RE: Model building

From: [email protected] [mailto:[email protected]] On Behalf Of [email protected] Sent: Wednesday, December 09, 2009 12:29 PM To: [email protected] 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 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: [email protected] on behalf of Nick Holford 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: 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 <[email protected]<mailto:[email protected]> <mailto:[email protected]><mailto:[email protected]>> wrote: 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 [email protected] <mailto:[email protected]><mailto:[email protected]>_ _ _ P Please consider the environment before printing this e-mail ------------------------------------------------------------------------ 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. *From:* [email protected]<mailto:[email protected]> <mailto:[email protected]><mailto:[email protected]> [mailto:[email protected] <mailto:[email protected]><mailto:[email protected]>] *On Behalf Of *Indranil Bhattacharya *Sent:* 03 December 2009 15:41 *To:* [email protected]<mailto:[email protected]> <mailto:[email protected]><mailto:[email protected]> *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: [email protected]<mailto:[email protected]> 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: [email protected]<mailto:[email protected]> http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford