Re: ETAs & SIGMA in external validation

Hi Ruben, I think I misread Tingjies original posting as taking ABS(ETA), whereas his initial attempt was actually ABS(1+ETA), which is less problematic. The latter would not bias simulations much if IIV is e.g. 30% CV, agreed. However, as Tingjies is mainly interested in estimation, I believe that without the ABS-correction, no subject will have the EBE at ETA <= -1 for a parameter that could not be <=0. Unless possibly in a subject which is a) uninformative on that parameter and b) where the eta is also part of an omega-block - a scenario which seems unlikely to me, but may occur in theory. Implementing the ABS-korrection ETA=-1.2 would give the same solution (parameter value) as ETA=-0.8, but at a higher OFV for that subject. It seems to me, if negative parameter values are only a problem in the eta search for the EBE, whereas the EBE for individual parameters are always positive, then it should be more straightforward to use FOCE, with the addition e.g.: IF(PARA.LT.0.001) PARA=0.001 Probably, no subject will have such a low individual parameter value, when looking into the table output? If there are any such subjects I would look for errors in the data set and nonmem code (as outlined in my initial reply). The above concerns estimation. In simulation (unless %CV is low), we may get a fraction of subject with PARA=0.001, which may be an unreasonably low parameter value. Whether that is acceptable or not depends on the objectives and in this case there was no need for simulations even for model evaluation (?), so I will not elaborate further. Cheers Jakob