medians of the simulation in VPC are systematically below the medians of the observations when the model fit looks fine.

3 messages 3 people Latest: Feb 06, 2012

medians of the simulation in VPC are systematically below the medians of the observations when the model fit looks fine.

From: Xiaoli Shirley Hou Date: February 03, 2012 technical
Dear All, I have built a non-compartment model, in which the medians of IPREDs and Observations are very close. But in VPC plot, the medians of simulations are systematically below the medians of observations Any idea why it happens? Thanks. Shirley Notice: This e-mail message, together with any attachments, contains information of Merck & Co., Inc. (One Merck Drive, Whitehouse Station, New Jersey, USA 08889), and/or its affiliates Direct contact information for affiliates is available at http://www.merck.com/contact/contacts.html) that may be confidential, proprietary copyrighted and/or legally privileged. It is intended solely for the use of the individual or entity named on this message. If you are not the intended recipient, and have received this message in error, please notify us immediately by reply e-mail and then delete it from your system.

Re: medians of the simulation in VPC are systematically below the medians of the observations when the model fit looks fine.

From: Nick Holford Date: February 04, 2012 technical
Shirley, IPREDs are notoriously unreliable for model evaluation (Holford 2005) especially if there is more than 25% shrinkage (Karlsson & Savic 2007). The VPC, although not without pitfalls, is more likely to be showing you how well your model is performing (Bergstrand et al. 2011). If there is a systematic under-prediction of the observations then you should consider reasons why this might be and try another model to test your ideas. I am afraid I have no idea what you mean by a 'non-compartment model' in this context. Nick Holford NHG. The visual predictive check – superiority to standard diagnostic (Rorschach) plots [www.page-meeting.org/?abstract=738]. PAGE. 2005;14. Karlsson MO, Savic RM. Diagnosing model diagnostics. Clin Pharmacol Ther. 2007;82(1):17-20. Bergstrand M, Hooker AC, Wallin JE, Karlsson MO. Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. AAPS J. 2011;13(2):143-51.
Quoted reply history
On 4/02/2012 11:48 a.m., Hou, Xiaoli Shirley wrote: > Dear All, > > I have built a non-compartment model, in which the medians of IPREDs and Observations are very close. But in VPCplot, the medians of simulations are systematically below the mediansof observations > > Any idea why it happens? > > Thanks. > > Shirley > > Notice: This e-mail message, together with any attachments, contains > information of Merck & Co., Inc. (One Merck Drive, Whitehouse Station, > New Jersey, USA 08889), and/or its affiliates Direct contact information > for affiliates is available at > http://www.merck.com/contact/contacts.html) that may be confidential, > proprietary copyrighted and/or legally privileged. It is intended solely > for the use of the individual or entity named on this message. If you are > not the intended recipient, and have received this message in error, > please notify us immediately by reply e-mail and then delete it from > > your system. -- Nick Holford, Professor Clinical Pharmacology Dept Pharmacology& Clinical Pharmacology, Bldg 505 Room 202D 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] http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford

RE: medians of the simulation in VPC are systematically below the medians of the observations when the model fit looks fine.

From: Kenneth Kowalski Date: February 06, 2012 technical
Hi Shirley, What this suggests is that the distributions of the empirical Bayes' predictions of the ETAs (which are used to generate the IPREDs) have some departures from the normality assumptions (including zero mean with constant variance omega^2) when you use the model in simulations. I suggest that you look at box plots of the ETAs for each parameter stratified by key features of the design such as dose and generate histograms of the ETAs to verify that the distributions are symmetrically distributed about zero. If you observe departures from the normality assumptions that are being used in your simulations (e.g., trends in ETAs versus dose, right-skewed distribution, etc.) this may provide some insight as to where the deficiencies lie in your model. While I agree that ETA predictions are an imperfect diagnostic since they can suffer from shrinkage, as long as you continue to use simulations and a VPC approach to verify the adequacy of your model, a cautious look at these ETA plots to provide some guidance as to how to modify your model to improve the VPC may be helpful. Best regards, Ken
Quoted reply history
From: [email protected] [mailto:[email protected]] On Behalf Of Hou, Xiaoli Shirley Sent: Friday, February 03, 2012 5:48 PM To: nmusers Subject: [NMusers] medians of the simulation in VPC are systematically below the medians of the observations when the model fit looks fine. Dear All, I have built a non-compartment model, in which the medians of IPREDs and Observations are very close. But in VPC plot, the medians of simulations are systematically below the medians of observations Any idea why it happens? Thanks. Shirley Notice: This e-mail message, together with any attachments, contains information of Merck & Co., Inc. (One Merck Drive, Whitehouse Station, New Jersey, USA 08889), and/or its affiliates Direct contact information for affiliates is available at http://www.merck.com/contact/contacts.html) that may be confidential, proprietary copyrighted and/or legally privileged. It is intended solely for the use of the individual or entity named on this message. If you are not the intended recipient, and have received this message in error, please notify us immediately by reply e-mail and then delete it from your system.