From: Huali Wu <*hualiw*>

Date: Thu, 3 Jul 2008 19:12:15 -0400

Dear Dr. Gibiansky:

You are correct about that. I have double checked my simulations with

WinNonlin and ADAPTII. And I found a mistake in the order of parameter

values.

Thank you very much for your correction!

Best regards,

Huali

----- Original Message -----

From: Leonid Gibiansky <LGibiansky

To: "Huali Wu" <hualiw

Cc: <nmusers

Sent: Thursday, July 03, 2008 5:40 PM

Subject: Re: [NMusers] Estimation of standard error

*> 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 - 19:12:15 EDT

Date: Thu, 3 Jul 2008 19:12:15 -0400

Dear Dr. Gibiansky:

You are correct about that. I have double checked my simulations with

WinNonlin and ADAPTII. And I found a mistake in the order of parameter

values.

Thank you very much for your correction!

Best regards,

Huali

----- Original Message -----

From: Leonid Gibiansky <LGibiansky

To: "Huali Wu" <hualiw

Cc: <nmusers

Sent: Thursday, July 03, 2008 5:40 PM

Subject: Re: [NMusers] Estimation of standard error

Received on Thu Jul 03 2008 - 19:12:15 EDT