AW: Problem with HESSIAN
Jacob,
I would say you missed the scale parameter for the peripheral compartment.
So adding S3=V3 should fix your problem.
Regards, Andreas.
____________________________
Andreas Lindauer
Department of Clinical Pharmacy
Institute of Pharmacy
University of Bonn
An der Immenburg 4
D-53121 Bonn
phone: + 49 228 73 5781
fax: + 49 228 73 9757
-----Ursprüngliche Nachricht-----
Von: [email protected] [mailto:[email protected]] Im
Auftrag von Brogren, Jacob
Gesendet: Donnerstag, 25. Juni 2009 10:12
An: Nmusers (E-mail)
Betreff: [NMusers] Problem with HESSIAN
Hi all,
surely a trivial, but still, problem:
I get
"HESSIAN OF POSTERIOR DENSITY IS NON-POSITIVE-DEFINITE DURING SEARCH"
when trying to run the model (model1 below).
I managed to run the ADVAN4 version (model2 below) and got successful
minimization and plausible estimates, but now when I want to restate the
model as defferential equations the problem occurs. What I could find out
from nmusers was that this has something to do with predictions being zero
(right?). I try to "protect" with the DEL variable (see code).
Any suggestions?
==========================================================================
Model 1
==========================================================================
$PROB Restate model using $DES
$INPUT ID DAT2=DROP TIME EVID AMT DV MDV UVOL CMT DOSE FOOD OCC AGE CREA
CLCR TYP
$DATA ../data/data5.csv IGNORE=@
$SUBS ADVAN6 TOL=3
$MODEL COMP=DEPOT ; 1. Absorption
COMP=CENTRAL ; 2. Central
COMP=PERIPH ; 3. Peripheral
COMP=URINE ; 4. Urine (output)
$PK
TVF1 = 1
TVLG = THETA(1)
TVKA = THETA(2)
TVCL = THETA(3)
TCLR = THETA(4)
TVV2 = THETA(5)
TVQ = THETA(6)
TVV3 = THETA(7)
ALAG1 = TVLG
KA = TVKA
F1 = TVF1*EXP(ETA(1))
CL = TVCL
CLR = TCLR
V2 = TVV2
Q = TVQ
V3 = TVV3
S2 = V2
S4 = UVOL
$DES
K23 = Q/V2
K32 = Q/V3
K24 = CLR/V2
K20 = (CL-CLR)/V2
DADT(1) = - KA*A(1)
DADT(2) = KA*A(1) - K23*A(2) + K32*A(3) - K20*A(2) - K24*A(2)
DADT(3) = K23*A(2) - K32*A(3)
DADT(4) = K24*A(2)
$ERROR
CP = A(2)/S2
CUR = A(4)/S4
FX = (1-TYP)*CP + TYP*CUR
DEL = 0
IF (FX.EQ.0) DEL=1
IPRED= FX
W = SQRT(THETA(8)**2*FX**2 + (1-TYP)*THETA(9)**2 + TYP*THETA(10)**2 +
DEL)
IRES = DV-IPRED
IWRES= IRES/W
Y = IPRED + ERR(1)*W
$THETA
(0,...) ; ALAG1 (lag time)
(0,...) ; KA
(0,...) ; CL
(0,...) ; CLR
(0,...) ; V2
(0,...) ; Q
(0,...) ; V3
(0,...) ; proportional error
(0,...) ; additive error (plasma)
(0,...) ; additive error (urine)
$OMEGA 0.09
$SIGMA 1 FIX
$EST PRINT=1 MAXEVAL=9999 METHOD=1 INTER POSTHOC
$COV PRINT=E
==========================================================================
Model 2
==========================================================================
$PROB Renal data included
$INPUT ID DAT2=DROP TIME EVID AMT DV MDV UVOL CMT DOSE FOOD OCC AGE CREA
CLCR TYP
$DATA ../data/data4.csv IGNORE=@
$SUBS ADVAN4 TRANS4
$PK
TVF1 = 1
TVLG = THETA(1)
TVKA = THETA(2)
TVCL = THETA(3)
TCLR = THETA(4)
TVV2 = THETA(5)
TVQ = THETA(6)
TVV3 = THETA(7)
ALAG1 = TVLG*EXP(ETA(1))
KA = TVKA
F1 = TVF1
CL = TVCL
CLR = TCLR
V2 = TVV2
Q = TVQ
V3 = TVV3
F0 = CLR/CL
S2 = V2
S0 = UVOL
$ERROR
DEL = 0
IF (F.EQ.0) DEL=1
IPRED=F
W = SQRT(THETA(8)**2*FX**2 + (1-TYP)*THETA(9)**2 + TYP*THETA(10)**2 +
DEL)
IRES = DV-IPRED
IWRES= IRES/W
Y = F + ERR(1)*W
$THETA
(0,...) ; ALAG1 (lag time)
(0,...) ; KA
(0,...) ; CL
(0,...) ; CLR
(0,...) ; V2
(0,...) ; Q
(0,...) ; V3
(0,...) ; proportional error (plasma)
(0,...) ; additive error (plasma)
(0,...) ; additive error (urine)
