Dear NONMEM users,
I am trying to use the method M3 for including BLQ observation in the
estimation process in NONMEM. I am using NM 7.1. The code is attached in the
end of the e-mail.
At the very beginning, the run failed. And then I made log transformation of
DV, the run went through, with THETA similar estimation for CL/Ka/V to the
model with no BLQ data included. However, the covariance step failed, with
error message shown below:
0R MATRIX ALGORITHMICALLY SINGULAR
AND ALGORITHMICALLY NON-POSITIVE-SEMIDEFINITE
0COVARIANCE STEP ABORTED
My questions are:
1. Is log transformation of DV required for M3 method?
2. Why covariance step failed? What the error message means? Anything to fix?
Any comment is highly appreciated.
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$INPUT TIME ID EVID MDV DOSE AMT ADDL II DVO=DROP SEX BLQ FLAG DV
$DATA xxxx.csv IGNORE=@
$SUBROUTINES ADVAN2 TRANS2
$PK
STRT=DOSE
TVCL=THETA(1)
CL=TVCL*EXP(ETA(1))
TVV=THETA(2)
V=TVV*EXP(ETA(2))
TVKA=THETA(3)
KA=TVKA*EXP(ETA(3))
TVED50=THETA(4)
F1=DOSE/(DOSE+TVED50)
S2=V*46500/1000/1000/1000
$ERROR
SIG=THETA(5)
LOQ=LOG(184.4) ; define the LLOQ
IPRED = LOG(0.025)
IF(F.GT.0) IPRED = LOG(F)
W=SIG
IRES=IPRED-DV
IWRES=IRES/W
DUM=(LOQ-IPRED)/SIG
CUMD = PHI(DUM)
IF(BLQ.EQ.0) THEN
F_FLAG=0
Y = IPRED+W*ERR(1)
END IF
IF (BLQ.EQ.1) THEN
F_FLAG=1
Y=CUMD
END IF
$THETA ;
(0,0.002) ; THETA(1) CL
(0,0.19) ; THETA(2) V
(0,0.1) ; THETA(3) KA
(0,0.05) ; THETA(4) A
(0,0.33); THETA(5) RES_ERR
$OMEGA DIAGONAL(1)
0.09 ; [P] iivCL
$OMEGA BLOCK(2)
0.09
0.01 0.09
$SIGMA
1 FIXED ;prop
$EST METHOD=1 INTERACTION LAPLACE SLOW NUMERICAL SIG=4 MSFO=xxx.msf
$COVARIANCE SLOW PRINT=E MATRIX=R
--------------------------------------------------------------------
Thanks,
Yan
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