Question on Bias est. and the conditional method
From: "Panetta, Carl" <Carl.Panetta@stjude.org>
Subject: Question on Bias est. and the conditional method
Date: Wed, 10 Jan 2001 10:26:02 -0600
I am relatively new to using NONMEM and have several questions about the results I am obtaining and errors I am getting. The data set that I am working with contains 182 individuals who received 5 courses of I.V. MTX (currently I am working with each course separately). There are approximately 4 samples per individual. First, I am just trying to estimate the population PK. Below is attached a copy of the NONMEM file I am using.
1.)Using the first-order method (using the first $ESTIMATION line in the file) everything runs well, but the resulting population PK parameters are between 10 and 20% below the estimates obtained when using a two-step method with Bayesian estimation. Also, the variance (inter-individual variability) estimates are lower by as much as about half. Is this to be expected with the first-order method, or am I coding something wrong in the file?
2.)Using the conditional method (using the second $ESTIMATION line in the file) I am unable to get NONMEM to successfully run. If I use additive etas I get the following error:
______________________________
Starting nonmem execution ...
MONITORING OF SEARCH:
0PRED EXIT CODE = 1
0INDIVIDUAL NO. 23 ID=0.10988500E+06 (WITHIN-INDIVIDUAL) DATA REC NO.
2
THETA=
1.00E+02 9.40E+00 8.00E-02 5.00E-02
OCCURS DURING SEARCH FOR ETA AT A NONZERO VALUE OF ETA
PK PARAMETER FOR K21 IS NON-POSITIVE
1 file(s) copied
______________________________
If I use mult. etas I get the following error:
______________________________
Starting nonmem execution ...
MONITORING OF SEARCH:
0ITERATION NO.: 0 OBJECTIVE VALUE: 0.2418E+04 NO. OF FUNC.
EVALS.: 7
CUMULATIVE NO. OF FUNC. EVALS.: 7
PARAMETER: 0.1000E+00 0.1000E+00 0.1000E+00 0.1000E+00 0.1000E+00
0.1000E
+00 0.1000E+00 0.1000E+00 0.1000E+00
GRADIENT: -0.3924E+04 0.3541E+04 0.3452E+04 -0.3465E+04 0.4125E+03
-0.6664E
+02 -0.4546E+03 -0.1414E+02 0.2731E+04
forrtl: error (72): floating overflow
1 file(s) copied
______________________________
Is there some option that I should be using so that this will run?
______________________________
NONMEM calling file.
______________________________
$PROBLEM T12 POPULATION DATA
$INPUT ID TIME CP=DV DOSE=AMT RATE AGE SEX RACE BSA W H AC TX DAT
$DATA pk_t12_nonmem_mtx501.dat
$SUBROUTINES ADVAN3
$PK
CALLFL=1
TCL=THETA(1)
TV=THETA(2)
;additive eta
CL=TCL+ETA(1)
SC=TV+ETA(2)
K12=THETA(3)+ETA(3)
K21=THETA(4)+ETA(4)
;Mult. eta
;CL=TCL*EXP(ETA(1))
;SC=TV*EXP(ETA(2))
;K12=THETA(3)*EXP(ETA(3))
;K21=THETA(4)*EXP(ETA(4))
K=(3.0/50.0)*CL/SC
$ERROR
Y=F*(1.0+ERR(1))
;Y=F+ERR(1)
$SIGMA 0.1
$THETA (0.07 100.0) (0.9 9.4) (0.0008 0.08) (0.00011 0.05)
;additive eta
$OMEGA 250.0 2.0 0.01 0.01
;mult. eta
;$OMEGA 0.0685 0.083 0.303 0.0013
$ESTIMATION MAXEVAL=9999 NOABORT PRINT=25 SIGDIGITS=3
;$ESTIMATION METHOD=1 NOABORT MAXEVAL=9999 PRINT=25
$COVR
$TABLE ID SC K K12 K21
FIRSTONLY NOAPPEND NOPRINT FILE=t12par.out
$TABLE ID TIME AGE SEX RACE AC ONEHEADER NOPRINT FILE=t12.out
$SCAT RES VS TIME
$SCAT CP VS PRED UNIT
$SCAT AGE VS RES
$SCAT SEX VS RES
$SCAT RACE VS RES
$SCAT AC VS RES
______________________________________________________
J. Carl Panetta, Ph.D.
Biomedical Modeler
Department of Pharmaceutical Sciences
St. Jude Children's Research Hospital
332 North Lauderdale St.
Memphis, TN 38105-2794
Phone: (901) 495-3172
FAX: (901) 525-6869
e-mail: carl.panetta@stjude.org