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RE: Very small P-Value for ETABAR

From: Ribbing, Jakob <Jakob.Ribbing>
Date: Thu, 13 Nov 2008 16:27:56 -0000

Hi Jian,

As Bill says, including a covariate may fix your problem. However, two
other underlying problems may also be causing this:
1. Asymmetric shrinkage of the eta. Two examples of this that I
have seen is if you have an eta on epsilon (different residual-error
magnitude in different subjects) or if the doses yield a clear effect in
some subjects but not in others (eta on EC50/EC50 may become more shrunk
on the right tail, since any drug effect in the less sensitive subjects
is difficult to separate from the background noise or circadian
variation). An important covariate may reduce the degree of shrinkage
and the asymmetry in the shrinkage. Other than that, shrinkage is not an
issue unless you use the empirical Bayes estimates for diagnostics, i.e.
use the individual parameters in graphs, calculations, PK predictions as
input to the PD model (IPK approach), etc.
2. Incorrect distributional assumptions: The parametric model
assumes e.g. a log-normal distribution of the parameter, around its
typical value. If this is not correct eta bar may become biased. You may
try other transformations in nonmem, e.g. proportional or other,
so-called semi-parametric distributions.

For references on Semi-parameteric distributions, search abstracts from
Petterson, Hanze, Savic and Karlsson. For reference on shrinkage, see
the publication below.



Clin Pharmacol Ther. 2007 Jul;82(1):17-20. Links
Diagnosing model diagnostics.Karlsson MO, Savic RM.
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala,

Conclusions from clinical trial results that are derived from
model-based analyses rely on the model adequately describing the
underlying system. The traditionally used diagnostics intended to
provide information about model adequacy have seldom discussed
shortcomings. Without an understanding of the properties of these
diagnostics, development and use of new diagnostics, and additional
information pertaining to the diagnostics, there is risk that adequate
models will be rejected and inadequate models accepted. Thus, a
diagnosis of available diagnostics is desirable.

From: owner-nmusers
On Behalf Of Denney, William S.
Sent: 13 November 2008 15:41
To: Jian Xu; nmusers
Subject: RE: [NMusers] Very small P-Value for ETABAR

Hi Jian,
I would look for a covariate effect on that parameter.

From: owner-nmusers
On Behalf Of Jian Xu
Sent: Thursday, November 13, 2008 10:16 AM
To: nmusers
Subject: [NMusers] Very small P-Value for ETABAR
A few years back, there was a discussion on the P-value for ETABAR.
However, I am not sure how to appropriately handle very small P-value(s)
for ETABAR situation during the development of a model.
I need some clarifications to a few questions:
1: Should we just ignore this small P-Value warning?
2: Can we change IIV model to avoid small P-value for ETABAR? Or any
other suggestions?
3: Does NONMEM make any assumptions on ETA distribution?
This P-value for ETABAR really bugs me a lot. I look forward to seeing
some input.
Thank you and I appreicate your time and help.

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Received on Thu Nov 13 2008 - 11:27:56 EST

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