covariance step

5 messages 5 people Latest: Jul 20, 2009

covariance step

From: Varsha Mehta Date: July 16, 2009 technical
Dear NONMEM users: I have a data set for 30 infants where I am running a 2 COMPT PK model. I got the following error message for the covariance step. I need some help with trying to fix this error. Any suggestions? should I increase the upper boundries of initial estimates? MINIMIZATION SUCCESSFUL NO. OF FUNCTION EVALUATIONS USED: 289 NO. OF SIG. DIGITS IN FINAL EST.: 3.0 0PARAMETER ESTIMATE IS NEAR ITS BOUNDARY THIS MUST BE ADDRESSED BEFORE THE COVARIANCE STEP CAN BE IMPLEMENTED any help is appreciated. Thanks Varsha Mehta, MS(CRDSA), Pharm.D., FCCP Clinical Associate Professor Pharmacy, Pediatrics and Communicable Diseases Clinical Pharmacist Neonatal Critical Care University of Michigan (O) 734-936-8985 (F) 734-936-6946 [email protected] ********************************************************** Electronic Mail is not secure, may not be read every day, and should not be used for urgent or sensitive issues

RE: covariance step

From: Atul Bhattaram Venkatesh Date: July 16, 2009 technical
Hello You should increase the upper boundaries. Also you might try using allometric models while fixing some of the parameters, if data is limited. Atul Venkatesh Atul Bhattaram Pharmacometrics Office of Clinical Pharmacology US Food and Drug Administration "The contents of this message are mine personally and do not necessarily reflect any position of the Government or the Food and Drug Administration."
Quoted reply history
-----Original Message----- From: [email protected] [mailto:[email protected]] On Behalf Of Varsha Mehta Sent: Thursday, July 16, 2009 1:21 PM To: [email protected]; [email protected] Subject: [NMusers] covariance step Dear NONMEM users: I have a data set for 30 infants where I am running a 2 COMPT PK model. I got the following error message for the covariance step. I need some help with trying to fix this error. Any suggestions? should I increase the upper boundries of initial estimates? MINIMIZATION SUCCESSFUL NO. OF FUNCTION EVALUATIONS USED: 289 NO. OF SIG. DIGITS IN FINAL EST.: 3.0 0PARAMETER ESTIMATE IS NEAR ITS BOUNDARY THIS MUST BE ADDRESSED BEFORE THE COVARIANCE STEP CAN BE IMPLEMENTED any help is appreciated. Thanks Varsha Mehta, MS(CRDSA), Pharm.D., FCCP Clinical Associate Professor Pharmacy, Pediatrics and Communicable Diseases Clinical Pharmacist Neonatal Critical Care University of Michigan (O) 734-936-8985 (F) 734-936-6946 [email protected] ********************************************************** Electronic Mail is not secure, may not be read every day, and should not be used for urgent or sensitive issues

RE: covariance step

From: Yaming Hang Date: July 16, 2009 technical
Hi Varsha, You may need to fix some of the OMEGAs. During a recent simulation exercise, I used the true model to fit data randomly generated from a model and the same message showed up. I fixed the OMEGA for one parameter which the data has limited information on and the covariance step became successful. Hope this helps, Yaming
Quoted reply history
-----Original Message----- From: [email protected] [mailto:[email protected]] On Behalf Of Varsha Mehta Sent: Thursday, July 16, 2009 1:21 PM To: [email protected]; [email protected] Subject: [NMusers] covariance step Dear NONMEM users: I have a data set for 30 infants where I am running a 2 COMPT PK model. I got the following error message for the covariance step. I need some help with trying to fix this error. Any suggestions? should I increase the upper boundries of initial estimates? MINIMIZATION SUCCESSFUL NO. OF FUNCTION EVALUATIONS USED: 289 NO. OF SIG. DIGITS IN FINAL EST.: 3.0 0PARAMETER ESTIMATE IS NEAR ITS BOUNDARY THIS MUST BE ADDRESSED BEFORE THE COVARIANCE STEP CAN BE IMPLEMENTED any help is appreciated. Thanks Varsha Mehta, MS(CRDSA), Pharm.D., FCCP Clinical Associate Professor Pharmacy, Pediatrics and Communicable Diseases Clinical Pharmacist Neonatal Critical Care University of Michigan (O) 734-936-8985 (F) 734-936-6946 [email protected] ********************************************************** Electronic Mail is not secure, may not be read every day, and should not be used for urgent or sensitive issues 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 (which may be known outside the United States as Merck Frosst, Merck Sharp & Dohme or MSD and in Japan, as Banyu - 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: covariance step

