five cents worth of thought in the early morning,
>
> Good luck,
>
> Joachim
>
> ------------------------------
>
> 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
> *On Behalf Of *Indranil Bhattacharya
> *Sent:* 20 August 2009 17:07
> *To:* nmusers
> *Subject:* [NMusers] Linear VS LTBS
>
> Hi, while data fitting using NONMEM on a regular PK data set and its log
> transformed version I made the following observations
>
> - PK parameters (thetas) were generally similar between regular and when
> using LTBS.
> -ETA on CL was similar
> -ETA on Vc was different between the two runs.
> - Sigma was higher in LTBS (51%) than linear (33%)
>
> Now using LTBS, I would have expected to see the ETAs unchanged or actually
> decrease and accordingly I observed that the eta values decreased showing
> less BSV. However the %RSE for ETA on VC changed from 40% (linear) to 350%
> (LTBS) and further the lower 95% CI bound has a negative number for ETA on
> Vc (-0.087).
>
> What would be the explanation behind the above observations regarding
> increased %RSE using LTBS and a negative lower bound for ETA on Vc? Can a
> negative lower bound in ETA be considered as zero?
> Also why would the residual vriability increase when using LTBS?
>
> Please note that the PK is multiexponential (may be this is responsible).
>
> Thanks.
>
> Neil
>
> --
> Indranil Bhattacharya
>
>


--
Indranil Bhattacharya

Received on Fri Aug 21 2009 - 07:52:49 EDT

The NONMEM Users Network is maintained by ICON plc. Requests to subscribe to the network should be sent to: nmusers-request@iconplc.com.

Once subscribed, you may contribute to the discussion by emailing: nmusers@globomaxnm.com.