Alison,
Thank you for the additional information. Especially the part about $DES
computing at the event time in a data record for output to the $TABLE. I
would like to make sure that I understand a specific point correctly.
During a step from t=T1 to t=T2, NONMEM may still take on a value of
t=T2+i (i=a tiny number) and compute the equations at this time point.
When it is done, it goes back and computes the values at t=T2 for output
to the table file.
So if you have an expression like the following in your $DES block,
would you still need to set flags to 'help' processing along at t=T2.
(context of example from a previous note from Li Li)
Example:
integrating from TIME=T1 to TIME=T2 (which = a multiple of 24)
RM=THETA(1)
$DES
TS=T-24*INT(T/24)
KIN=TS*RM
DADT(1) = -KIN*A(1)
This function for Kin creates a cusp at every multiple of 24. So the
limit of Kin as you approach a multiple of 24 from the left is a maximum
and as you approach from the right the limit of Kin=0 (similar if not
same situation that occurs for an absorption alag). So if an integral
step of size h (within the advance from T1 to T2) encompasses a multiple
of 24 should flags be set to allow the integration routine to use
TS=T- 24*INT(time at beginning of interval h/24) for the full step?
Or in terms of the an ALAG situation:
What happens if NONMEM is taking a step (size h within an advance from
T1 to T2) that encompasses the value of ALAG?
Does it use DADT(1) = 0*A(1) until t=ALAG and then switch to
DADT(1)=-Ka*A(1) at t >= ALAG (creating a cusp within the interval h)?
or
Does it use DAD(1) = 0 until t=end of the h interval (even though it's a
small bit past ALAG) and then switch to DADT(1)=-Ka*A(1) at the end of
the h interval?
I really appreciate that you take the time to continue expanding our
knowledge about NONMEM.
Best Regards,
Luann Phillips
Director PK/PD
Cognigen Corporation
(716) 633-3463 ext. 236
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"
<[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,
