How to solve it? ERROR: PARAMETER ESTIMATE IS NEAR ITS BOUNDARY

Dear NM Users, Currently, I am running some Pop PK models in NM VI. Sometimes, I hit the following error message: PARAMETER ESTIMATE IS NEAR ITS BOUNDARY THIS MUST BE ADDRESSED BEFORE THE COVARIANCE STEP CAN BE IMPLEMENTED. This error message is self-explained, but when I checked the final parameter estimates, none of which is close to its boundary. Sometimes, if I remove the boundary, it will work, but not always. Could someone here give some suggestions to help me out? and point out what is the possible reason to cause this error message? I appreciate your input. Thanks a lot, Jian --------------------------------- Park yourself in front of a world of choices in alternative vehicles. Visit the Yahoo! Auto Green Center.

Jian, I think this is the same problem addressed by Tom Ludden recently, see his response below. The easiest way to fix it is to use MetrumRGs NMQUAL, which fixes all known bugs in NONMEM (as well as many other useful qualification features). Here is the web site: http://metruminstitute.org/downloads/nmqual/ Here is Toms response if you want to do it yourself: Mark Dear Dr. Meineke,You are correct, if a parameter is too different from the initialestimate this message will be issued. Also, if a between subjectvariance is close to 0 or a between subject covariance yields acorrelation close to 0, -1 or 1, then this message may be issued. Withthis knowledge, it is usually easy to identify the offending parameterestimate(s). This is a new "feature" that Stuart Beal added to NONMEMVI. Some users have had positive comments ! while others what to suppressit. To suppress this message for most situations change the statementDATA INCR/1E-02/ found in NONMEM routines (nm directory) named CN.for,CN1.for and DECN1.forto DATA INCR/0/Delete all *.obj and *.lib files in the nm directory and recompile byrerunning CDSETUP6 with the original arguments, which can usually befound in SETUP.TXT, from the NONMEM home directory.The Introduction to NONMEM VI does alert the user that there are newerror messages but does not provide the details. This response will becopied to nmusers so that users are better informed.Thank you for your message.Tom Ludden Mark Sale MD Next Level Solutions, LLC www.NextLevelSolns.com