Colleagues
I have encountered a problem during NONMEM execution.
Most subjects are dosed daily but a small number of subjects have large
intervals (> 30 days) between successive doses.
For subjects dosed daily, concentrations 24 hours after a dose are BQL and
there is no evidence of accumulation.
For the problem subjects, NONMEM either:
1. aborts (despite a NOABORT option) with an error message at the first dose
after the lengthy gap
2. or sends the following error message:
0PRED EXIT CODE = 1
0INDIVIDUAL NO. 103 ID= 3.11040000000000E+04 (WITHIN-INDIVIDUAL) DATA
REC NO. 56
THETA=
1.66E+02 1.15E-01 2.95E+01 1.81E+01 4.33E+01 3.01E+02 8.26E+00
0.00E+00 1.00E+00 0.00E+00
0.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00
OCCURS DURING SEARCH FOR ETA AT INITIAL VALUE, ETA=0
NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE.
MAXIMUM NO. OF EVALUATIONS OF DIFFERENTIAL EQUATIONS, 1000000, EXCEEDED.
The error occurs with METHOD=1 but NOT with METHOD=0.
For one subject in whom doses were administered on Days 1, 30, and 60 (followed
by daily dosing), I deleted the first two dosing records and the error no
longer occurs with METHOD=1. I speculate that the error might relate to the
predicted concentration becoming Infinitesimally small after a lengthy interval
between doses, However, I have no idea if this is the explanation. And I am
reluctant to change the dataset so I seek other solutions.
Any ideas as to an explanation or a work-around?
Dennis
Dennis Fisher MD
P < (The "P Less Than" Company)
Phone / Fax: 1-866-PLessThan (1-866-753-7784)
www.PLessThan.com
NONMEM error
Hi Dennis,
You could try any of the following to prevent the suspected numerical issue:
- insert $ABBR PROTECT
- set ONLY OBSERVATIONS in the error block
- insert a reset event (EVID=4) after the 30-day hiatus
Hope this helps,
Jeroen
http://pd-value.com [email protected] @PD_value +31 6 23118438 -- More value out of your data!
Quoted reply history
> Op 5 dec 2024 om 20:45 heeft Dennis Fisher <
>
> [email protected]
>
> > het volgende geschreven:
>
>
> Colleagues
>
> I have encountered a problem during NONMEM execution.
>
> Most subjects are dosed daily but a small number of subjects have large intervals (> 30 days) between successive doses.
>
> For subjects dosed daily, concentrations 24 hours after a dose are BQL and there is no evidence of accumulation.
>
> For the problem subjects, NONMEM either:
>
> 1. aborts (despite a NOABORT option) with an error message at the first dose after the lengthy gap
>
> 2. or sends the following error message:
>
> 0PRED EXIT CODE = 1
>
> 0INDIVIDUAL NO. 103 ID= 3.11040000000000E+04 (WITHIN-INDIVIDUAL) DATA REC NO. 56
>
> THETA=
>
> 1.66E+02 1.15E-01 2.95E+01 1.81E+01 4.33E+01 3.01E+02 8.26E+00 0.00E+00 1.00E+00 0.00E+00
>
> 0.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00
>
> OCCURS DURING SEARCH FOR ETA AT INITIAL VALUE, ETA=0
>
> NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE.
>
> MAXIMUM NO. OF EVALUATIONS OF DIFFERENTIAL EQUATIONS, 1000000, EXCEEDED.
>
> The error occurs with METHOD=1 but NOT with METHOD=0.
>
> For one subject in whom doses were administered on Days 1, 30, and 60 (followed by daily dosing), I deleted the first two dosing records and the error no longer occurs with METHOD=1. I speculate that the error might relate to the predicted concentration becoming Infinitesimally small after a lengthy interval between doses, However, I have no idea if this is the explanation. And I am reluctant to change the dataset so I seek other solutions.
>
> Any ideas as to an explanation or a work-around?
>
> Dennis
>
> Dennis Fisher MD P < (The "P Less Than" Company) Phone / Fax: 1-866-PLessThan (1-866-753-7784) www.PLessThan.com
Are there any measurements that are not BQLs and that are more than 24 hrs from the last dose? What is the residual error ? Combined error (rather than proportional or exponential) may help. Random effect on residual error is very helpful to identify aberrant subjects/observations. $ABBREV PROTECT helps sometimes. NOHABORT (with H) can help but it is dangerous, so it can be used for debugging, but not for the final models.
