I agree with Paolo's explanation, but I suspect it isn't something
specific to NONMEM. When LSODA integrates up to the time of the
end of the infusion, there is no guarantee that it will never go
past that time. Rather, it's likely that it will "overshoot" that
time and interpolate back to the place where it was supposed to
stop (the end of the infusion). That might be why Leonid is seeing the
bias.
I couldn't find the docs that specifically discuss this, but maybe
NONMEM uses ITASK 1 when it advances the system?
https://github.com/metrumresearchgroup/mrgsolve/blob/master/src/opk_dlsoda_mrg.f#L378-L381
You can also see the overshoot discussed in the deSolve docs:
https://www.rdocumentation.org/packages/deSolve/versions/1.20/topics/lsoda
(see the tcrit argument)
Kyle
On Fri, May 4, 2018 at 11:03 AM, Paolo Denti <paolo.de...@uct.ac.za
<mailto:paolo.de...@uct.ac.za>> wrote:
Dear all,
Very interesting, just adding my two cents, but not sure it's 100%
relevant.
When I played with ADVAN13 before and asked NONMEM to print out all
the steps in a file, I could see that the time (T) was not always
going forward, but sometimes NONMEM was taking some steps back in
time and then proceeding again.
Not sure if this is because of how LSODA is implemented in NONMEM. I
remember - but I am happy to stand corrected - that some DES work in
such a way that they rework the size of the time steps dynamically
when they solve the ODEs and if the TOL (precision) criterion is not
met, they go back and retry with a small step size. So I was
thinking that maybe the difference in Cmax could be from one of
those "faux pas" when NONMEM has overshot the solution and then it
would take a step back?
Just an idea on something to check. But I guess the NONMEM
developers may have a quick answer to this one (hint hint).
Paolo
On 2018/05/04 17:32, Leonid Gibiansky wrote:
The procedure described in the original post is working without extra
points. It is working fine, just have a small bias, and the bias
seems
to be zero with ADVAN6. For all the practical purposes it can be used
without extra points. I was just surprised that it is not exact in
some
cases, so extra check is warranted each time when it is used (may
be we
can switch to ADVAN6 rather than ADVAN13 when computing Cmax/Cmin
in the
DES block).
Latest NONMEM versions have "finedata" Utility Program that can be
used
to add extra points to the dataset (nm741.pdf, page 237).
Leonid
On 5/4/2018 11:01 AM, Bob Leary wrote:
> One of the problems with all of this is that the user must
manually enter artificial time points (or at least in 2007 had to
do this - I don't know if this has been fixed in
> The latest NM versions) in the data set in order to evaluate the
fitted model over more grid points than are in the original data.
> To get a fine grid and good resolution on Cmax and Tmax
> You have to enter a lot of extra time points., which is a pain
in the neck. The various ODE routines are also remarkably
sensitive to how the grid is set up.
>
> Much better would be to have a grid generator within NMTRAN that
lets you just specify beginning and end points and number of
points in the grid.
> I would point out that Phoenix NLME PML has always had this
capability.
> Bob Leary
>
> -----Original Message-----
> From: owner-nmus...@globomaxnm.com
<mailto:owner-nmus...@globomaxnm.com>
<owner-nmus...@globomaxnm.com>
<mailto:owner-nmus...@globomaxnm.com> On Behalf Of Leonid Gibiansky
> Sent: Thursday, May 3, 2018 7:59 PM
> To: nmusers@globomaxnm.com <mailto:nmusers@globomaxnm.com>
> Subject: [NMusers] Cmax/Tmax in the DES block
>
> Interesting experience concerning computation of Cmax and Tmax
(and probably other stats) in the DES block. We used to use this way:
>
> http://cognigencorp.com/nonmem/current/2007-December/4125.html
<https://protect-za.mimecast.com/s/L8T-CAnX51ilA2ops83Si8>
>
> Specifically, reserved the place in the memory:
>
> $ABB COMRES=2
>
> Set these values to zero for each new subject:
> $PK
> IF(NEWIND.LE.1) THEN
> COM(1)=0
> COM(2)=0
> ENDIF
>
> and computed Cmax/TMAX as
> $DES
> IF(CONC.GT.COM <http://CONC.GT.COM>(1)) THEN
> COM(1)=CONC
> COM(2)=T
> ENDIF
>
> $ERROR
> CMAX=COM(1)
> TMAX=COM(2)
>
> Recently I applied the same procedure to compute Cmax following
1 hr IV infusion. Unexpectedly, Tmax was estimated at times > 1
hr, and Cmax was higher than 1-hr concentration (true Cmax is at 1
hr).
>
> After some experiments, the explanation was that Nonmem computes
concentration-time course (with infusion ON) for longer than 1 hr,
and resulting Cmax/Tmax are at the end of the "computation window"
rather than at 1 hr.
>
> Turns out that the results also depend on ADVAN routine. The
largest deviation (still small, 1-3 percents) was for ADVAN8,
ADVAN9, and ADVAN13. ADVAN15 was better but still off. ADVAN14 was
almost perfect but still slightly (0.01%) off. ADVAN6 provided
correct answer (up to the precision of the output). So, the
discrepancy is small but if 1-2% difference is important, one has
to be careful when using DES block computations.
>
> Thanks
> Leonid
>
>
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--
------------------------------------------------
Paolo Denti, PhD
Pharmacometrics Group
Division of Clinical Pharmacology
Department of Medicine
University of Cape Town
K45 Old Main Building
Groote Schuur Hospital
Observatory, Cape Town
7925 South Africa
phone: +27 21 404 7719
fax: +27 21 448 1989
email:paolo.de...@uct.ac.za <mailto:paolo.de...@uct.ac.za>
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