RE: OMEGA matrix
Hi Jeroen,
I think we might be on the same page but I wanted to get clarification about
your suggestion that we “not apply the concept of over-parameterization” with
respect to evaluating the omega structure. I’m assuming by
‘over-parameterization’ you mean a model that has more elements in omega than
might be necessary to be parsimonious. If so, I certainly agree but I wouldn’t
call such a model that has more parameters than necessary to be parsimonious as
necessarily over-parameterized. An over-parameterized model is one in which
there can be an infinite set of solutions to the parameter values that yields
the same fit. Such a setting can occur when the R-matrix in NONMEM is
singular. Such over-parameterized models are often also referred to as being
ill-conditioned or not stable. I think we should always avoid
over-parameterization, ill-conditioning and unstable models regardless of the
source (i.e., fixed effects, IIV random effects and omega-structure, or
residual error structure). However, I do agree that parsimony in omega is
probably not as important as say looking for a parsimonious set of covariate
parameter fixed effects when performing covariate modeling to obtain a final
model for prediction purposes. This is why in my earlier response below I
suggested fitting the “largest omega structure that can be supported by the
data”. What I meant by this statement is that we fit the largest number of
elements of omega while avoiding over-parameterization or ill-conditioning.
Such an omega structure might not be parsimonious (i.e., the smallest omega
structure that adequately describes the features in the data). The point I
was trying to make is that the smallest omega structure that adequately
describes the features in the data may not be a diagonal omega structure (i.e.,
when correlations do exist) particularly if we are interested in describing the
variation in the data and not just in predictions of central tendency.
Best,
Ken
Quoted reply history
From: [email protected] [mailto:[email protected]] On
Behalf Of Jeroen Elassaiss-Schaap
Sent: Monday, September 29, 2014 7:00 PM
To: [email protected]; [email protected]; [email protected];
[email protected]; [email protected]
Subject: Re: [NMusers] OMEGA matrix
Dear Pavel, others,
The underlying technical difference is that SAEM is in its core a sampling
methodology. Off-diagonal elements (as explained by Bob Bauer) are available as
sample correlations and do not have to be separately computed in contrast to
linearization approaches such as FOCE.
The more interesting question to me, as also eluted to by Ken, is what criteria
to set up for inclusion of an off-diagonal element. I completely support his
argument for simulation performance of the model, as e.g. judged using a VPC.
Whether to score it as an additional degree of freedom may be up to debate. An
off-diagonal element in essence limits the freedom of the model as the random
space in which samples can be generated will be smaller. In that perspective
one could argue to retain any off-diagonal element that is sufficiently
deviating from zero regardless of ofv changes, and to not apply the concept of
over-parametrization (or at least not in comparison to other types of
parameters). In practice inclusion of an important off-diagonal is mostly
accompanied by a sound improvement in ofv anyway.
More can be found in earlier discussions we had on this list, see e.g.
https://www.mail-archive.com/[email protected]/msg02736.html for quite an
extensive one from 2010. Here also an r-script to visualize the parameter space
impact can be found ;-).
In cases where a larger full or banded omega block is found, I would advice to
explore its properties further using matrix decomposition approaches (PCA etc)
to evaluate propagated correlations across the matrix. But also on the basis
of physiology/pharmacology as a data sample may not be informative enough to
support robust interpretation of correlations. A discussion along those lines
in reporting seems the more fruitful to me.
Best regards,
Jeroen
http://pd-value.com
-- More value out of your data!
-----Original Message-----
From: [email protected] [mailto:[email protected]] On
Behalf Of Standing Joseph (GREAT ORMOND STREET HOSPITAL FOR CHILDREN NHS
FOUNDATION TRUST)
Sent: Friday, September 26, 2014 09:15
To: Kowalski, Ken; 'Eleveld, DJ'; 'Pavel Belo'; [email protected]
Subject: RE: [NMusers] OMEGA matrix
Dear Pavel,
To answer your question I suggest you go on Bob Bauer's NONMEM 7 course. The
understanding I gleaned from that course (which I think was enhanced by the
excellent wine we had at lunch in Alicante) was that with appropriate MU
parameterisation there is virtually no computational disadvantage to estimating
the full block with the newer algorithms. So you might as well do it, at least
in early runs where you want an idea of which parameter correlations might be
useful/reasonably estimated.
BW,
Joe
Joseph F Standing
MRC Fellow, UCL Institute of Child Health
Antimicrobial Pharmacist, Great Ormond Street Hospital
Tel: +44(0)207 905 2370
Mobile: +44(0)7970 572435
_____
From: [email protected] [[email protected]] On Behalf Of
Ken Kowalski [[email protected]]
Sent: 25 September 2014 22:43
To: 'Eleveld, DJ'; 'Pavel Belo'; [email protected]
Subject: RE: [NMusers] OMEGA matrix
Warning: This message contains unverified links which may not be safe. You
should only click links if you are sure they are from a trusted source.
Hi Douglas,
My own thinking is that you should fit the largest omega structure that can
be supported by the data rather than just always assuming a diagonal omega
structure. This does not necessarily mean always fitting a full block omega
structure, as it can often lead to an ill-conditioned model, however, there
may be a reduced block omega structure that is more parsimonious than the
diagonal omega structure. Getting the omega structure right is particularly
important for simulation of individual responses. For example, if you
always simulate from a diagonal omega structure for CL and V when there is
evidence that the random effects are highly positively correlated then you
may end up simulating individual PK profiles for combinations of individual
CLs and Vs that are not represented in your data (i.e., high correlation
would suggest that individuals with high CL will tend to also have high V
and vice versa whereas a simulation assuming that they are independent will
result in simulating for some individuals with high CL and low V and some
individuals with low CL and high V that might not be represented in your
data). This could lead to simulations that over-predict the variation in
the concentration-time profiles even though the diagonal omega may be
sufficient for purposes of predicting central tendency in the PK profile.
You can confirm this by VPC looking at your ability to predict say the 10th
and 90th percentiles in comparison to the observed 10th and 90th percentiles
in your data. That is, if you simulate from the diagonal omega when there
is correlation in the random effects you may find that your prediction of
the 10th and 90th percentiles are more extreme than that in your observed
data. I see this all the time in VPC plots where the majority of the
observed data are well within the predictions of the 10th and 90th
percentiles when we should expect about 10% of our data above the 90th
percentile prediction and 10% below the 10th percentile prediction.
Best regards,
Ken
Kenneth G. Kowalski
President & CEO
A2PG - Ann Arbor Pharmacometrics Group, Inc.
110 Miller Ave., Garden Suite
Ann Arbor, MI 48104
Work: 734-274-8255
Cell: 248-207-5082
Fax: 734-913-0230
[email protected]
www.a2pg.com
-----Original Message-----
From: [email protected] [mailto:[email protected]] On
Behalf Of Eleveld, DJ
Sent: Thursday, September 25, 2014 4:36 PM
To: Pavel Belo; [email protected]
Subject: RE: [NMusers] OMEGA matrix
Hi Pavel,
My question is: Why is it desirable to fit a complete omega matrix if its
physical interpretation is unclear? Etas are variation of unknown origin
i.e. not explained by the structural model. A full omega matrix allows the
unknown variation of one paramater to have a (linear?) relationship with
some other thing that is also unknown. If unknown A is found to have a
linear relationship with unknown B, then what knowlegde is gained? I do
think it can be instructive to to look at correlations and use this
information to make a better structural model. But I think diagonal OMEGA
matrix is more desirable if it works ok.
warm regards,
Douglas Eleveld
_____
From: [email protected] [[email protected]] on behalf
of Pavel Belo [[email protected]]
Sent: Thursday, September 25, 2014 4:24 PM
To: [email protected]
Subject: [NMusers] OMEGA matrix
Hello Nonmem Community,
It seems like NONMEM developers may advise to start with full OMEGA matrix
at the beginning of model development. Monolix developers may advise to
start with a diagonal matrix. Is there something different in NONMEM SAEM
algorithms that makes model stable when a lot of statistically insignificant
correlations/covariances are estimated in the model?
It seems like NONMEM SAEM can be very stable in very "hard cases" (a lot of
outliers, partially misspecified model, overparameterized model, etc.). The
omega matrix is a part of the puzzle.
When it is impossible to test every correlation coefficient for significance
due to some limitations, it becomes a regulatory issue. We may need to be
able to make a statement that the model is safe and sound even when OMEGA
matrix can be overparameterized (tries to estimate too many insignificant
parameters within the OMEGA matrix).
Kind regards,
Pavel
_____