Dear Jules, You are correct in pointing out where the problem lies. However, the covariance matrix is not fine since it is at the boundary just as much as the translation into correlation. Correlation is calculated by this equation: Cor(eta1,eta2)=OM1,2 /(sqrt(OM1,1)*sqrt(OM2,2)) Where: OM1,1 and OM2,2, represents eta variance (as reported by nonmem output in the OMEGA cov matrix, i.e. on var scale and not the sd scale that is reported in the OMEGA corr matrix) and OM1,2 represents Cov(eta1,eta2), i.e. as reported for the off diagonal on the OMEGA cov matrix
I did not check your control stream thoroughly, but apparently, with the current data and model baseline (E0) and Emax are completely correlated on the individual level, maybe because of lack of information, maybe because of physiology – you currently have an additive effect, but maybe Emax would be bringing the PD endpoint all the way to zero or reducing the endpoint by a certain fraction (i.e. a multiplicative model), or maybe healthy can not be reduced at all, wheras elevated values can be reduced (almost) down to healthy values? If you get that “structural” part of your drug-effects model right, you may then be able to estimate correlation (or conclude with the new structure these two etas are no longer correlated). Best regards Jakob From: [email protected] [mailto:[email protected]] On Behalf Of Jules Heuberger Sent: 17 September 2013 11:42 To: [email protected] Subject: [NMusers] 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
