Decrease in OFV with a fixed effect
From: "Bonate, Peter" pbonate@ilexonc.com
Subject: [NMusers] Decrease in OFV with a fixed effect
Date: Mon, August 23, 2004 9:06 am
Hi, everyone.
I am having trouble understanding how something could happen.
Perhaps I am having a brain hiccup. I don't know. I fit a
2-compartment model to data from 97 subjects (2 to 9 observations per
subject) using FOCE-I. Abbreviated NONMEM code:
TVCL = THETA(1)*(CRCL/7.2)**THETA(5)*EXP(ETA(1))
V1 = THETA(2)
Q = THETA(3)
V2 = THETA(4)
The variance associated with V1, Q2, and V2 was small, <1E-4, and so I removed these
from the model. The remaining variance component on CL was ~30% with 15% IOV. Residual
error was an exponential error model (15%). The OFV was -134.
With this class of drugs, weight has been shown to be a consistent predictor of V1.
Now in my model, V1 is a fixed effect. Just to see what would happen I modeled V1
using the following
TVCL = THETA(1)*(CRCL/7.2)**THETA(5)*EXP(ETA(1))
V1 = THETA(2)*(WGT/60)**THETA(6)
Q = THETA(3)
V2 = THETA(4)
Theta(6) was 1.19 +/- 0.551. The OFV for this model was -155, a decrease of
21 points. Imagine my surprise.
At first I thought maybe I was at a local minima with the reduced model. I
perturbed the estimates of the reduced model a few times but consistently obtained
-134 as the OFV. I don't think local minima explains this.
I am having a hard time understanding this. How can a covariate explain a fixed
effect when the effect is a constant?
Any thoughts on this would be appreciated.
As an aside, how many people reduce their base model, removing small variance
components, prior to moving on towards covariate model development? I can see
arguments for and against both practices. I'd be interested in hearing arguments
for and against both sides.
Thanks alot.
Pete Bonate
Peter L. Bonate, PhD, FCP
Director, Pharmacokinetics
ILEX Oncology
4545 Horizon Hill Blvd
San Antonio, TX 78229
phone: 210-949-8662
fax: 210-949-8219
email: pbonate@ilexonc.com