Ann,
In addition to my early suggestion to include an additive error in your
residual error model here is another reason for doing that.
If you have any observations before the lag time then NONMEM will always
complain if you only have a proportional residual error model. This is
because the model predicts zero and the residual error will be zero if
it is only proportional. The residual error is used in the denominator
of the objective function and the divide by zero causes NONMEM to
generate an error. An additive residual error will stop this happening.
Can you explain what input you are trying to describe? Your code implies
a bolus input into the central compartment with a bimodal lag time with
the modes conditioned on a DUR (duration?) data item which is either 1
or 10 min. Is this something like a patient controlled analgesia system
with a lockout of either 1 or 10 min before pressing the button causes a
rapid intravenous injection of drug? What is the cause of the lag time
after the nominal time of bolus input?
Nick
On 30/10/2010 3:03 a.m., Ann Rigby-Jones wrote:
Dear Nick
Many thanks for your reply J The reason I am using $DES is because as
my next step will evaluate adding transit compartments to the model.
I'm currently trying to sort the late kinetics before I tackle the
early disposition. I've already investigated transit models with this
data set having just deleted BQL data but the WRES vs time plots show
bias at the late time points (FOCE).
I've been trying out your suggestions (and others suggested by Jeroen
Elassaiss, many thanks Jeroen);
If I fix all ETAs to zero, I then get problems with:
ERROR: NONMEM terminated with the error message:
SUM OF "SQUARED" WEIGHTED INDIVIDUAL RESIDUALS IS INFINITE
If I allow an ETA on CL only (initial estimate 0.01) I get
0PRED EXIT CODE = 1
0INDIVIDUAL NO. 1 ID= 1.00000000000000E+00
(WITHIN-INDIVIDUAL) DATA REC NO. 2
THETA=
6.96E+02 5.13E+02 2.60E+02 5.60E+03 2.05E+04 3.80E+04
5.48E-01 1.01E-01 2.00E-01
OCCURS DURING SEARCH FOR ETA AT A NONZERO VALUE OF ETA
ERROR IN LSODI1: CODE 21
ERROR OCURRED WHILE ATTEMPTING TO OBTAIN INITIAL VALUES FOR ATOL
Elapsed estimation time in seconds: 0.05
This time point is my first occurrence of BQL (FLG=1), not sure if
this is relevant. I don't think the initial estimates of THETA are
too far out, as above, this data set has been modelling before using
FOCE and omitted BQL data points.
I'm wondering whether log transforming the data may help, but unsure
of the implementation with M3.
Many thanks for your input, much appreciated J
All best wishes
Ann
------------------------------------------------------------------------
*From:*owner-nmus...@globomaxnm.com
[mailto:owner-nmus...@globomaxnm.com] *On Behalf Of *Nick Holford
*Sent:* Friday, 29 October, 2010 11:50
*To:* 'nmusers@globomaxnm.com'
*Subject:* Re: [NMusers] Hessian of posterior density is non positive
definite during search
Ann,
This error message usually means try NONMEM thinks your OMEGA initial
estimates are weird. A leading suspect would be the OMEGA estimates
for the two lag time parameters. Try fixing both of them to zero and
see if that gets your model going. If that doesn't work then you could
try fixing all OMEGA values to zero then adding them in one at a time.
You don't need to use $DES for your linear model. $SUB ADVAN11 is a
closed form 3 cpt model with bolus/zero order input (or ADVAN12 with
first order absorption as well).
An efficiency tip -- there is no point calling the time consuming
PHI() function until you really need it and also no need for a FLG
data item. You can simplify your $ERROR code like this:
$ERROR
SD=F*THETA(9) ; any residual error model you like assuming $SIGMA 1 FIX
LLOQ = 0.4 ; nm/L
IF (DV.GE.LLOQ) THEN ; non BQL values
F_FLAG=0
Y = F + SD*ERR(1))
ELSE ; BQL values
F_FLAG=1
Y = PHI((LLOQ-F)/SD)
ENDIF
Best wishes,
Nick
On 29/10/2010 9:50 p.m., Ann Rigby-Jones wrote:
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 J
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
_______________________________________________________________________
--
Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology& Clinical Pharmacology
University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
tel:+64(9)923-6730 fax:+64(9)373-7090 mobile:+64(21)46 23 53
email:n.holf...@auckland.ac.nz <mailto:n.holf...@auckland.ac.nz>
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
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--
Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology& Clinical Pharmacology
University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
tel:+64(9)923-6730 fax:+64(9)373-7090 mobile:+64(21)46 23 53
email: n.holf...@auckland.ac.nz
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
