RE: COEFFICIENT MATRIX IS ALGORITHMICALLY SINGULAR
From: Luann Phillips luann.phillips@cognigencorp.com
Subject: RE:[NMusers] COEFFICIENT MATRIX IS ALGORITHMICALLY SINGULAR
Date: Wed, August 11, 2004 6:27 pm
Partha,
Do you have IV and oral data? or do you have a zero-order input for oral
data only?
Are any of the gradients zero?
If you have IV and oral data, the oral dose should have CMT=1 and the IV
dose should have CMT=2 and the CTL stream should have D2=THETA(6)
instead of D1=THETA(6). If you only have oral data then F1 is not
identifiable.
A few other things to note:
> FX=0
> IF(F.EQ.0) FX=1
> W=F+FX
This code will alter the OBJ function value if you obtain F=0 on an
observation record. F=0 generally happens on the first dose records, so
the following code will prevent division by zero for the dose records
and not alter your OBJ function.
FX=0
IF(AMT.NE.0) FX=1
W=F+FX
For further details see:
http://www.cognigencorp.com/nonmem/nm/99feb072003.html
It should also be noted that W=F is the weight for a constant CV error
model only (Y=F*(1+EPS(1)). For an additive error model (Y=F+EPS(1)),
W=1. For an additive + constant CV error model (Y=F*(1+EPS(1))+EPS(2))
there are 2 ways to code for W:
(1)
IPRED=F
W=(F**2+THETA(N)**2)
IRES=DV-IPRED
IWRES=IRES/W
Y=IPRED+W*EPS(1)
THETA(N) represents the ratio of sqrt(sigma2/sigma1 in the rpt file from
original code) in the original code and EPS(1) represents EPS(1) in the
original code.
(2)
IPRED=F
W=(1+F**2*THETA(N)**2)
IRES=DV-IPRED
IWRES=IRES/W
Y=IPRED+W*EPS(1)
THETA(N) represents the ratio of sqrt(sigma1/sigma2 in the rpt file from
original code) in the original model and EPS(1) represents EPS(2) in the
original code.
You might also want to consider the fact that TIME is not continuous
within $PK. Therefore, you might want to implement this model using a
"Change Point" model and ADVAN6. This would allow induction to remain
off until an estimated time (ALAG#) and by putting the CL equation in
the $DES block time will be continuous. This will also allow the
function to differiniate smoothly at the time induction starts.
For information about 'change point' models see my posting within:
http://www.cognigencorp.com/nonmem/nm/98may312002.html
In your case, you would need only one dummy dose compartment to turn on
the induction (addl=0) with an input of 1 at time=0.
Regards,
Luann
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