Hi,
I agree with Leonid -- especially this:
If population K and KA are close, then it is unclear why individual K
and KA should be consistently ordered as K < KA and not vice versa for
some subjects. If so, why not to allow the model to decide whether to
have flip flop or not?
I do not understand what the concern is with flip-flop kinetics and why
people want to force K<KA. If you have a good reason then various
methods are available (as reviewed again by Paulo).
I wonder if someone would like to describe why it is of interest to
force K<KA?
Nick
Leonid Gibiansky wrote:
Paolo,
Option 1 is very helpful. Option 2 is not attractive for the reason
that you stated, especially, extra correlation introduced by this
trick. If used, it should be used with the full OMEGA block (CL-V-KA).
I used it once but only as the last resort when nothing else worked. I
have not tried option 3 but this option artificially restricts
distributions, so I am not sure whether it is good or not even when it
is working.
On the other hand, if population K and KA are sufficiently far apart,
you are unlikely to get individual K and KA flip-flopped.
If population K and KA are close, then it is unclear why individual K
and KA should be consistently ordered as K < KA and not vice versa for
some subjects. If so, why not to allow the model to decide whether to
have flip flop or not?
I would try to use option (1), and if you like the model, diagnostic
plots, etc, I would not worry about individual K and KA relation. One
of the diagnostics could be the fraction of patients with the
flip-flop. If it is small, this would justify the approach. Another
possible diagnostic is ETA_KA - ETA_K differences, If it is close to
normal you are OK, if it has two mirror-symmetric (relative to the
y-axis) peaks, then flip flop is interfering with the model.
Thanks
Leonid
--------------------------------------
Leonid Gibiansky, Ph.D.
President, QuantPharm LLC
web: www.quantpharm.com
e-mail: LGibiansky at quantpharm.com
tel: (301) 767 5566
Paolo Denti wrote:
Dear NMUsers,
having to deal with the flip-flop kinetics phenomenon, I had a look
at previous posts on the NMusers list.
I found this post particularly enlightening:
http://www.cognigencorp.com/nonmem/nm/99aug072003.html
Some code was proposed to avoid the flip-flop at population and
individual level. Here's a not-so-brief summary.
This parameterization solves the issue at population level:
CL=THETA(1)*EXP(ETA(1))
V=THETA(2)*EXP(ETA(2))
TVKE=THETA(1)/THETA(2)
TVKA=TVKE+THETA(3)
KA=TVKA*EXP(ETA(3))
However, it does not prevent the phenomenon occurring at individual
level. Vlamidir Piotrovsky proposed the code below, which does solve
the problem at individual level, but makes the interpretation of the
results a bit awkward and introduces correlation among the model
parameters. In particular, variance of ETA3 was greatly increased.
CL=THETA(1)*EXP(ETA(1))
V=THETA(2)*EXP(ETA(2))
KE=CL/V
KA=KE+THETA(3)*EXP(ETA(3))
Another approach, suggested by Nick Holford, implements error
recovery using EXIT 1. The code is reported below:
CL=THETA(cl)*EXP(ETA(cl))
V=THETA(v)*EXP(ETA(v))
KA=THETA(ka)*EXP(ETA(ka))
K=CL/V
IF (KA.LE.K) EXIT 1 101 ; try again (PREDERR message error code 101)
As far as I understand, this interrupts the computation whenever the
flip-flop occurs and lets NONMEM restart. However, if such an error
arises at initialization, NONMEM does not recover and the run goes no
further. Nick probably experienced something similar, but apparently
received no answer
http://www.cognigencorp.com/nonmem/nm/99oct072004.html
Does anyone know of a way around this drawback? Or have other code to
deal with flip-flop kinetics?
Thank you in advance,
Paolo
--
------------------------------------------------
Paolo Denti, Post-Doctoral Fellow
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
------------------------------------------------
--
Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
n.holf...@auckland.ac.nz tel:+64(9)923-6730 fax:+64(9)373-7090
mobile: +64 21 46 23 53
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
