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RE: FW: NONMEM VI 2.x Bug Alert #2 and NONMEM 7.1.0 Bug Alert #1

From: Ludden, Thomas <Thomas.Ludden>
Date: Mon, 2 Nov 2009 09:29:44 -0500

Sam,

There should not be an important difference in the objective function
value between NM5.1 and NM6.2 if the parameter estimates are the same.
The ETA search algorith is what changed between NM5 and NM6 not the
calculation of the OFV. In the case you describe, the two versions
terminated at different points in the parameter space. If the problem
is relatively unstable, (the high residual error suggests that it may
be), then the different search procedures may terminate at different
points. The suggestion is to try a range of initial estimates to see if
a common termination can be achieved. If you wish to share the control
stream and data file with me, I will be glad to investigate it myself.

Tom

-----Original Message-----
From: Sam Liao [mailto:sliao
Sent: Saturday, October 31, 2009 11:50 AM
To: Ludden, Thomas; nmusers
Subject: RE: [NMusers] FW: NONMEM VI 2.x Bug Alert #2 and NONMEM 7.1.0
Bug Alert #1

Dear Tom:
I have a question on the different results from NM5.1 vs. NM6.20. I
have PK
data fitted by a two-compartment open model with first-order absorption.
The results from NM5.10 and NM6.20 are quite different in that all BSV
of
CL/F, V2/F, V3/F, etc were smaller, yet the proportional residue was
higher
(49% vs. 36%) in NM5.10. It appears to me that the results from NM6.20
has
better estimates than that from NM5.10. However, the objective function
from NM5.1 is much smaller than that from NM6.20. Can we compare the
objective function from these two version of NM? I know there were
changes
made in the Laplacian method and FOCI.

Best regards,
Sam

-----Original Message-----
From: owner-nmusers
On
Behalf Of Ludden, Thomas
Sent: Friday, October 23, 2009 4:00 PM
To: nmusers
Subject: [NMusers] FW: NONMEM VI 2.x Bug Alert #2 and NONMEM 7.1.0 Bug
Alert
#1

It has been found that the NONMEM VI 2.x fix for the SS=2 bug =
described
in the previous Bug Alert (see below) can, in certain cases, result in:
1) the program hanging when the initial steady-state feature is used
with SS=2
2) the failure to provide the intended steady-state dose when SS=2 is
used.
At this time, problem 2) has only been observed with ADVAN12.

If you have made the fix to PRED.for or installed the fixed routine
provided at the IDS ftp site it should be backed out.

Tom

Thomas M. Ludden Ph.D.
Vice-President, Pharmacometrics R&D
ICON Development Solutions

Tel: + 1 410 696 3040
Mob: + 1 410 258 2411
Fax: + 1 410 480 0776
Email: thomas.ludden

Web: www.icondevsolutions.com


-----Original Message-----
From: Ludden, Thomas
Sent: Thursday, October 15, 2009 3:09 PM
To: Nmusers
Subject: NONMEM VI 2.x Bug Alert #2 and NONMEM 7.1.0 Bug Alert #1

==========================
==========================
======================
==========

Two bugs that affect NONMEM VI and NONMEM 7.1.0 have recently been
discovered.
Fixes and fixed routines are available for NONMEM VI 2.x as
described below. After all code changes listed here and in NONMNEM VI
2.0
Bug Alert #1 (see
ftp://nonmem.iconplc.com/Public/nonmem/NONMEM_VI_buglist/NONMEM_VI_2.1_B
ug_List.txt
for a cumulative list) are made, the nm\BLKDAT.for routine should be
edited.
The value of LEV in BLKDAT should be changed to 2.2. All routines in
nm, pr and tr
directories should be recompiled. Rerun the CDsetup6.bat or SETUP
script from the
installation directory using the same arguments used for the original
installation
with the exception of the last argument. This argument should be y to
indicated the
need to recompile.

Fix code for NONMEM 7.1.0 will be made available soon.

The NONMEM Development Team

_______________________________________________________________________

PREDPP

There is a PREDPP bug in pr/PRED.for (NONMEM VI 2.x) and pr/PRED.f90
(NONMEM 7.1.0) that affects the behavior of the steady-state (SS) data
item when:

1) SS has a value of 2

and

2) the record with SS=2 precedes all other records with a non-zero SS
data item in an individual record or after a reset record, EVID=3 or =
4.

The bug causes the steady state dose to be applied twice.

Fix for NONMEM VI 2.x:

In pr/PRED locate
 
      IF (ISSNOW.NE.0) THEN
      ISSNOW=0
      GO TO 2200
      ENDIF

Change the test from .NE. to .GE.

      IF (ISSNOW.GE.0) THEN
      ISSNOW=0
      GO TO 2200
      ENDIF

A fixed subroutine is available at

ftp://nonmem.iconplc.com/Public/nonmem/NONMEM_VI_fixed_routines/

To access this folder point your browser to

ftp://nonmem.iconplc.com/Public/nonmem/ and login.

user: nonmemvi
password: updates

then open the folder named NONMEM_VI_fixed_routines.
The fixed PRED.for routine is in the subfolder named PREDPP_14OCT2009

Workaround:

1) If SS=2 is the first record of the individual
record, then a work around is to specify the AMT value on the
affected record to be one-half the intended dose.

Or, the $PK block could be modified instead. Suppose there is only
one steady state dose record having SS=2, and the dose is for
compartment 1.

Add:
$PK
F1=1
IF (SS.EQ.2) F1=.5

2) If SS=2 is used in a subsequent record (with a change in TIME) and =
it
is not preceded by a record with a non-zero value for SS then there is
no
workaround. This situation occurs when a transient dose precedes the
steady
state dose.

Suggestion: The behavior of the steady-state data item, even in the
absence of the bug, is relatively complex. A user planning to
incorporate the
SS data item into a data set should review Chapter V, Section F of
NONMEM Users
Guide VI, PREDPP, and Chapter 6, Section 8.2.3 of Guide V, Introductory
Guide.

__________________________________________________________________

NONMEM

There is a bug in NONMEM VI 1.x & 2.x and NONMEM 7.1.0 that results in
the spurious error message below, or a similar message, when certain
band symmetric matrices are defined in $OMEGA.

PROGRAM TERMINATED BY OBJ
OMEGA ESTIMATED TO BE SINGULAR
MESSAGE ISSUED FROM ESTIMATION STEP
AT INITIAL OBJ. FUNCTION EVALUATION

Fix for NONMEM VI 2.x requires changes to several subroutines.

The fixed subroutines are available at
ftp://nonmem.iconplc.com/Public/nonmem/NONMEM_VI_fixed_routines/

To access this folder point your browser to
ftp://nonmem.iconplc.com/Public/nonmem/ and login.

user: nonmemvi
password: updates

then open the folder named NONMEM_VI_fixed_routines.
The fixed CN.for, CN1.for, CN2.for, RESCN.for, and RSCN.for routines are
in the subfolder named NONMEM_14OCT2009.

Workaround:

None is available.
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Received on Mon Nov 02 2009 - 09:29:44 EST

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