Andreas,
Your simulations highlight a limitation with the combined (additive + proportional or slope-intercept) residual error model. The combined residual error model cannot be the correct model at very low concentrations since the normal distribution will put non-zero probability mass at concentrations less than zero if the mean is low relative to its SD. The purist in me says don't truncate as that will lead to bias in your simulations although it may be minimal if few observations are simulated with negative concentrations. A better approach would be to consider an alternative residual error model that bounds the concentrations to be positive such as the log-normal residual error model (log-transform both sides approach) or fit a model that takes into account the censored BQL data ( see Beal, Ways to Fit a PK Model with Some Data Below the Quantification Limit. JPP 2001;28:481-504). Ken Kenneth G. Kowalski President & CEO A2PG - Ann Arbor Pharmacometrics Group 110 E. Miller Ave., Garden Suite Ann Arbor, MI 48104 Work: 734-274-8255 Cell: 248-207-5082 [EMAIL PROTECTED] From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED] On Behalf Of andreas lindauer Sent: Friday, May 23, 2008 6:23 AM To: nmusers@globomaxnm.com Subject: [NMusers] Visual predictive check! Dear NMusers, I have a question regarding simulations for a VPC. When a combined residual error is used it happens that for low concentrations negative values are simulated. While this is statistically correct, I wonder if it is correct to use these results for the VPC because the distribution of the observed low concentrations is truncated by the LLOQ. So the VPC might suggest model misspecification for lower concentrations. Further, when one wants to use the model for clinical trial simulation should then the negative (BQL) values be omitted because they would never appear in reality? I would like to know how the more experienced NMusers handle this. Thanks in advance, Andreas. ____________________________ Andreas Lindauer University of Bonn Department of Clinical Pharmacy An der Immenburg 4 D-53121 Bonn phone:+49 228 73 5781 fax: +49 228 73 9757
