RE: FO vs FOCE, sequential vs simultaneous

From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED] On Behalf Of Gastonguay, Marc Sent: Tuesday, December 09, 2008 7:56 PM To: Gibiansky Leonid; Xiao, Alan; Hussein, Ziad; nmusers nmusers Subject: Re: [NMusers] FO vs FOCE, sequential vs simultaneous There's an additional, related point to consider with respect to estimation method, in selecting a simultaneous vs sequential approach.... In the case where simultaneous modeling under conditional estimation is not feasible (run-time, convergence, etc), it is preferable to use a sequential approach. In the first step, model PK (or parent) using conditional estimation or FO/POSTHOC, and run the second sequential step (e.g. PD or metabolite) conditioned on the individual estimates obtained in the first step. By doing so, the second step (PD or metabolite) model will be driven by individual conditional random effect estimates obtained the first step. This is preferable to running a simultaneous model under FO, where only the population typical values would be used to drive the second stage endpoint (PD or metabolite) model. For more on this point, see: Zhang L, Beal SL, Sheiner LB. J Pharmacokinet Pharmacodyn. 2003 Dec;30(6):387-404. Simultaneous vs. sequential analysis for population PK/PD data I: best-case performance. Regards, Marc Marc R. Gastonguay, Ph.D. President & CEO, Metrum Research Group LLC [www.metrumrg.com] Scientific Director, Metrum Institute [www.metruminstitute.org] Direct: 860-670-0744 Main: 860-735-7043 Email: [EMAIL PROTECTED] On Dec 9, 2008, at 12:33 PM, Leonid Gibiansky wrote: Hi Alan, Here: http://quantpharm.com/pdf_files/PAGE_2008_Poster_1268_web.pdf I used all datasets that I had, and I was not able to find any problem where FO was superior to FOCE. Not-converged FOCE is better, in my opinion, than converged FO (although you can always check using diagnostic plots). If you cannot use FOCE due to time restrictions, it is better to use FO than just abandon modeling. Still, I would try to run the final model with FOCEI. Concerning sequential vs simultaneous: there are several points to consider, and this is usually relates to the PK-PD case. For PK-PD, the main question is the comparison of PK and PD variabilities. Usually, PK variability is smaller, and PK data are more reliable. Then, sequential modeling can be more warranted. If PK and PD variabilities are similar (both residual and inter-subject) you can use joint fit. I usually do PK first, then PK-PD, and then try to fit combined model at the very last stage. For parent-metabolite case, both sets of data are equally reliable (or not reliable), and variability is usually similar. Then the question boils down to time and convenience. Again, I usually do parent fist, then fix parameters and do metabolite, and then, if possible, do simultaneous fit. This often saves time: parent model is more simple, it can be done in standard ANDANs for 1-2 compartment models that are much quicker. You can experiment freely with random effect, covariates, residual error, etc. Joint model often needs to be solved using ADVAN5, 7 or even $DES which are more CPU-consuming. You want to do minimum number of runs here. Thus, you want to start with good parent model, and study metabolite part only. The final joint run fits all parts together. Thanks Leonid -------------------------------------- Leonid Gibiansky, Ph.D. President, QuantPharm LLC web: www.quantpharm.com e-mail: LGibiansky at quantpharm.com tel: (301) 767 5566 Xiao, Alan wrote: Dear All, I know this is an old topic, too, but would like to see the statistics. When you have a dataset with about 10% of dense Phase II data (predose, 2, 4, 8, and 12 hrs post dose on day 1 and at steady state, twice-daily dose regimen) and about 90% of very sparse Phase III data (1-2 samples/patient), which method do you prefer: FO or FOCE? or FO for model development but FOCE for model refinement/finalization? If FOCE is not practical because of long run-time or numerical difficulties in converge, do you stop here or would you use FO? Thanks, Alan