RE: Model building

From: Jurgen Bulitta <jbulitta>
Date: Wed, 9 Dec 2009 17:07:44 -0500

Dear Luis,

I guess your biggest concern regarding the residuals is whether residuals a=
re independent and identically distributed (i.i.d.). I think residual analy=
sis becomes more important, if you have only a few samples
per subject, since it is much easier to judge the goodness of fit on a DV v=
s. TIME plot on linear and semi-log scale in the case of many samples per s=
ubject.

Could you please give us some examples where you made a real-life decision =
based on one of the types of residual plots which you would not have been a=
ble to make from a thorough analysis of individual fit vs. time plots or fr=
om basic and advanced (visual) predictive checks?

I would be especially interested in the type of residuals you found most he=
lpful, types of observed variables, the study design, and software for calc=
ulation of the residuals when you found those residuals were most helpful.

Best wishes
Juergen

Jurgen Bulitta, Ph.D., Senior Scientist
Ordway Research Institute, Albany, NY

From: owner-nmusers
Behalf Of Luis.Pereira
Sent: Wednesday, December 09, 2009 12:29 PM
To: nmusers
Subject: RE: [NMusers] Model building

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 i=
s nothing more than a single characteristic of a type of residuals. So, raw=
residuals, standardized residuals, partial residuals, studentized residual=
s and so on, are essential to assess serial correlation, collinearity, leve=
rage, hat-matrix, scedasticity, transformations, and on, and on, particular=
ly in multivariable and nonlinear regression. The fact that Nonmem only pro=
vides some residuals by default does not mean we should look at them and ev=
en calculate others. Using just the value of the objective function and a p=
redictive check measure is like stirring a boat in the fog with the eyes ju=
st glued on the bow. The picture is much broader. Please check the extensiv=
e 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 objec=
tive.

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 functi=
on but that is when the VPC is most helpful. I like to use the VPC to decid=
e 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 b=
ut 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 b=
ut good WRES plots versus converged problem with bad WRES plots. Your answe=
r 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 hav=
e meaning even when the minimization terminates"

I do not agree with Joachim that RES, WRES are useful. IMHO these have almo=
st no diagnostic merit except for the most extreme cases of a bad model. Si=
mulation based diagnostics (VPC, SPC) have better diagnostic properties and=
are being actively evaluated by many groups interested in modelling method=
ology.

See Karlsson MO, Savic RM. Diagnosing model diagnostics. Clin Pharmacol The=
r. 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 t=
ime 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
.com<mailto:Joachim.Grevel
eca.com><mailto:Joachim.Grevel

Hi Neil,

"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
ca.com>_

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*From:* owner-nmusers
m>
<mailto:owner-nmusers
om>
[mailto:owner-nmusers
<mailto:owner-nmusers
om>] *On Behalf Of *Indranil
Bhattacharya
*Sent:* 03 December 2009 15:41

*To:* nmusers
sers
*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 - 17:07:44 EST

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