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Re: Model building

From: Leonid Gibiansky <LGibiansky>
Date: Fri, 04 Dec 2009 15:56:41 -0500

Hi Nick,
As usual, you are very extreme. VPC could be more sensitive in some
cases but the first step is to get the model with good fits, RES, WRES
plots. The original question was whether to choose the model with
numerical problems but good WRES plots versus converged problem with bad
WRES plots. Your answer effectively means: do VPC fists, then decide.

Let me disagree and recommend the model with better WRES plots even if
this model does not converge.

Thanks
Leonid


--------------------------------------
Leonid Gibiansky, Ph.D.
President, QuantPharm LLC
web: www.quantpharm.com
e-mail: LGibiansky at quantpharm.com
tel: (301) 767 5566




Nick Holford wrote:
>
>
> Indranil Bhattacharya wrote:
>
> “So my question is whether the fits, RES, WRES plots and the ofv values
> have meaning even when the minimization terminates”
>
> I do not agree with Joachim that RES, WRES are useful. IMHO these have
> almost no diagnostic merit except for the most extreme cases of a bad
> model. Simulation based diagnostics (VPC, SPC) have better diagnostic
> properties and are being actively evaluated by many groups interested in
> modelling methodology.
>
> See Karlsson MO, Savic RM. Diagnosing model diagnostics. Clin Pharmacol
> Ther. 2007 Jul;82(1):17-20. for a demonstration of the problems.
>
> Nick
>
>> Thanks Joachim, that is what I thought. I wanted to be sure that I
>> invest time building the right model and not just some model which
>> works (converges) but is biased.
>>
>> Neil
>>
>> On Fri, Dec 4, 2009 at 3:31 AM, Grevel, Joachim
>> <Joachim.Grevel
>> <mailto:Joachim.Grevel
>>
>> Hi Neil,
>>
>>
>>
>> You ask:
>>
>>
>>
>> “So my question is whether the fits, RES, WRES plots and the ofv
>> values have meaning even when the minimization terminates”
>>
>>
>>
>> The answer: you bet they matter! Residual plots are the most
>> informative output NONMEM gives you. They should guide you when
>> you determine the basic structure of your model that is supported
>> by the data. Successful termination, covariance step, standard
>> errors, Eigen values, messages, warnings... are just icing on the
>> cake vis-a-vis the residual plots.
>>
>>
>>
>> These are my two pennies worth of advice,
>>
>>
>>
>> Joachim
>>
>>
>>
>>
>>
>> *Joachim Grevel *
>>
>> Senior Pharmacometrician
>>
>> _____________________________________________________________________
>>
>> *AstraZeneca R&D Charnwood*
>>
>> Clinical Pharmacology & DMPK, Charnwood
>>
>> Bakewell Road, Loughborough, Leics., LE11 5RH, England
>>
>> Tel +44 (0) 1509 644035 Fax +44 (0) 1509 645576 Mobile +44 (0)
>> 7920 285905
>>
>> _joachim.grevel
>> <mailto:joachim.grevel
>>
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>> *From:* owner-nmusers
>> <mailto:owner-nmusers
>> [mailto:owner-nmusers
>> <mailto:owner-nmusers
>> Bhattacharya
>> *Sent:* 03 December 2009 15:41
>>
>> *To:* nmusers
>> *Subject:* [NMusers] Model building
>>
>>
>>
>> Hi, I am in the process of developing a PK/PD model and have a
>> naive question regarding model building.
>>
>> I currently do not have all the PD data and more data would be
>> available in the future. For the current data set, I have tried
>> models say A to D.
>>
>> Now model A (cell kill) and B (cell kill +transduction) converges
>> using FOCE (no CV% but I am willing to live with that) but from
>> the RES and WRES plots we can clearly see that there is some bias.
>> The fit is OK but not great. The ofv values are around 400.
>>
>> Now models B (cell cycle specific kill), C (cell + precursor cell
>> kill +transduction) and D (cell cycle specific + indirect response
>> model) do not converge using FO or FOCE methods but when I look at
>> the fits from the terminated runs, the fits are much better than
>> those obtained with Model A, and there seems very little bias.
>> Also the ofv values are between 160-250.
>>
>>
>>
>> So my question is whether the fits, RES, WRES plots and the ofv
>> values have meaning even when the minimization terminates.
>>
>>
>>
>> Regards
>>
>>
>>
>> Neil
>>
>> --
>> Indranil Bhattacharya
>>
>>
>>
>>
>> --
>> Indranil Bhattacharya
>>
>
> --
> Nick Holford, Professor Clinical Pharmacology
> Dept Pharmacology & Clinical Pharmacology
> University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
> tel:+64(9)923-6730 fax:+64(9)373-7090 mobile:+64(21)46 23 53
> email: n.holford
> http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
>
Received on Fri Dec 04 2009 - 15:56:41 EST

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