OMEGA - CORR MATRIX FOR RANDOM EFFECTS - ETAS

Dear NM Users, I ran into a problem with a NM 7.2 run with an OMEGA BLOCK (2), receiving an error message saying the parameter estimate is near its boundary (See also the discussion in [NMusers] How to solve it? ERROR: PARAMETER ESTIMATE IS NEAR ITS BOUNDARY ). After digging through the documentation I am still unsure where the problem is originating from. What I figured out is that the problem lies in the OMEGA - CORR MATRIX FOR RANDOM EFFECTS - ETAS *******, a matrix I believe is only introduced since NM7.2. The estimate in this matrix that is giving problems is the one for the OMEGA BLOCK, which is estimated to be 1 (a boundary). Now, as far as I know, the OMEGA - CORR MATRIX is related to the OMEGA - COV MATRIX as the sqrt of its estimate. However, it is unclear to me how the OMEGA BLOCK estimate (COV MATRIX), which gives the correlation between the two ETAs, is related to the OMEGA - CORR MATRIX value. What does this value actually mean, and what does it mean for my error message, as the correlation estimate itself seems to be fine? In the print below you can see the model and resulting estimates, the important ones being 5.26E-02 (OMEGA - COV MATRIX of ETA1-ETA2) and 1.00E+00 (OMEGA - CORR MATRIX of ETA1-ETA2). The model has two ETAs and an proportional error model, Thanks in advance for any insights and help, Best, Jules Heuberger $SUB ADVAN=6 TOL=5 $MODEL COMP=(CENTRAL) COMP=(PERI) $PK ; structural model K10=IK10 V1 =IV1 K12=EXP(-1.29) K21=EXP(-0.63) V2=K12*V1/K21 BSL=IBSL E0=THETA(1)*EXP(ETA(1)) EMAX=THETA(2)*EXP(ETA(2)) EC50=THETA(3) ; $DES DADT(1) = -K10*A(1)-K12*A(1)+K21*A(2) DADT(2) = K12*A(1)-K21*A(2) $ERROR CP=F EFF=E0-EMAX*F/(EC50+F) Y= EFF*(1+ERR(1))+ERR(2) IPRE=EFF $THETA 55 20.9 364 ; $OMEGA BLOCK(2) 0.2 0.01 0.2 $SIGMA 0.01 0 FIX $EST PRINT=5 MAX=9999 METHOD=1 INTERACTION POSTHOC NOABORT MSFO=mfi __________________________________________________________ OMEGA - COV MATRIX FOR RANDOM EFFECTS - ETAS ******** ETA1 ETA2 ETA1 + 2.44E-02 ETA2 + 5.26E-02 1.13E-01 SIGMA - COV MATRIX FOR RANDOM EFFECTS - EPSILONS **** EPS1 EPS2 EPS1 + 1.11E-02 EPS2 + 0.00E+00 0.00E+00 1 OMEGA - CORR MATRIX FOR RANDOM EFFECTS - ETAS ******* ETA1 ETA2 ETA1 + 1.56E-01 ETA2 + 1.00E+00 3.37E-01 SIGMA - CORR MATRIX FOR RANDOM EFFECTS - EPSILONS *** EPS1 EPS2 EPS1 + 1.05E-01 EPS2 + 0.00E+00 0.00E+00 Jules Heuberger Clinical Scientist Centre for Human Drug Research Zernikedreef 8 2333 CL Leiden The Netherlands ' +31 (0)71 5246400 ( +31 (0)6 43937461 7 +31 (0)71 5246499 + [email protected] http://www.chdr.nl