From: Nick Holford Date: July 17, 2009 technical
Varsha, The message you show below is not an error. It is just a warning. Errors and warnings are very different. An error will cause NONMEM to stop and usually give you some clue to the problem. A warning does not mean there is a problem -- it is just a clue that there may be a problem and its up to the user to do some thinking. There may be nothing for you to worry about. As others have pointed out the message you show often turns up in NONMEM VI because the OMEGA estimate is close to 0. Many people found this message irritating when NONMEM VI first came out so in later versions you can tell NONMEM (via NM-TRAN) abbreviated code) not to issue this kind of warning. In the end it is up to you to make a decision about whether the model is reasonable or not. NONMEM has no idea. Indeed it has been discussed many times on this list that there is typically no difference between models which NONMEM reports as successful versus those that NONMEM terminates because of rounding errors. You have to learn to take responsibility for modelling decisions and not pay too much attention to the messages that NONMEM issues. Nick Varsha Mehta wrote: > Dear NONMEM users: > > I have a data set for 30 infants where I am running a 2 COMPT PK model. I got > the following error message for the covariance step. I need some help with > trying to fix this error. Any suggestions? should I increase the upper > boundries of initial estimates? > > MINIMIZATION SUCCESSFUL > NO. OF FUNCTION EVALUATIONS USED: 289 > NO. OF SIG. DIGITS IN FINAL EST.: 3.0 > 0PARAMETER ESTIMATE IS NEAR ITS BOUNDARY > THIS MUST BE ADDRESSED BEFORE THE COVARIANCE STEP CAN BE IMPLEMENTED > > any help is appreciated. > Thanks > > Varsha Mehta, MS(CRDSA), Pharm.D., FCCP > Clinical Associate Professor > Pharmacy, Pediatrics and Communicable Diseases > Clinical Pharmacist Neonatal Critical Care > University of Michigan > (O) 734-936-8985 > (F) 734-936-6946 > [email protected] > > ********************************************************** > Electronic Mail is not secure, may not be read every day, and should not be > used for urgent or sensitive issues -- Nick Holford, Professor Clinical Pharmacology Dept Pharmacology & Clinical Pharmacology University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand [email protected] tel:+64(9)923-6730 fax:+64(9)373-7090 mobile: +33 64 271-6369 (Apr 6-Jul 20 2009) http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford

RE: covariance step

From: Scott VanWart Date: July 20, 2009 technical
Hi Varsha, AS Nick had mentioned in his reply, if you have NONMEM VI Level 2.0 you can add the following options to $EST to help get around the warning and implement the covariance step to get standard errors for the parameters: $EST METHOD=CONDITIONAL INTER MAXEVAL=9999 PRINT=5 NOTHETABOUNDTEST NOOMEGABOUNDTEST NOSIGMABOUNDTEST Since you did hit a boundary condition (the final parameter estimate was at least two decimal places off from the initial estimate you provided) and you are using NONMEM VI Level 1.0 you could also simply update your initial estimates to be the final values of the previous run and then rerun the existing model and that might work as well. Best wishes, Scott Van Wart
Quoted reply history
-----Original Message----- From: [email protected] [mailto:[email protected]] On Behalf Of Nick Holford Sent: Friday, July 17, 2009 4:27 AM To: nmusers Subject: Re: [NMusers] covariance step Varsha, The message you show below is not an error. It is just a warning. Errors and warnings are very different. An error will cause NONMEM to stop and usually give you some clue to the problem. A warning does not mean there is a problem -- it is just a clue that there may be a problem and its up to the user to do some thinking. There may be nothing for you to worry about. As others have pointed out the message you show often turns up in NONMEM VI because the OMEGA estimate is close to 0. Many people found this message irritating when NONMEM VI first came out so in later versions you can tell NONMEM (via NM-TRAN) abbreviated code) not to issue this kind of warning. In the end it is up to you to make a decision about whether the model is reasonable or not. NONMEM has no idea. Indeed it has been discussed many times on this list that there is typically no difference between models which NONMEM reports as successful versus those that NONMEM terminates because of rounding errors. You have to learn to take responsibility for modelling decisions and not pay too much attention to the messages that NONMEM issues. Nick Varsha Mehta wrote: > Dear NONMEM users: > > I have a data set for 30 infants where I am running a 2 COMPT PK model. I got > the following error message for the covariance step. I need some help with > trying to fix this error. Any suggestions? should I increase the upper > boundries of initial estimates? > > > > MINIMIZATION SUCCESSFUL > NO. OF FUNCTION EVALUATIONS USED: 289 > NO. OF SIG. DIGITS IN FINAL EST.: 3.0 > 0PARAMETER ESTIMATE IS NEAR ITS BOUNDARY > THIS MUST BE ADDRESSED BEFORE THE COVARIANCE STEP CAN BE IMPLEMENTED > > any help is appreciated. > Thanks > > > Varsha Mehta, MS(CRDSA), Pharm.D., FCCP > Clinical Associate Professor > Pharmacy, Pediatrics and Communicable Diseases > Clinical Pharmacist Neonatal Critical Care > University of Michigan > (O) 734-936-8985 > (F) 734-936-6946 > [email protected] > > ********************************************************** > Electronic Mail is not secure, may not be read every day, and should not be > used for urgent or sensitive issues > -- Nick Holford, Professor Clinical Pharmacology Dept Pharmacology & Clinical Pharmacology University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand [email protected] tel:+64(9)923-6730 fax:+64(9)373-7090 mobile: +33 64 271-6369 (Apr 6-Jul 20 2009) http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford