From: Leonid Gibiansky <*LGibiansky*>

Date: Thu, 03 Jul 2008 17:40:05 -0400

Huali

Even if it gives a good fit, S2=V1 is still an error. You may try to

assume that V2=V1, and then S2=V2=V1, it is fine, but in the current

form, equations are incorrect

Thanks

Leonid

--------------------------------------

Leonid Gibiansky, Ph.D.

President, QuantPharm LLC

web: www.quantpharm.com

e-mail: LGibiansky at quantpharm.com

tel: (301) 767 5566

Huali Wu wrote:

*> Dear Dr. Gibiansky:
*

*>
*

*> Thank you very much for your suggestions.
*

*>
*

*> MATRIX=S did work. But S2 = V2 did not. Also, S2 = V1 is not an error, I
*

*> validated that by comparing the simulation results from WinNonlin and
*

*> NONMEM without adding any error. I don't understand why but if S2 = V2
*

*> will only give discrepant result.
*

*>
*

*> For the error model, I have tried separate errors for each CMT. But it
*

*> did not give good fit of released drug.
*

*>
*

*> Thanks again,
*

*>
*

*> Best regards,
*

*>
*

*> Huali
*

*>
*

*> ----- Original Message ----- From: "Leonid Gibiansky"
*

*> <LGibiansky *

*> To: "Huali Wu" <hualiw *

*> Cc: <nmusers *

*> Sent: Thursday, July 03, 2008 3:00 PM
*

*> Subject: Re: [NMusers] Estimation of standard error
*

*>
*

*>
*

*>> Huali and Nick,
*

*>> Failure of $COV step sometimes tells about errors in the code. In this
*

*>> case, I think the problem is in
*

*>> S2 = V1
*

*>>
*

*>> should it be
*

*>> S2 = V2 ?
*

*>>
*

*>> Also,
*

*>> > Y1=F+F*EPS(1)
*

*>> > Y2=F+F*EPS(1)
*

*>> > Y=R1*Y1+R2*Y2
*

*>>
*

*>> results in
*

*>> Y =F+F*EPS(1)
*

*>> for both MCT=1 and CMT=2
*

*>> so R1 / R2 /Y1 /Y2 part can be omitted. Or you can use separate errors
*

*>> for each CMT:
*

*>>
*

*>> > Y1=F+F*EPS(1)
*

*>> > Y2=F+F*EPS(2)
*

*>> > Y=R1*Y1+R2*Y2
*

*>> --
*

*>>
*

*>> S2 = V2 should help to get SE. If not, try MATRIX=S on $COV line.
*

*>> Leonid
*

*>>
*

*>> --------------------------------------
*

*>> Leonid Gibiansky, Ph.D.
*

*>> President, QuantPharm LLC
*

*>> web: www.quantpharm.com
*

*>> e-mail: LGibiansky at quantpharm.com
*

*>> tel: (301) 767 5566
*

*>>
*

*>>
*

*>>
*

*>>
*

*>> Huali Wu wrote:
*

*>>> Dear NMusers:
*

*>>> I am trying to fit a data set with concentrations of encapsulated
*

*>>> drug and released drug. These concentrations were measured after an
*

*>>> hour infusion of encapsulated drug. The problem is that I cannot get
*

*>>> standard error estimated from simultaneous fitting of all the data.
*

*>>> And I got an error message as below:
*

*>>> MINIMIZATION SUCCESSFUL
*

*>>> HOWEVER, PROBLEMS OCCURRED WITH THE MINIMIZATION.
*

