Baseline as a covariate
I'd like to get the group's opinion on something. I have a pharmacodynamic
model and the baseline was shown to be a covariate on one of the model
parameters. I was hoping to get general thoughts on the use of the baseline as
a covariate. Is there a preference for using the observed baseline vs. NONMEM
predicted baseline? And does your opinion change if you have a large residual
error?
Thanks
Pete bonate
Peter L. Bonate, PhD, FCP, FAAPS
GlaxoSmithKline
Clinical Pharmacology, Modeling, and Simulation
5 Moore Drive, 17.2259
Research Triangle Park, NC 27709
phone: 919-483-7534
fax: 919-483-8948
email: [email protected]
This is a long one but worth it...
Scientists will never make as much money as business executives. There is now
mathematical proof for this statement.
Postulate 1: Knowledge is power
postulate 2: Time is money
According to the laws of physics,
Work
-------- = Power (Eq. 1)
Time
Since, from the 2 postulates above,
Knowledge = Power and
Time = Money,
we can substitute into the equation 1 and come up with
Work
-------- = Knowledge
Money
Solving for money,
Work
------------ = Money
Knowledge
Hence, there are 2 ways to make money. If we slug our guts out working, we can
improve our money situation. This is the normal scientific approach. However
the suits usually opt for the easier solution, i.e., the less you know, the
more you'll make, regardless of the amount of work done.
Quoted reply history
-----Original Message-----
From: [email protected] [mailto:[email protected]] On
Behalf Of Leonid Gibiansky
Sent: Wednesday, August 11, 2010 9:01 AM
To: Ann Rigby-Jones
Cc: '[email protected]'
Subject: Re: [NMusers] Rounding errors with TRANSIT model
Ann
Try ADVAN6 or ADVAN8 or ADVAN13 .
Also, TOL=3 is too small. Increase it to 6-7 or even 9, and also change
to NSIG=3 SIGL=9 ($EST step, as recommended in the guide).
Also, at least initially, I would remove ETAs from the third compartment
and from one of the parameters (Q2 or V2) of the second compartment. Do
you really need both ALAG and transit compartment? They serve the same
goal, to delay the input, so could be strongly correlated; you may see
it on the POSTHOC plot of ETA7-ETA8 versus ETA9. I would try to remove
ETAs from ALAG or KTR to check whether they are needed.
If nothing helps, use UNCONDITIONAL on the $COV to get standard errors,
and if they are reasonable, ignore the error, it may disappear on the
next steps of the modeling process
Leonid
--------------------------------------
Leonid Gibiansky, Ph.D.
President, QuantPharm LLC
web: www.quantpharm.com
e-mail: LGibiansky at quantpharm.com
tel: (301) 767 5566
On 8/11/2010 5:57 AM, Ann Rigby-Jones wrote:
> Dear All
>
> I'm trying to evaluate a transit model approach in an attempt to better
> describe early drug concentrations following intravenous injection (1
> minute and 10 minute infusions) of a sedative-hypnotic drug. However,
> every minimisation attempt is terminated due to rounding errors (E=134).
> I've tried the usual strategies to overcome this e.g using final
> estimates of a terminated run as initial estimates for the next,
> changing number of sig dig requested, changing from a diagonal omega to
> a block omega, but nothing has been successful.
>
> I'd be very grateful for any suggestions of what I might try next J
> Standard 3-comp and 4-comp mamillary models minise successful with these
> data, but so far no luck with any of the transit models, I have tried
> model with 1 to 6 transit compartments. An example control stream is
> shown below. I'm using NONMEM 7 with Intel Fortran.
>
> With thanks and all best wishes
>
> Ann
>
> $PROBLEM 3comp 2 transit
>
> $INPUT ID DOSE AMT RATE DUR TIME ORI DV EVID ART AGE WGT
>
> $DATA PKcen12LN.csv IGNORE=#
>
> $SUBROUTINES ADVAN9 TOL=3
>
> $MODEL
>
> ;NCOMPS=9
>
> COMP(CENTRAL, DEFOBS) ;1
>
> COMP(PERIPH1) ;2
>
> COMP(PERIPH2) ;3
>
> COMP(TRANS1, DEFDOSE) ;4
>
> COMP(TRANS2) ;5
>
> ;COMP(TRANS3) ;6
>
> ;COMP(TRANS4) ;7
>
> ;COMP(TRANS5) ;8
>
> ;COMP(TRANS6) ;9
>
> $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
>
> ALAG4=THETA(7)*EXP(ETA(7))
>
> ELSE
>
> ALAG4=THETA(8)*EXP(ETA(8))
>
> ENDIF
>
> KTR=THETA(9)*EXP(ETA(9))
>
> $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
>
> DADT(1)=A(5)*KTR + 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
>
> DADT(4)=-A(4)*KTR
>
> DADT(5)=A(4)*KTR - A(5)*KTR
>
> ;DADT(6)=A(5)*KTR - A(6)*KTR
>
> ;DADT(7)=A(6)*KTR - A(7)*KTR
>
> ;DADT(8)=A(7)*KTR - A(8)*KTR
>
> ;DADT(9)=A(8)*KTR - A(9)*KTR
>
> $ERROR
>
> W=1
>
> IPRED= -2
>
> IF (F.GT.0) IPRED=LOG(F)
>
> Y=IPRED + ERR(1)
>
> IRES=DV-IPRED
>
> IWRES=IRES/W
>
> $THETA (0, 725) ;CL
>
> $THETA (0, 238) ;Q2
>
> $THETA (0, 2920) ;Q3
>
> $THETA (0, 311) ;V1
>
> $THETA (0, 38700) ;V2
>
> $THETA (0, 39500) ;V3
>
> $THETA (0.2167, 0.522,1) ;ALAG 10MIN
>
> $THETA (0.00833, 0.122, 1) ;ALAG 1MIN
>
> $THETA (0, 0.720) ;KTR
>
> $OMEGA BLOCK(6)
>
> 0.0959 ; ETA CL
>
> 0.00804 0.0211 ; ETA Q2
>
> 0.00631 0.00143 0.166 ; ETA Q3
>
> -0.00506 0.00121 -0.0635 0.0491 ; ETA V1
>
> 0.00293 -0.00746 0.00708 -0.00315 0.0328 ; ETA V2
>
> 0.00836 0.00688 0.00144 -0.00497 0.00741 0.153 ; ETA V3
>
> $OMEGA 0.217 ; ETA ALAG 10
>
> $OMEGA 0.4 ; ETA ALAG 1
>
> $OMEGA 0.0171 ; ETA KTR
>
> ;$OMEGA (0.0686) ; ETA CL
>
> ;$OMEGA (0.01) ; ETA Q2
>
> ;$OMEGA (0.0251) ; ETA Q3
>
> ;$OMEGA (0 FIX) ; ETA V1
>
> ;$OMEGA (0.0328) ; ETA V2
>
> ;$OMEGA (0 FIX) ; ETA V3
>
> ;$OMEGA (0.170) ; ETA ALAG10
>
> ;$OMEGA (1.37) ; ETA ALAG1
>
> ;$OMEGA (0.00409) ; ETA KTR
>
> $SIGMA (0.0944)
>
> $ESTIMATION METHOD=1 PRINT=1 MAX=9999 NOABORT SIG=3 ;POSTHOC INTER
>
> MSFO=msfo.outputfile
>
> ;$COVA
>
> $TABLE ID EVID AMT TIME IPRED IRES
>
> NOPRINT FILE=AllRecords.txt
>
> $TABLE ID
>
> CL Q2 Q3 V1 V2 V3
>
> ETA1 ETA2 ETA3 ETA4 ETA5 ETA6 ETA7 ;ETA8
>
> FIRSTONLY NOPRINT NOAPPEND FILE=FirstRecords.txt
>
> Ann
>
> _______________________________________________________________________
>
> *Ann Rigby-Jones PhD MRSC*
> Research Fellow in Pharmacokinetics & Pharmacodynamics
>
> Peninsula College of Medicine & Dentistry
>
> N31, ITTC Phase 1
> Tamar Science Park
> 1 Davy Road
> Derriford
> Plymouth
> PL6 8BX
>
> Tel: +44 (0) 1752 432014
> _______________________________________________________________________
>