Hi,
I would not be worried by rounding errors. Its more important to
consider whether the parameter estimates are plausible and to evaluate
the predictions using VPC. If the parameters are plausible and the VPC
looks good then you can have some trust in your model.
I see you are doing a joint model of tumour size and hazard. Did you
satisfy yourself that the tumour size model was good before trying to
estimate the hazard parameters? I would always analyse this kind of data
in a sequential fashion by fitting the tumour size first then fixing
the tumour size parameters then fitting the hazard with the full data
(tumour and event) (see Zhang et al. 2003). Once you have got some
plausible hazard estimates you can then try doing a simultaneous fit.
There is usually very little point in doing a simultaneous fit.
Best wishes,
Nick
Zhang L, Beal SL, Sheiner LB. Simultaneous vs. sequential analysis for
population PK/PD data I: best-case performance. J Pharmacokinet
Pharmacodyn. 2003;30(6):387-404.
Quoted reply history
On 23-Apr-16 01:37, Mai, Tu [MED] wrote:
>
> Dear NMUsers,
>
> Our model keeps having the rounding error (error4). I tried to fix
> it using the following methods or their combinations, however,
> sometimes I then got the message error6 instead of error4. But
> minimization still unsuccessful. Can you please help pointing out how
> I can solve this problem? I really appreciate it!
>
> Thank you
>
> 1) Use the estimates for THETA that are ~10% deviated from the
> estimates provided after scm run.
>
> 2) Set TOL=9, NSIG=2, SIGL=6
>
> I attached here the code:
>
> $PROBLEM IRM code
>
> $INPUT ID TIME EX DV DVID ECOG AGE HT WT RACE SITE DIAG=DROP HEM
>
> ALK ALB LAC TES STUDY DRUG PRIORDOC
>
> $DATA survival.csv
>
> $SUBROUTINE ADVAN13 TOL=9
>
> $MODEL NCOMP=1 COMP(HAZ)
>
> $PK
>
> ;;; DECECOG-DEFINITION START
>
> IF(ECOG.EQ.1) DECECOG = 1 ; Most common
>
> IF(ECOG.EQ.0) DECECOG = ( 1 + THETA(27))
>
> IF(ECOG.EQ.2) DECECOG = ( 1 + THETA(28))
>
> ;;; DECECOG-DEFINITION END
>
> ;;; GROPRIORDOC-DEFINITION START
>
> IF(PRIORDOC.EQ.0) GROPRIORDOC = 1 ; Most common
>
> IF(PRIORDOC.EQ.1) GROPRIORDOC = ( 1 + THETA(26))
>
> ;;; GROPRIORDOC-DEFINITION END
>
> ;;; GROECOG-DEFINITION START
>
> IF(ECOG.EQ.1) GROECOG = 1 ; Most common
>
> IF(ECOG.EQ.0) GROECOG = ( 1 + THETA(24))
>
> IF(ECOG.EQ.2) GROECOG = ( 1 + THETA(25))
>
> ;;; GROECOG-DEFINITION END
>
> ;;; GROALK-DEFINITION START
>
> IF(ALK.EQ.-99) THEN
>
> GROALK = 1
>
> ELSE
>
> GROALK = ( 1 + THETA(23)*(ALK - 94.00))
>
> ENDIF
>
> ;;; GROALK-DEFINITION END
>
> ;;; GRO-RELATION START
>
> GROCOV=GROALK*GROECOG*GROPRIORDOC
>
> ;;; GRO-RELATION END
>
> ;;; DECDRUG-DEFINITION START
>
> IF(DRUG.EQ.3) DECDRUG = 1 ; Most common
>
> IF(DRUG.EQ.2) DECDRUG = ( 1 + THETA(21))
>
> IF(DRUG.EQ.1) DECDRUG = ( 1 + THETA(22))
>
> ;;; DECDRUG-DEFINITION END
>
> ;;; DECAGE-DEFINITION START
>
> DECAGE = ( 1 + THETA(20)*(AGE - 64.00))
>
> ;;; DECAGE-DEFINITION END
>
> ;;; DEC-RELATION START
>
> DECCOVCAGE*DECDRUG*DECECOG
>
> ;;; DEC-RELATION END
>
> ;;; BSLHEM-DEFINITION START
>
> IF(HEM.LE.124.00) BSLHEM = ( 1 + THETA(18)*(HEM - 124.00))
>
> IF(HEM.GT.124.00) BSLHEM = ( 1 + THETA(19)*(HEM - 124.00))
>
> IF(HEM.EQ.-99) BSLHEM = 1
>
> ;;; BSLHEM-DEFINITION END
>
> ;;; BSLECOG-DEFINITION START
>
> IF(ECOG.EQ.1) BSLECOG = 1 ; Most common
>
> IF(ECOG.EQ.0) BSLECOG = ( 1 + THETA(16))
>
> IF(ECOG.EQ.2) BSLECOG = ( 1 + THETA(17))
>
> ;;; BSLECOG-DEFINITION END
>
> ;;; BSLALK-DEFINITION START
>
> IF(ALK.EQ.-99) THEN
>
> BSLALK = 1
>
> ELSE
>
> BSLALK = ( 1 + THETA(15)*(ALK - 94.00))
>
> ENDIF
>
> ;;; BSLALK-DEFINITION END
>
> ;;; BSL-RELATION START
>
> BSLCOV=BSLALK*BSLECOG*BSLHEM
>
> ;;; BSL-RELATION END
>
> ;;; BSHZPRIORDOC-DEFINITION START
>
> IF(PRIORDOC.EQ.0) BSHZPRIORDOC = 1 ; Most common
>
> IF(PRIORDOC.EQ.1) BSHZPRIORDOC = ( 1 + THETA(14))
>
> ;;; BSHZPRIORDOC-DEFINITION END
>
> ;;; BSHZALK-DEFINITION START
>
> IF(ALK.EQ.-99) THEN
>
> BSHZALK = 1
>
> ELSE
>
> BSHZALK = ( 1 + THETA(13)*(ALK - 94.00))
>
> ENDIF
>
> ;;; BSHZALK-DEFINITION END
>
> ;;; BSHZ-RELATION START
>
> BSHZCOV=BSHZALK*BSHZPRIORDOC
>
> ;;; BSHZ-RELATION END
>
> ;;; BETAHEM-DEFINITION START
>
> IF(HEM.EQ.-99) THEN
>
> BETAHEM = 1
>
> ELSE
>
> BETAHEM = ( 1 + THETA(12)*(HEM - 124.00))
>
> ENDIF
>
> ;;; BETAHEM-DEFINITION END
>
> ;;; BETAECOG-DEFINITION START
>
> IF(ECOG.EQ.1) BETAECOG = 1 ; Most common
>
> IF(ECOG.EQ.0) BETAECOG = ( 1 + THETA(10))
>
> IF(ECOG.EQ.2) BETAECOG = ( 1 + THETA(11))
>
> ;;; BETAECOG-DEFINITION END
>
> ;;; BETADRUG-DEFINITION START
>
> IF(DRUG.EQ.3) BETADRUG = 1 ; Most common
>
> IF(DRUG.EQ.2) BETADRUG = ( 1 + THETA(8))
>
> IF(DRUG.EQ.1) BETADRUG = ( 1 + THETA(9))
>
> ;;; BETADRUG-DEFINITION END
>
> ;;; BETAAGE-DEFINITION START
>
> BETAAGE = ( 1 + THETA(7)*(AGE - 64.00))
>
> ;;; BETAAGE-DEFINITION END
>
> ;;; BETA-RELATION START
>
> BETACOVTAAGE*BETADRUG*BETAECOG*BETAHEM
>
> ;;; BETA-RELATION END
>
> IF (NEWIND.LE.1) THEN
>
> SRVZ=1 ; Survivor function at TIME=0
>
> ENDIF
>
> ;-----------BASELINE PSA--------------
>
> TVBSL = THETA(1)
>
> TVBSL = BSLCOV*TVBSL
>
> BSL = TVBSL*EXP(ETA(1))
>
> ;-----------PSA PARAMETERS--------------
>
> TVGRO = THETA(2)
>
> TVGRO = GROCOV*TVGRO
>
> TVDEC = THETA(3)
>
> TVDEC = DECCOV*TVDEC
>
> GRO = TVGRO*EXP(ETA(2))
>
> DEC = TVDEC*EXP(ETA(3))
>
> ;-----------SURVIVAl MODEL PARAMETERS--------------
>
> TVBSHZ = THETA(5) ; Baseline Hazard
>
> TVBSHZ = BSHZCOV*TVBSHZ
>
> BSHZ = TVBSHZ
>
> TVBETA = THETA(6) ; Parameter relating dropout hazard to PSA estimate
>
> TVBETA = BETACOV*TVBETA
>
> BETA = TVBETA
>
> $DES
>
> DSIZE = LOG(BSL*(EXP(-DEC*TIME) + EXP(GRO*TIME) - 1)+1)
>
> TEMP = BETA*DSIZE
>
> DADT(1) = BSHZ*EXP(TEMP)
>
> $ERROR
>
> IF (DVID.EQ.1) THEN
>
> F_FLAG=0 ; If continuous type data
>
> SIZE = LOG(BSL*(EXP(-DEC*TIME) + EXP(GRO*TIME) - 1)+1)
>
> IPRED = SIZE
>
> ADD = THETA(4)
>
> SDSIZE = SQRT(ADD*ADD)
>
> Y = SIZE + SDSIZE*EPS(1)
>
> W = Y
>
> IRES = DV-IPRED
>
> IWRES = IRES/(W)
>
> ENDIF
>
> ;-----------HAZARD PREDICTION--------------
>
> CMHZ = A(1)
>
> SRVT = EXP(-CMHZ)
>
> IF (DVID.EQ.2.AND.DV.EQ.0) THEN
>
> F_FLAG=1
>
> Y = SRVT
>
> ENDIF
>
> IF (DVID.EQ.2.AND.DV.EQ.1) THEN
>
> F_FLAG=1
>
> Y = SRVZ-SRVT
>
> ENDIF
>
> $THETA (50,85,150) ; POP_BSL
>
> (0,0.0004,0.1) ; POP_GRO
>
> (0,0.02,0.1) ; POP_DEC
>
> (0,0.3,0.35) ; ADD_SD
>
> (0,0.0009,0.0014) ; BSHZ
>
> (0.1,0.3,0.7) ; BETA
>
> $THETA (-0.038,-0.003,0.016) ; BETAAGE1
>
> $THETA (-1,0.3,5) ; BETADRUG1
>
> (-1,0.1,5) ; BETADRUG2
>
> $THETA (-1,-0.2,5) ; BETAECOG1
>
> (-1,0.3,5) ; BETAECOG2
>
> $THETA (-0.023,-0.01,0.016) ; BETAHEM1
>
> $THETA (0,0.001,0.010) ; BSHZALK1
>
> $THETA (-1,-0.4,5) ; BSHZPRIORDOC1
>
> $THETA (0,0.002,0.010) ; BSLALK1
>
> $THETA (-1,-0.3,5) ; BSLECOG1
>
> (-1,0.2,5) ; BSLECOG2
>
> $THETA (-1000000,-0.05,0.016) ; BSLHEM1
>
> (-0.023,-0.0002,100) ; BSLHEM2
>
> $THETA (-0.038,-0.0009,0.016) ; DECAGE1
>
> $THETA (-1,-0.6,5) ; DECDRUG1
>
> (-1,-0.8,5) ; DECDRUG2
>
> $THETA (0,98E-006,0.010) ; GROALK1
>
> $THETA (-1,-0.02,5) ; GROECOG1
>
> (-1,0.5,5) ; GROECOG2
>
> $THETA (-1,5,7) ; GROPRIORDOC1
>
> $THETA (-1,0.0004,5) ; DECECOG1
>
> (-1,-0.2,5) ; DECECOG2
>
> $OMEGA 2.5 ; PPV_BSL
>
> 2 ; PPV_GRO
>
> 1.5 ; PPV_DEC
>
> ;-------------------------
>
> $SIGMA 1. FIX
>
> ;-------------------------
>
> $ESTIMATION METHOD=COND INTER NUMERICAL LAPLACE SLOW MAX99 NSIG=2
>
> SIGL=6 NOABORT PRINT=5
>
> $COVARIANCE
>
> $TABLE ID TIME IPRED BSL GRO DEC STUDY DRUG WRES CWRES ETA1 ETA2
>
> ETA3 ONEHEADER NOPRINT
>
> FILE=C:\Users\fulldata.tab
>
> $TABLE ID TIME PRED RES WRES ONEHEADER NOPRINT
>
> FILE=C:\Users\original.tab
>
> ********************************************************************************
> This e-mail is intended only for the use of the individual or entity
> to which
> it is addressed and may contain information that is privileged and
> confidential.
> If the reader of this e-mail message is not the intended recipient,
> you are
> hereby notified that any dissemination, distribution or copying of this
> communication is prohibited. If you have received this e-mail in
> error, please
> notify the sender and destroy all copies of the transmittal.
>
> Thank you
> University of Chicago Medicine and Biological Sciences
> ********************************************************************************
--
Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A
University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
office:+64(9)923-6730 mobile:NZ+64(21)46 23 53 FR+33(6)62 32 46 72
email: n.holford_at_auckland.ac.nz
http://holford.fmhs.auckland.ac.nz/
"Declarative languages are a form of dementia -- they have no memory of events"
Holford SD, Allegaert K, Anderson BJ, Kukanich B, Sousa AB, Steinman A, Pypendop, B., Mehvar, R., Giorgi, M., Holford,N.H.G. Parent-metabolite pharmacokinetic models - tests of assumptions and predictions. Journal of Pharmacology & Clinical Toxicology. 2014;2(2):1023-34.
Holford N. Clinical pharmacology = disease progression + drug action. Br J Clin Pharmacol. 2015;79(1):18-27.