Hello NMUsers
I am trying to reanalyse some data using the M3 method (Ahn et al, Likelihood
based approaches to handling data below the quantification limit using NONMEM
VI, J Pharmacokinet Pharmacodyn. 2008). I had previously used M6 and wanted to
try something potentially more robust.
I'm having problems with a "Hessian of posterior density is non positive
definite during search" error occurring as soon as NONMEM is started. It is
suggested that this may be caused by including time zero records in the
analysis (when MDV or EVID = 0) but I've double-checked and I can't find any
incidence of this.
My control stream is pasted below and I can send an extract of data if that
helps?
Any ideas very gratefully received!
Many thanks :)
Ann
$PROBLEM PK 3comp LAG BLQ M3
$INPUT ID DOSE AMT RATE DUR TIME DV EVID ART FLG AGE WGT MDV
$DATA step1&2PKBLQ.csv IGNORE=#
$SUBROUTINES ADVAN9 TOL=9
$MODEL
COMP(CENTRAL, DEFOBS) ;1
COMP(PERIPH1) ;2
COMP(PERIPH2) ;3
$PK
CL=THETA(1)*EXP(ETA(1))
Q2=THETA(2)*EXP(ETA(2))
Q3=THETA(3)*EXP(ETA(3))
V1=THETA(4)*EXP(ETA(4))
V2=THETA(5)*EXP(ETA(5))
V3=THETA(6)*EXP(ETA(6))
K10=CL/V1
K12=Q2/V1
K13=Q3/V1
K21=Q2/V2
K31=Q3/V3
S1=V1
IF (DUR.EQ.10) THEN
ALAG1=THETA(7)*EXP(ETA(7))
ELSE
ALAG1=THETA(8)*EXP(ETA(7))
ENDIF
$DES
DADT(1)=A(2)*K21 + A(3)*K31 - A(1)*(K10+K12+K13)
DADT(2)=A(1)*K12 - A(2)*K21
DADT(3)=A(1)*K13 - A(3)*K31
$ERROR
SIG1=THETA(9)
LOQ = 0.4 ; nm/L
IPRED = F
DUM = (LOQ-IPRED)/(SIG1*IPRED)
CUMD=PHI(DUM)
IF(FLG.EQ.0)THEN ; FLG=0, MDV=0 non BQL values
F_FLAG=0
Y = F*(1+SIG1*ERR(1))
ENDIF
IF(FLG.EQ.1)THEN ; FLG=1, MDV=0 BQL values
F_FLAG=1
Y=CUMD
ENDIF
$THETA (0, 696) ;CL
$THETA (0, 213) ;Q2
$THETA (0, 2600) ;Q3
$THETA (0, 5600) ;V1
$THETA (0, 50500) ;V2
$THETA (0, 38000) ;V3
$THETA (0.2167, 0.548,1) ;ALAG 10MIN
$THETA (0.00833, 0.101, 1) ;ALAG 1MIN
$THETA (0, 0.2) ;SIG1
$OMEGA (0.0121) ; ETA CL
$OMEGA (0.455) ; ETA Q2
$OMEGA (0.118) ; ETA Q3
$OMEGA (0.0919) ; ETA V1
$OMEGA (0.324) ; ETA V2
$OMEGA (0.0664) ; ETA V3
$OMEGA (1.02) ; ETA LAG SHARED
$SIGMA (0.0622)
$ESTIMATION METHOD=1 LAPLACIAN NUMERICAL SLOW PRINT=1 MAX=9999 NOABORT SIG=3
$COVA
$TABLE ID EVID AMT TIME IPRED
NOPRINT FILE=AllRecords.txt
$TABLE ID CL Q2 Q3 V1 V2 V3
ETA1 ETA2 ETA3 ETA4 ETA5 ETA6 ETA7
FIRSTONLY NOPRINT NOAPPEND FILE=FirstRecords.txt
_______________________________________________________________________
Ann Rigby-Jones PhD MRSC
Research Fellow in Pharmacokinetics & Pharmacodynamics
Peninsula College of Medicine & Dentistry, UK
_______________________________________________________________________
