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RE: Model building

From: Luis.Pereira
Date: Wed, 9 Dec 2009 12:29:29 -0500

Dear All,

For the sake of correctness, Residuals Analysis is one of the most
relevant topics in the field of Regression. The very notion of objective
function is nothing more than a single characteristic of a type of
residuals. So, raw residuals, standardized residuals, partial residuals,
studentized residuals and so on, are essential to assess serial
correlation, collinearity, leverage, hat-matrix, scedasticity,
transformations, and on, and on, particularly in multivariable and
nonlinear regression. The fact that Nonmem only provides some residuals
by default does not mean we should look at them and even calculate
others. Using just the value of the objective function and a predictive
check measure is like stirring a boat in the fog with the eyes just
glued on the bow. The picture is much broader. Please check the
extensive literature on Regression and model identification.

Cheers

 

Luis

 

-----------------------

Luis Pereira, PhD

Associate Professor

Childrens' Hospital Boston

Harvard Medical School

Boston MA02115

 

________________________________

From: owner-nmusers
Sent: Fri 12/4/2009 10:14 PM
To: nmusers
Subject: Re: [NMusers] Model building

Leonid,

I rely on the objective function for model development. Note the word
objective.

I have never looked at a RES or WRES plot except to laugh at the
subjective foolishness one can imagine there. Note the word subjective.

Of course one can run into problems by looking only at the objective
function but that is when the VPC is most helpful. I like to use the VPC
to decide which model(s) are fit for purpose.

Thank you for recognizing my extreme views. I prefer to be an outlier
than lost among the pseudo-random residuals :-)

Nick

Leonid Gibiansky wrote:

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 <http://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
<mailto:joachim.grevel

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    [mailto:owner-nmusers
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    Bhattacharya
    *Sent:* 03 December 2009 15:41

    *To:* nmusers
<mailto: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





--
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 Wed Dec 09 2009 - 12:29:29 EST

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