$OMEGA 0.09
$SIGMA 1 FIX
$EST PRINT=1 MAXEVAL=9999 METHOD=1 INTER POSTHOC
$COV PRINT=E
============================================================================
==
Data file (data5.csv) for ADVAN6 model. First ID. ([...]=masked data)
============================================================================
==
ID DAT2 TIME EVID AMT DV MDV UVOL CMT
[...] TYP
101 1973-07-10 08:19 2 . . 1 . 4
[...] 1
101 1973-07-10 08:21 0 . . 1 . 2
[...] 0
101 1973-07-10 08:30 1 10000 . 1 . 1
[...] 0
101 1973-07-10 08:46 0 . [...] 0 . 2
[...] 0
101 1973-07-10 09:01 0 . [...] 0 . 2
[...] 0
101 1973-07-10 09:17 0 . [...] 0 . 2
[...] 0
101 1973-07-10 09:31 0 . [...] 0 . 2
[...] 0
101 1973-07-10 10:01 0 . [...] 0 . 2
[...] 0
101 1973-07-10 10:31 0 . [...] 0 . 2
[...] 0
101 1973-07-10 11:01 0 . [...] 0 . 2
[...] 0
101 1973-07-10 11:31 0 . [...] 0 . 2
[...] 0
101 1973-07-10 12:30 0 . [...] 0 . 2
[...] 0
101 1973-07-10 14:14 0 . [...] 0 0.6 4
[...] 1
101 1973-07-10 14:14 2 . . 1 . -4
[...] 1
101 1973-07-10 14:14 2 . . 1 . 4
[...] 1
101 1973-07-10 14:31 0 . [...] 0 . 2
[...] 0
101 1973-07-10 17:30 0 . . 1 . 2
[...] 0
101 1973-07-10 20:30 0 . . 1 . 2
[...] 0
101 1973-07-10 20:44 0 . [...] 0 0.8 4
[...] 1
101 1973-07-10 20:44 2 . . 1 . -4
[...] 1
101 1973-07-10 20:44 2 . . 1 . 4
[...] 1
101 1973-07-11 08:31 0 . . 1 . 2
[...] 0
101 1973-07-11 08:51 0 . [...] 0 0.7 4
[...] 1
101 1973-07-11 08:51 2 . . 1 . -4
[...] 1
[...]
============================================================================
==
Data file (data4.csv) for ADVAN4 model. First ID. ([...]=masked data)
============================================================================
==
ID DAT2 TIME EVID AMT DV MDV UVOL CMT
[...] TYP
101 1973-07-10 08:19 2 . . 1 . 4
[...] 1
101 1973-07-10 08:21 0 . . 1 . 2
[...] 0
101 1973-07-10 08:30 1 10000 . 1 . 1
[...] 0
101 1973-07-10 08:46 0 . [...] 0 . 2
[...] 0
101 1973-07-10 09:01 0 . [...] 0 . 2
[...] 0
101 1973-07-10 09:17 0 . [...] 0 . 2
[...] 0
101 1973-07-10 09:31 0 . [...] 0 . 2
[...] 0
101 1973-07-10 10:01 0 . [...] 0 . 2
[...] 0
101 1973-07-10 10:31 0 . [...] 0 . 2
[...] 0
101 1973-07-10 11:01 0 . [...] 0 . 2
[...] 0
101 1973-07-10 11:31 0 . [...] 0 . 2
[...] 0
101 1973-07-10 12:30 0 . [...] 0 . 2
[...] 0
101 1973-07-10 14:14 0 . [...] 0 0.6 -4
[...] 1
101 1973-07-10 14:14 2 . . 1 . 4
[...] 1
101 1973-07-10 14:31 0 . [...] 0 . 2
[...] 0
101 1973-07-10 17:30 0 . . 1 . 2
[...] 0
101 1973-07-10 20:30 0 . . 1 . 2
[...] 0
101 1973-07-10 20:44 0 . [...] 0 0.5 -4
[...] 1
101 1973-07-10 20:44 2 . . 1 . 4
[...] 1
101 1973-07-11 08:31 0 . . 1 . 2
[...] 0
101 1973-07-11 08:51 0 . [...] 0 0.7 -4
[...] 1
[...]
====================================================================
Best regards
Jacob
-------------------------------------------------
Jacob Brogren MSc Pharm
Senior Research Scientist
Pharmacometrics
Clinical Pharmacology and DMPK
AstraZeneca R&D Södertälje
SE-151 85 Södertälje Sweden
Tel. +46 8 553 236 33
Fax +46 8 553 274 91
[email protected]
www.astrazeneca.com
--------------------------------------------------------------------------
Confidentiality Notice: This message is private and may contain confidential
and proprietary information. If you have received this message in error,
please notify us and remove it from your system and note that you must not
copy, distribute or take any action in reliance on it. Any unauthorized use
or disclosure of the contents of this message is not permitted and may be
unlawful.