*>>> REGARD THE RESULTS OF THE ESTIMATION STEP CAREFULLY, AND ACCEPT THEM
*

*>>> ONLY
*

*>>> AFTER CHECKING THAT THE COVARIANCE STEP PRODUCES REASONABLE OUTPUT.
*

*>>> NO. OF FUNCTION EVALUATIONS USED: 968
*

*>>> NO. OF SIG. DIGITS IN FINAL EST.: 3.2
*

*>>> R MATRIX ALGORITHMICALLY NON-POSITIVE-SEMIDEFINITE
*

*>>> BUT NONSINGULAR
*

*>>> R MATRIX IS OUTPUT
*

*>>> COVARIANCE STEP ABORTED
*

*>>> But if I fit the encapsulated drug first and then fit data of both
*

*>>> encapsulated drug and released drug by fixing the typical values of
*

*>>> parameters associated with encapsulated drug compartment, I can get
*

*>>> an estimation of standard errors. And GOF plots look good.
*

*>>> So my question is can I use this stepwise strategy to build up my
*

*>>> base model? If not, what can I do to get standard error estimated in
*

*>>> simultaneous fitting?
*

*>>> Any comment or suggestion will be highly appreciated.
*

*>>> Below is my code:
*

*>>> $SUBROUTINES ADVAN9 TRANS1 TOL=3
*

*>>> $MODEL NPAR=8, NCOMP=3, COMP=(CENTRAL,DEFOBS),
*

*>>> COMP=(PERIPH1), COMP=(PERIPH2)
*

*>>> $PK
*

*>>> V1 = THETA(1)*EXP(ETA(1))
*

*>>> V2 = THETA(2)*EXP(ETA(2))
*

*>>> V3 = THETA(3)
*

*>>> VM = THETA(4)
*

*>>> KM = THETA(5)
*

*>>> Q2 = THETA(6)*EXP(ETA(3))
*

*>>> Q3 = THETA(7)
*

*>>> Q4 = THETA(8) S1 = V1
*

*>>> S2 = V1
*

*>>> $ERROR
*

*>>> R1=0
*

*>>> IF (CMT.EQ.1) R1=1
*

*>>> R2=0
*

*>>> IF (CMT.EQ.2) R2=1
*

*>>> Y1=F+F*EPS(1)
*

*>>> Y2=F+F*EPS(1)
*

*>>> Y=R1*Y1+R2*Y2
*

*>>> IPRED=F
*

*>>> IRES=DV-IPRED
*

*>>> $DES
*

*>>> C1 = A(1)/V1
*

*>>> DADT(1) = - C1*VM/(KM+C1)-Q2*A(1)/V1
*

*>>> DADT(2) = C1*VM/(KM+C1)+Q2*A(1)/V1 + Q4*A(3)/V3-
*

*>>> Q3*A(2)/V2-Q4*A(2)/V2
*

*>>> DADT(3) = Q4*A(2)/V2-Q4*A(3)/V3 $THETA (5.27 FIX)
*

*>>> (0, 0.5) (0, 3.38) (0.329 FIX) (4.38 FIX) (0.136 FIX) (0, 0.0626) (0,
*

*>>> 0.0461)
*

*>>> $OMEGA (0.01) (0.01) (0.01)
*

*>>> $SIGMA (.1)
*

*>>>
*

*>>> $EST MAXEVAL=9999 PRINT=5
*

*>>> $COV
*

*>>> $TABLE ID TIME DV AMT RATE CMT NOPRINT FILE=ENCAP4 ONEHEADER
*

*>>> $SCAT (RES WRES) VS TIME BY ID
*

*>>> Best regards,
*

*>>> Huali
*

*>>>
*

*>>
*

*>
*

*> *

Received on Thu Jul 03 2008 - 17:40:05 EDT

Date: Thu, 03 Jul 2008 17:40:05 -0400

Huali

Even if it gives a good fit, S2=V1 is still an error. You may try to

assume that V2=V1, and then S2=V2=V1, it is fine, but in the current

form, equations are incorrect

Thanks

Leonid

--------------------------------------

Leonid Gibiansky, Ph.D.

President, QuantPharm LLC

web: www.quantpharm.com

e-mail: LGibiansky at quantpharm.com

tel: (301) 767 5566

Huali Wu wrote:

Received on Thu Jul 03 2008 - 17:40:05 EDT