From: "Paul Hutson" prhutson@pharmacy.wisc.edu 
Subject: [NMusers] When should a long run be aborted?
Date: Mon, November 22, 2004 11:27 am

Good Monday to you all (Tuesday to Nick and Steve):
I have a run underway on a 1 GHz TabletPC running NONMEM under Wings for 
NONMEM.  It has been underway since last Wednesday.  I am not getting 
every-10 reports of the parameters and gradients, but this has been the 
case for me with WFN.  Last Friday I did get a warning message:
PRED EXIT CODE 1
THETA= ...
OCCURS DURING SEARCH FOR ETA AT A NONZERO VALUE OF ETA
NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE
MAXIMUM NO. OF EVALUATIONS OF DIFFERENTIAL EQUATIONS, 100000, EXCEEDED.

(I have the GENFOR fix included in the installation.)
Haven't had an error message (or anything else for that matter) pop up over 
the weekend.   This is the most data-rich fit I've ever tried, with 8 
observations of parent and metabolite for each of 33 subjects.  Nothing in 
terms of the PHARMA runs, I'm sure, but still I have no frame of reference 
on how long I should wait.  I would like advice regarding how long to let 
this run continue before I assume that the thing is just chasing its 
tail.  I have another run on my 350 MHz desktop that is even more complex 
(two metabolites), but I figured that if the 1 GHz wasn't ready, I 
shouldn't expect my desktop dog to be done.
Control stream and  data from 2 of the 33 subjects are appended.  Thanks 
for your advice.  Paul

$PROBLEM E AND METABOLITE

$INPUT ID SUBJ TIME AMT II SS ADDL DV CMT EVID
$DATA ..\EXE3.CSV IGNORE=C

$SUBROUTINES ADVAN6 TRANS1 TOL=5
$MODEL NPAR=5 NCOMP=3 COMP=(DEPOT,DEFDOSE) COMP=(PARENT) COMP=(METAB)

$PK

      KA=THETA(1)*EXP(ETA(1));      KABS
      K=THETA(2)*EXP(ETA(2));       CL
      V2=THETA(3)*EXP(ETA(3));      VC

      FME=THETA(4);               FME
      KME=THETA(5)*EXP(ETA(4));               KME

      S2=V2/1000; SCALING FOR PARENT
      S3=V2/1000
     CL=K/V2
     AUC=AMT/CL
     CLF=CL*FME


$DES
      DADT(1)=-A(1)*KA;            GUT
      DADT(2)=A(1)*KA-A(2)*K;         PARENT
      DADT(3)=(A(2)*K*FME)-A(3)*KME;  METABOLITE


$ERROR
     FX=0
     IF (F.EQ.0) FX=1

     W=F+FX
      IPRED=F
      IRES=DV-IPRED
     IWRES=IRES/W
      Y = F*EXP(EPS(1))+EPS(2)

          IF (CMT.EQ.3) THEN
          Y= F*EXP(EPS(3))+EPS(4)
          ENDIF




$THETA  1000 FIXED      ;   KA
$THETA  (0.001,0.542,10)         ;   K
$THETA  (0.001,1320,100000)     ;   V2
$THETA  (0.001,0.829,1)         ;   FME
$THETA  (0.01,3.11,100)       ;   KME

$OMEGA  .189
$OMEGA  .194
$OMEGA  .459
$OMEGA  .01

$SIGMA  .619 .343           ;   SIGP
$SIGMA  .384 .128         ;   SIGM

$ESTIMATION METHOD=1 SIGDIGITS=3 MAXEVAL=9999 POSTHOC PRINT=10
          NOABORT MSFO=exem5.msf
;$COVR
$TABLE ID TIME KA K V2 FME KME CL AUC CLF NOPRINT FILE=exem5.fit


$SCAT    ID VS (DV CMT CL)
$SCAT    DV VS TIME BY CMT
$SCAT    PRED VS TIME BY CMT
$SCAT    RES VS TIME BY CMT
$SCAT    IWRES VS DV BY CMT
$SCAT    PRED VS DV BY CMT UNIT


