From: Leonid Gibiansky <*LGibiansky*>

Date: Thu, 03 Jul 2008 15:00:43 -0400

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 - 15:00:43 EDT

Date: Thu, 03 Jul 2008 15:00:43 -0400

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,

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:

--

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:

Received on Thu Jul 03 2008 - 15:00:43 EDT