RE: GAM analysis and further action
From: "Jakob Ribbing" Jakob.Ribbing@farmbio.uu.se
Subject: RE: [NMusers] GAM analysis and further action
Date: Thu, 30 Mar 2006 11:39:56 +0200
Dear all,
Lewis Sheiner used to advocate investigating delta-parameters (e.g. CL-TVCL) on covariates when using the GAM or investigating
graphs of covariate effects. This is especially important if you plan to import the functional form found in the GAM into the
NONMEM model. Otherwise, if a linear relation is found between etaCL(=log(CL/TVCL)) and a covariate in the GAM this represents
an exponential function of the covariate in the NONMEM model. It is easy to output the delta-parameters in the table file and
use these instead of the etas, to avoid this problem.
Regarding this comment: "GAM analysis (in X-pose) does not account for correlated covariates since univariate analyses are performed."
For a graphical analysis of covariate relations this is correct, but I think that the GAM in Xpose do account for correlation
between covariates since it performs a stepwise-multiple regression[1] similar to what is performed in NONMEM using e.g. SCM[2].
The Xpose-GAM however does not manage correlation of estimate between structural parameters. For example, if we have correlation
on the population level between CL and V, the corresponding etas from the basic model may become (sometimes falsely) correlated
causing inclusion of a covariate on both parameters even if only one is supported when investigating within NONMEM. Is this
something you (with more experience on the GAM) often see when transferring models from xpose to NONMEM? It is not relevant in
Toufigh's example since covariates are found only for CL.
Also, I got the sign wrong my previous e-mail:
AIC is still: AIC=chi2 2 * #covariate-parameters
However, using this criterion in NONMEM it should be:
deltaAIC = deltaOFV + 2 * delta#parameters
This means that using the AIC criterion, a drop in OFV of 2 is required for each additional parameter which translates into a
p-value of 0.157 when comparing two nested models with one extra parameter.
Jakob
1. Wahlby, U., E.N. Jonsson, and M.O. Karlsson, Comparison of stepwise covariate model building strategies in population
pharmacokinetic-pharmacodynamic analysis. AAPS PharmSci, 2002. 4(4): p. 27.
2. Jonsson, E.N. and M.O. Karlsson, Automated covariate model building within NONMEM. Pharm Res, 1998. 15(9): p. 1463-8.
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