CID Subject  TIME AMT II SS ADDL DV CMT EVID
28 1313 0 25 24 2 2 . 1 1
28 1313 0 . . . . 0.424 2 0
28 1313 0 . . . . 0.102 3 0
28 1313 0.5 . . . . 26.8 2 0
28 1313 0.5 . . . . 4.29 3 0
28 1313 1 . . . . 10.9 2 0
28 1313 1 . . . . 2.89 3 0
28 1313 2 . . . . 4.45 2 0
28 1313 2 . . . . 1.12 3 0
28 1313 4 . . . . 1.24 2 0
28 1313 4 . . . . 0.443 3 0
28 1313 6 . . . . 0.749 2 0
28 1313 6 . . . . 0.257 3 0
28 1313 24 . . . . 0.433 2 0
28 1313 24 . . . . 0.151 3 0
28 1313 48 . . . . 0.372 2 0
28 1313 48 . . . . 0.124 3 0
10 1316 0 25 24 2 2 . 1 1
10 1316 0 . . . . 0.625 2 0
10 1316 0 . . . . 0.169 3 0
10 1316 0.5 . . . . 45 2 0
10 1316 0.5 . . . . 4.41 3 0
10 1316 1 . . . . 25.4 2 0
10 1316 1 . . . . 3.46 3 0
10 1316 2 . . . . 7.81 2 0
10 1316 2 . . . . 1.54 3 0
10 1316 4 . . . . 4.09 2 0
10 1316 4 . . . . 1.01 3 0
10 1316 6 . . . . 2.72 2 0
10 1316 6 . . . . 0.722 3 0
10 1316 24 . . . . 0.616 2 0
10 1316 24 . . . . 0.181 3 0
10 1316 48 . . . . 0.627 2 0
10 1316 48 . . . . 0.184 3 0




Paul Hutson, Pharm.D.
Associate Professor (CHS)
UW School of Pharmacy
777 Highland Avenue
Madison, WI 53705-2222
Tel:    (608) 263-2496
FAX:    (608) 265-5421
Pager: (608) 265-7000, #7856
_______________________________________________________

From: "Nick Holford" n.holford@auckland.ac.nz
Subject: RE: [NMusers] When should a long run be aborted?
Date: Mon, November 22, 2004 1:52 pm

Paul,

This run is not necessarily pathological. You can check for continued progress by
looking in the run directory and looking at the time and date of the files e.g.
output which are updated after each iteration.

I don't think the lack of intermediate screen output is because you use WFN. WFN
does not modify the way that NONMEM runs. This is a g77 bug/feature. Screen output
to the CONOUT$ device does not go immediately to the screen.

Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
email:n.holford@auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
_______________________________________________________

From: "Sam Liao" sliao@pharmaxresearch.com
Subject: RE: [NMusers] When should a long run be aborted?
Date: Mon, November 22, 2004 2:09 pm 

Hi Paul:

I would like to suggest you to try log-transform of your DV and F by FO
method instead of FOCE method.  You can check out some discussion of this
on the usersnet.

I had experience fitting one parent, 3 metabolites in 8 DE recently, it took
more than 24 hrs to converge with log-transformed data using FO method.  So,
if you try my suggestion, I expected it converged in few hours.  A faster
CPU will certainly be helpful to you too.

Best regards,
Sam Liao
PharMax Research
_______________________________________________________

From: "Paul Hutson" prhutson@pharmacy.wisc.edu
Subject: RE: [NMusers] When should a long run be aborted?
Date: Mon, November 22, 2004 2:54 pm 

Nick:
Thanks for the reassurance.  OUTPUT file on the 1 GHz is only 30 minutes 
old (3hrs on the 350 MHz machine).

You are correct that my output to screen troubles started not with 
loading/using WFN, but with moving to g77.  My apologies.
Paul
_______________________________________________________