I would look on the data with large WRES (after the FO run) to see whether any of the observations are so far off that Nonmem cannot fit them and crashes.
Thank you
Leonid
Quoted reply history
On 12/5/2024 2:33 PM, Dennis Fisher wrote:
> Colleagues
>
> I have encountered a problem during NONMEM execution.
>
> Most subjects are dosed daily but a small number of subjects have large intervals (> 30 days) between successive doses. For subjects dosed daily, concentrations 24 hours after a dose are BQL and there is no evidence of accumulation.
>
> For the problem subjects, NONMEM either:
>
> 1. aborts (despite a NOABORT option) with an error message at the first dose after the lengthy gap
>
> 2. or sends the following error message:
>
> 0PRED EXIT CODE = 1
>
> 0INDIVIDUAL NO. 103 ID= 3.11040000000000E+04 (WITHIN-INDIVIDUAL) DATA REC NO. 56
>
> THETA=
>
> 1.66E+02 1.15E-01 2.95E+01 1.81E+01 4.33E+01 3.01E+02 8.26E+00 0.00E+00 1.00E+00 0.00E+00 0.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00
>
> OCCURS DURING SEARCH FOR ETA AT INITIAL VALUE, ETA=0
> NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE.
>
> MAXIMUM NO. OF EVALUATIONS OF DIFFERENTIAL EQUATIONS, 1000000, EXCEEDED.
>
> The error occurs with METHOD=1 but NOT with METHOD=0.
>
> For one subject in whom doses were administered on Days 1, 30, and 60 (followed by daily dosing), I deleted the first two dosing records and the error no longer occurs with METHOD=1. I speculate that the error might relate to the predicted concentration becoming Infinitesimally small after a lengthy interval between doses, However, I have no idea if this is the explanation. And I am reluctant to change the dataset so I seek other solutions.
>
> Any ideas as to an explanation or a work-around?
>
> Dennis
>
> Dennis Fisher MD
> P < (The "P Less Than" Company)
> Phone / Fax: 1-866-PLessThan (1-866-753-7784)
> www.PLessThan.com
Dear Dennis,
" NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE.
MAXIMUM NO. OF EVALUATIONS OF DIFFERENTIAL EQUATIONS, 1000000, EXCEEDED. "
This seem to indicate that is due to large gap from the first dose time to the next, causing the difficulty in numerical integration. For these subjects, can you try to add few dummy records with EVID=2 to resolve this problem.
Best regards,
Sam
Quoted reply history
On 12/5/2024 11:21 AM, Dennis Fisher wrote:
> Colleagues
>
> I have encountered a problem during NONMEM execution.
>
> Most subjects are dosed daily but a small number of subjects have large intervals
> (> 30 days) between successive doses.
> For subjects dosed daily, concentrations 24 hours after a dose are BQL and
> there is no evidence of accumulation.
>
> For the problem subjects, NONMEM either:
> 1. aborts (despite a NOABORT option) with an error message at the first dose
> after the lengthy gap
> 2. or sends the following error message:
>
> 0PRED EXIT CODE = 1
> 0INDIVIDUAL NO. 103 ID= 3.11040000000000E+04 (WITHIN-INDIVIDUAL) DATA
> REC NO. 56
> THETA=
> 1.66E+02 1.15E-01 2.95E+01 1.81E+01 4.33E+01 3.01E+02 8.26E+00
> 0.00E+00 1.00E+00 0.00E+00
> 0.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00
> OCCURS DURING SEARCH FOR ETA AT INITIAL VALUE, ETA=0
> NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE.
> MAXIMUM NO. OF EVALUATIONS OF DIFFERENTIAL EQUATIONS, 1000000, EXCEEDED.
>
> The error occurs with METHOD=1 but NOT with METHOD=0.
