different parameterizations of OMEGA matrix vs. chance of getting flip-flop estimates

On 6/22/2012 12:36 PM, Yaming Hang wrote: > Dear NONMEM Users, > > One of the tricks people often use is to specify the SD(ETA) as a THETA > and fix the OMEGA to be 1, which is a trick I often use when I determine > which parameter should I put an ETA on. > > Most of the time, I will get the same results whether I use this trick, > or just the normal way of specifying the OMEGA matrix. So my > understanding is that these two approaches are equivalent. Today I run > into some problem – I got a flip-flop estimate. All other aspects of the > codes are the same, including same initial values and estimation method. > In this one compartment first order absorption and first order > elimination model, the estimation of CL and residual error magnitude > SIGMA is not impacted by the method used, but V and Ka are totally > different (as a result of flip-flop), and accordingly, their OMEGA estimate. > > Has anyone encountered similar situation? What kind of difference does > these two approaches make in terms of searching for the minimizer? I’d > appreciate if someone can help me to understand what’s going on here. > > Here are my codes and NONMEM outcome: > > *Approach 1 (the usual way):* > > $SUBROUTINES ADVAN2 TRANS2 > > $PK > > TVCL=THETA(1) > > CL=TVCL*EXP(ETA(1)) > > TVV=THETA(2) > > V=TVV*EXP(ETA(2)) > > TVKA=THETA(3) > > KA=TVKA*EXP(ETA(3)) > > S2=V > > $ERROR > > DEL=0 > > IF(F.LE.0) DEL=1 > > W1=1 > > IPRED=0 > > IF(F.GT.0) IPRED=LOG(F) > > IRES=DV-IPRED > > W2=THETA(4) > > IWRES=IRES/(W1*DEL+W2) > > Y=IPRED + W2*ERR(1) > > $OMEGA DIAGONAL(3) > > 0.1 > > 0.1 > > 0.1 > > $SIGMA 1 FIX > > $THETA > > (0, 31) ; 1 [THETA1, TVCL] > > (0, 300) ; 2 [THETA2, TVV] > > (0,2) ; 3 [THETA3, TVKA] > > (0,0.2) ; 4 [THETA4, SD(EPISILON)] > > $EST METHOD=1 INTERACTION PRINT=5 MAX=9999 SIG=3 NOABORT MSFO=103.MSF > > $COV PRINT=E > > *The results:* > > *THETA OMEGA SIGMA * > > *THETA1 27.68 (0.03513) OMEGA(1,1) 0.371 (0.2428) SIGMA(1,1) 1 (........) * > > *THETA2 298.9 (0.01969) OMEGA(2,2) 0.1585 (0.2042) * > > *THETA3 0.8336 (0.05652) OMEGA(3,3) 0.6265 (0.1491) * > > *THETA4 0.4441 (0.03294) * > > *Approach 2 (using the trick):* > > $SUBROUTINES ADVAN2 TRANS2 > > $PK > > TVCL=THETA(1) > > CL=TVCL*EXP(THETA(5)*ETA(1)) > > TVV=THETA(2) > > V=TVV*EXP(THETA(6)*ETA(2)) > > TVKA=THETA(3) > > KA=TVKA*EXP(THETA(7)*ETA(3)) > > S2=V > > $ERROR > > DEL=0 > > IF(F.LE.0) DEL=1 > > W1=1 > > IPRED=0 > > IF(F.GT.0) IPRED=LOG(F) > > IRES=DV-IPRED > > W2=THETA(4) > > IWRES=IRES/(W1*DEL+W2) > > Y=IPRED + W2*ERR(1) > > $OMEGA DIAGONAL(3) > > 1 FIX > > 1 FIX > > 1 FIX > > $SIGMA 1 FIX > > $THETA > > (0, 31) ; 1 [THETA1, TVCL] > > (0, 300) ; 2 [THETA2, TVV] > > (0,2) ; 3 [THETA3, TVKA] > > (0,0.2) ; 4 [THETA4, SD(EPISILON)] > > (0,0.01) ; 5 [THETA5, IIV ON CL, SD(ETA1) > > (0,0.01) ; 6 [THETA6, IIV ON V, SD(ETA2)] > > (0,0.01) ; 7 [THETA7, IIV ON KA, SD(ETA3)] > > $EST METHOD=1 INTERACTION PRINT=5 MAX=9999 SIG=3 NOABORT MSFO=104.MSF > > $COV PRINT=E > > *Results:* > > *THETA OMEGA SIGMA * > > *THETA1 27.68 (0.03569) OMEGA(1,1) 1 (........) SIGMA(1,1) 1 (........) * > > *THETA2 33.57 (0.06407) OMEGA(2,2) 1 (........) * > > *THETA3 0.09296 (0.03003) OMEGA(3,3) 1 (........) * > > *THETA4 0.4442 (0.03295) * > > *THETA5 0.4001 (0.117) * > > *THETA6 0.6873 (0.08321) * > > *THETA7 0.3336 (0.1125) * > > Yaming Hang, Ph.D. > > Pharmacometrics > > Biogen Idec > > 14 Cambridge Center > > Cambridge, MA 02142 > > Office: 781-464-1741 > > Fax: 617-679-2804 > > Email: [email protected] <mailto:[email protected]> > > No virus found in this message. > Checked by AVG - www.avg.com http://www.avg.com > Version: 2012.0.2180 / Virus Database: 2437/5086 - Release Date: 06/22/12