Dear NMusers, Based on the NONMEM Inter-Occasion Variability (IOV) example control stream, located at NONMEM_install_dir/examples/example7.ctl, it seems that it is currently not possible to Mu parameterize IOV in NONMEM 7.3. The relevant lines from example7.ctl control stream are copypasted below:
MU_2=THETA(2) CLB=DEXP(MU_2+ETA(2)) DCL1=DEXP(ETA(3)) DCL2=DEXP(ETA(4)) DCL3=DEXP(ETA(5)) DCL=DCL1 IF(TIME.GE.5.0) DCL=DCL2 IF(TIME.GE.10.0) DCL=DCL3 CL=CLB*DCL My question is: Does this mean that the updating procedure of IIV/IOV parameters (omegas) does not have the EM efficiency when IOV is present? If we had no IOV, then I think NONMEM would calculate for the update step that THETA(2)=E(LOG(CLB)) OMEGA(2,2)=VAR(LOG(CLB)) where E() refers to computing mean and VAR() refers to computing variance. These expressions are useful, because with these there is no need to find the best THETA(2) or OMEGA(2,2) values with numerical optimization. It saves computation time that just mean and variance can be taken. Now, with the IOV model, I think the updating could be accomplished with THETA(2)=E(LOG(CLB)) OMEGA(2,2)=VAR(LOG(CLB)) OMEGA(3,3)=VAR(LOG(CL))-OMEGA(2,2) However, I'm not sure what actually happens inside NONMEM. -Is the updating done like this, or does the lack of MU referencing in IOV force the estimation process to use gradient descent for estimation of some/all parameters? -If gradient descent is used, how dramatically does it reduce the speed of the estimation process? -If MU referencing is impossible with the presence of IOV, would it then be possible to use occasion variable OCC as the ID, and somehow convince NONMEM not to reset the compartments when OCC changes? This way, MU referencing could be used for the OCC variable, and IIV would be just ignored for that run. This would be only for exploratory runs, of course. For this discussion, let's assume that -Adequate data exist to estimate occasion-specific random effects. -The IOV parameters are critical for the model to be able to describe the data nicely (e.g. large IOV in absorption) Looking forward to hear your thoughts! Best wishes, Pyry Välitalo Postdoc, Leiden University, Division of Pharmacology Senior Scientist, Orion Pharma, Drug Disposition and Pharmacometrics