>
> For one subject in whom doses were administered on Days 1, 30, and 60 (followed
> by daily dosing), I deleted the first two dosing records and the error no
> longer occurs with METHOD=1. I speculate that the error might relate to the
> predicted concentration becoming Infinitesimally small after a lengthy interval
> between doses, However, I have no idea if this is the explanation. And I am
> reluctant to change the dataset so I seek other solutions.
>
> Any ideas as to an explanation or a work-around?
>
> Dennis
>
> Dennis Fisher MD
> P < (The "P Less Than" Company)
> Phone / Fax: 1-866-PLessThan (1-866-753-7784)
> www.PLessThan.com
Hi Dennis,
One other idea that can help if all measures are BQL is to use a reset
record or reset and dose (EVID 3 or 4) on the subsequent doses. That way,
the integrator will be restarted for those participants and may help.
Thanks,
Bill
Quoted reply history
-----Original Message-----
From: [email protected] <[email protected]> On Behalf
Of Leonid Gibiansky
Sent: Thursday, December 5, 2024 3:14 PM
To: Dennis Fisher <[email protected]>; [email protected]
Subject: Re: [NMusers] NONMEM error
Are there any measurements that are not BQLs and that are more than 24 hrs
from the last dose? What is the residual error ? Combined error (rather than
proportional or exponential) may help. Random effect on residual error is
very helpful to identify aberrant subjects/observations. $ABBREV PROTECT
helps sometimes. NOHABORT (with
H) can help but it is dangerous, so it can be used for debugging, but not
for the final models.
I would look on the data with large WRES (after the FO run) to see whether
any of the observations are so far off that Nonmem cannot fit them and
crashes.
Thank you
Leonid
On 12/5/2024 2:33 PM, Dennis Fisher wrote:
> Colleagues
>
> I have encountered a problem during NONMEM execution.
>
> Most subjects are dosed daily but a small number of subjects have
> large intervals (> 30 days) between successive doses.
> For subjects dosed daily, concentrations 24 hours after a dose are BQL
> and there is no evidence of accumulation.
>
> For the problem subjects, NONMEM either:
> 1. aborts (despite a NOABORT option) with an error message at the
> first dose after the lengthy gap 2. or sends the following error
> message:
>
> 0PRED EXIT CODE = 1
> 0INDIVIDUAL NO. 103 ID= 3.11040000000000E+04
> (WITHIN-INDIVIDUAL) DATA REC NO. 56
> THETA=
> 1.66E+02 1.15E-01 2.95E+01 1.81E+01 4.33E+01 3.01E+02
> 8.26E+00 0.00E+00 1.00E+00 0.00E+00
> 0.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00
> 1.00E+00
> OCCURS DURING SEARCH FOR ETA AT INITIAL VALUE, ETA=0
> NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE.
> MAXIMUM NO. OF EVALUATIONS OF DIFFERENTIAL EQUATIONS, 1000000,
> EXCEEDED.
>
> The error occurs with METHOD=1 but NOT with METHOD=0.
>
> For one subject in whom doses were administered on Days 1, 30, and 60
> (followed by daily dosing), I deleted the first two dosing records and
> the error no longer occurs with METHOD=1. I speculate that the error
> might relate to the predicted concentration becoming Infinitesimally
> small after a lengthy interval between doses, However, I have no idea
> if this is the explanation. And I am reluctant to change the dataset
> so I seek other solutions.
>
> Any ideas as to an explanation or a work-around?
>
> Dennis
>
>
> Dennis Fisher MD
> P < (The "P Less Than" Company)
> Phone / Fax: 1-866-PLessThan (1-866-753-7784) www.PLessThan.com
>
Colleagues
Yesterday, I asked the group for suggestions to deal with a NONMEM error that
appeared to result from a lengthy interval between doses causing NONMEM to
abort.
I received many suggestions.
The one that I implemented successfully was to add records with EVID=3 2.0 days
after the record at the beginning of the interval (suggested by Bill Denney and
Jeroen Elassaiss-Schapp via email and Steve Shafer via phone). For example, if
there were dose records at 0, 30, and 60-90 days, I added records at 2.0 and
32.0 days.
Problem solved.
Thanks for the prompt response from the community.
Dennis
Dennis Fisher MD
P < (The "P Less Than" Company)
Phone / Fax: 1-866-PLessThan (1-866-753-7784)
www.PLessThan.com