RE: ETA1 tending to zero in a simple model
Dear Stephen,
The covariate relationship that you are trying seems unnatural to me. The
interpretation of THETA(1) will be the clearance for an individual with
SCR=0, and CL will increase as an exponential function of SCR?
I would suggest a parameterization with the covariates normalized to a
typical value in the population (i.e. with SCR normalized to a typical SCR,
TVSCR).
A possible "power" parameterization for SCR:
TVCL = THETA(1) * (SCR/TVSCR)**THETA(3)
A linear effect of PCA could look something like this:
TVCL = THETA(1) * (1 + THETA(4) * (PCA-TVPCA)) ; set boundaries for
THETA(4) so that the expression between the brackets cant become negative
With these two parameterizations the interpretation of THETA(1) will be CL
for a typical individual (SCR=TVSCR and PCA=TVPCA).
Furthermore it is from my recollection quite doubtful that serum creatinine
by itself will be a good predictor of renal function in this population
(Gordjani N. et al. Eur J Pediatr. 1988 Nov;148(2):143-5). Perhaps you
should also look into some of the available algorithms to predict GFR in
this population (modified Schwartz formula etc.).
I hope that my small suggestions will help you resolve your problems.
Best regards,
Martin Bergstrand, MSc, PhD student
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Pharmacometrics Research Group,
Department of Pharmaceutical Biosciences,
Uppsala University
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P.O. Box 591
SE-751 24 Uppsala
Sweden
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Work: +46 18 471 4639
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Quoted reply history
-----Original Message-----
From: [email protected] [mailto:[email protected]] On
Behalf Of Stephen Maxwell Montgomery
Sent: Thursday, August 05, 2010 2:23 PM
To: [email protected]
Subject: [NMusers] ETA1 tending to zero in a simple model
Hi,
I am currently model building with a neonatal PopPK dataset for a renally
eliminated drug and have encountered the following problem: When I add serum
creatinine level (SCR) or post-conceptual age (PCA) as a sole covariate, or
almost any combination of two covariates, on the clearance model my ETA1
goes to 1.00E-04 as if I had over-parametrised, yet I only have one ETA term
on the CL. This situation then triggers the failure of the covariance step
due to a parameter estimate being to close to its boundary.
What is the likely cause of this and what strategy can I pursue to avoid it?
For completeness the relevant excerpts of a typical control file are given
(using SCR as the sole covariate in this case):
$SUBROUTINE ADVAN1,TRANS2
$PK
TVCL=THETA(1)*EXP(THETA(3)*SCR)
CL=TVCL*EXP(ETA(1))
TVV=THETA(2)
V=TVV*EXP(ETA(2))
SC=V
$ERROR
Y=F+EPS(1)
$EST PRINT=5 METHOD=1
$COVARIANCE
Grateful for any help/suggestions/comments offered!
All the best,
--
Stephen Montgomery
School of Pharmacy
Queen's University Belfast
97 Lisburn Road
Belfast
BT9 7BL
Tel: (028) 9097 2033=