Re: Question regarding Calculation Process in $DES BLOCK
Nick,
I can't confirm anything about why we did or didn't do something
in 1998.
I may easily have forgotten something important.
I think Stuart's concern was that a DES block might contain
code such as
A=B/C
where B and C are data items, and that C might be 0 on the first
event record.
It would put a burden on the user to change the data file.
Or maybe the denominator would be a compartment amount.
Should the call to DES be made before or after bolus doses have
been applied by PREDPP?
The user would probably expect to see values from DES that are
post dose.
Then there is also the issue of Initial Steady State doses.
The user might expect to see values from DES that are at the
initial steady state.
Doses are entered into the system by PREDPP after the advance to
a new time.
PREDPP might have to make a call to the ADVAN routines post dose,
which it does not do right now.
Any change to PREDPP requires a lot of thought.
Its not that the code is too complicated to understand.
Its just that there are so many features that one must think it
all through carefully.
It is up to Bob Bauer and his team to make the change. I asked
Bob about this and he said:
"changing the DES/PREDPP path can
affect user's legacy control stream runs and offer unpleasant surprises.
One way to deal with this is to add an option (you know me, I am into
options), that the user deliberately sets so the PREDPP/DES call
sequence can be altered without affecting the default action."
So we can ask Bob to put this on his list of changes for the next
release.
Quoted reply history
On Fri, 03 Jun 2011 03:24 +1200, "Nick Holford"
<[email protected]> wrote:
Alison,
Thanks for these helpful explanations of some of the mysterious
behaviour of NONMEM.
The call to $DES at the time of the event record makes sense so
that the value reported for a $DES variable is the same as the
same value if it was calculated in $ERROR.
Would you please confirm that the only reason why NONMEM reports
the value of a variable in a $DES block from a previous
individual in the first individual record is because "Stuart Beal
may have been afraid that some of the computations in a
complicated DES might fail with values from the first event
record, "?
Given the extensive 'validation' efforts that go into every
release of NONMEM both by IDS and by many groups using NONMEM
isn't it worth a try to call $DES at TIME=0 before so that the
correct result is produced for the TABLE file? If the code is in
fact too complicated for anyone to understand anymore at least
one can have an empirical attempt to see if this change has any
effect -- other then producing the correct value in the TABLE
file.
Nick
On 2/06/2011 5:29 a.m., Alison Boeckmann wrote:
Here is a little background on how it works.
ADVAN routines such as ADVAN6 use a subroutine from third party sources
to do the integration. For example, ADVAN6 calls DVERK from IMSL,
ADVAN13 calls LSODA, etc. These subroutines are the ones that call DES.
They call DES with various values of T during the integration
("advance") from T1 to T2. (T1 and T2 are beginning and ending event
time. Typically, these are the times on a pair of event records.) The
integrating subroutine may decide it has enough information after a call
with a value of T that is not exactly T2 (might be a little less or a
little more.)
A change was made with NONMEM V so that, after an advance, DES is called
by the ADVAN routine itself (i.e., $DES statements are evaluated) at the
exact value of the event time.
>From the NONMEM V Supplemental Guide of March 1998 (guides/supp.pdf):
39. Displayed DES-defined Items
DES-defined items may be displayed in tables or scatterplots and are
computed at the event time in the data record. With previous versions
of PREDPP, the displayed items might have been computed at a slightly
different time and might have had slightly different values.
This fixes the difficulty that Luann mentioned.
Paul says:
A related caveat is that during integration between two time points,
the value of data items (in the $DES block) are set to the values
defined at the end time, not the start time. I'm afraid that I can't
give you a good explanation for this design decision.
Every variable displayed via $TABLE has the value that was calculated by
the last call to DES with the current event record. This is not a design
decision; it is inevitable. Values created by PREDPP for display by
NONMEM are stored in a common area (formerly COMMON NMPRD4; now MODULE
NMPRD4). To display values at the start time would require PREDPP to
save the values and to restore that part of NMPRD4. This could be rather
difficult. Also, Stuart Beal preferred to see DES-computed values at
the end time and that is why the change for a final call to DES at the
event time was made.
This also explains why the values for the first event record of the
individual are those from the last event record of the previous
individual. If there is no advance in time, then there is no call to
the integrating subroutine, and no call to DES, so the values in NMPRD4
are unchanged. Warning 48 was new with NONMEM V in 1998. Why did we not
at that time add a call to DES from the ADVAN routine with the first
event record? I can't remember. Stuart Beal may have been afraid that
some of the computations in a complicated DES might fail with values
from the first event record, whereas they were ok with values from the
second and subsequent event records.
On Thu, 26 May 2011 16:28 -0400, "Luann Phillips"
[1]<[email protected]> wrote:
Hi Lili,
In addition to the information Paul provided. DDTI for a specific row
should be the last value of T (continuous time) that the integration
step took. This may not match the event time identically. As NONMEM is
performing numerical integration between two event times T is taking
on many values between the two event times (TIME, discrete). During
this process, it may actually require taking a step that goes a small
amount past the 2nd event time.
Best regards,
Luann Phillips Director, PK/PD Cognigen Corporation
(716) 633-3463 ext. 236
Paul Matthias Diderichsen wrote:
Hi Lili,
On 5/26/2011 1:52 AM, Li Li wrote:
> When I output DDT1, the table will be: Subject Time (hr) DDT1
> 1 0 4???
[...]
> 2 0 5???
[...]
> Why the DDT1 for subject 1 at first time point is 4 and subject 2
> at first time point is 5? Why it holds the last time point value
> of each subject?
In the output, nonmem tells you that this is going to happen:
" (WARNING 48) DES-DEFINED ITEMS ARE COMPUTED ONLY WHEN EVENT TIME
INCREASES. E.G., DISPLAYED VALUES ASSOCIATED WITH THE FIRST EVENT
RECORD OF AN INDIVIDUAL RECORD ARE COMPUTED WITH (THE LAST ADVANCE
TO) AN EVENT TIME OF THE PRIOR INDIVIDUAL RECORD. "
A related caveat is that during integration between two time points,
the value of data items (in the $DES block) are set to the values
defined at the end time, not the start time.
I'm afraid that I can't give you a good explanation for this design
decision.
Kind regards,
--
Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology & Clinical Pharmacology
University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
tel:+64(9)923-6730 fax:+64(9)373-7090 mobile:+64(21)46 23 53
email: [2][email protected]
[3] http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
References
1. mailto:[email protected]
2. mailto:[email protected]
3. http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
--
Alison Boeckmann
[email protected]