RE: [NMusers] Minimization terminated ?

-------- Original Message --------
Subject: Re: [NMusers] Minimization terminated ?
From: Nick Holford <n.holford@auckland.ac.nz>
Date: Fri, July 20, 2007 5:04 pm
To: nmusers <nmusers@globomaxnm.com>

Navin,

NONMEM is quite unreliable when it comes to deciding if it has
converged. Minor changes in initial estimates with essentially no
difference in the final estimates and OBJ can produce 1) SUCCESSFUL +
COVARIANCE 2) SUCCESSFUL + FAILED COVARIANCE 3) TERMINATED. 

My guess this is because of numerical rounding errors (not the ones
that NONMEM refers to in its error message) so that essentially it
becomes a random event which of these outcomes you get. The bottom
line is NOT to pay attention to NONMEM's declarations of success but
to focus on whether the parameters make sense, whether the fits look
good, does a VPC look OK 
http://www.page-meeting.org/page/page2005/PAGE2005P105.pdf
and even (if you have got lots of spare time) does the npde fail to
reject the null.
http://www.page-meeting.org/pdf_assets/9146-ecomets_a4page07.pdf

Several investigations of bootstraps have shown that it makes little
difference if you include successful runs only or if you include all
runs. The advantage of all runs is that is simpler to process the
results and perhaps the confidence intervals are more precisely
estimated
because you have more runs.
http://www.cognigencorp.com/nonmem/nm/99jul152003.html
http://www.nature.com/clpt/journal/v77/n2/abs/clpt200514a.html
http://www.page-meeting.org/?abstract=992

Nick

navin goyal wrote:
> 
> Dear NM Users,
> I am using trying to model some POPPK data in NONMEM vi
> Sometimes I get the  following message in the output file
> 
> MINIMIZATION TERMINATED
>  DUE TO ROUNDING ERRORS (ERROR=134)
>  NO. OF FUNCTION EVALUATIONS USED: 1103
>  NO. OF SIG. DIGITS UNREPORTABLE
> 
> But when I change the SIGDIGITS to a lower value the minimization is
successful. What exactly
is happening in this case ? Is there something I am missing out?
> 
> what about the parameter estimates obtained in such a run ?
> 
> Another question related to this is that when I bootstrap a model in
wings for nonmem WFN, I
get few runs with similar message where in it also says the same
message as above
..MINIMIZATION TERMINATED DUE TO ROUNDING ERRORS (ERROR=134) NO. OF
SIG. DIGITS UNREPORTABLE.
> This means that I discard these runs from the calculations ?
> 

--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
n.holford@auckland.ac.nz tel:+64(9)373-7599x86730 fax:+64(9)373-7090
www.health.auckland.ac.nz/pharmacology/staff/nholford