Zähneputzen VOR oder NACH dem Frühs tück? What comes first? BSV, BOV, o r covariates?

Dear all, don't be discouraged by the subject, this is indeed NMUsers and not German 101, and this post is about pharmacometrics, please read on... ;) The subject of the message comes from when I was studying German, and from an exercise in our book with lots of colourful pictures. The point of the exercise was only to teach us how to say "tooth brushing", "have breakfast", "before" and "after", but instead it sprouted a lively discussion in the class about what comes first and last in everybody's morning routine... So I thought it would be an appropriate title for this post, which is a survey/question about what modelling approach people use/recommend for model development. Just to contextualize a bit, here at UCT we mainly study HIV and TB drugs, which are dosed repeatedly (once or twice per day) and administered orally. We often have data available on more than one sampling occasion, and many times these occasions are virtually equivalent: no changes in co-treatment or other covariates, just a mere repetition of the experiment on a different day. Confirming what Mats recently pointed out in a post about the use of BOV, our experience is that, especially in the absorption phase, the contribution of BOV is dominant, and cannot be ignored. The absorption is often subject to random delays and factors that are mostly occasion-specific and not measurable/available in the dataset. Therefore, when I start modelling new data, I normally proceed as follows: 1. I initially assume every occasion as a separate profile, either using dummy IDs (and pretending it's different subjects) or coding all variability as BOV. I believe this allows the maximum flexibility to test the structural model, and I find that, if I don't proceed like this, I may run into troubles detecting the correct structural model. In this early stage of model development, I mostly use individual plots, and try to see if my prediction profile is flexible enough to run through the points. 2. Then I try to see if some of the variability is subject-specific (normally V and CL) and can be better explained either by only BSV or both BSV and BOV. I use the OFV to guide this process, but if the BOV is much larger than BSV, and physiology supports the hypothesis that the parameter be occasion-specific, I tend to disregard BSV. 3. Once I believe I got my structural model right, and organized the hierarchy of random variability in a decent way, I start incorporating the covariates. If they turn out to be significant, I see that BOV and BSV decrease, and sometimes become superfluous in the model and can be removed. I know other modellers would recommend first introducing BSV and/or covariates, before considering BOV and I would be interested in knowing people's opinion about this. Each method probably has its pros and cons, and I would really value your input about this topic. What are the advantages and disadvantages of the different approaches? Since I favour the modus operandi I just explained, I give my reasons, and look forward to some comments. My opinion (but I am obviously biased) is that it does not hurt to include BOV first, since it is easy to remove from the model if the same variability is explained by covariates, and likely, if this is the case, BOV will decrease in size. On the other hand, disregarding BOV might prevent the identification of the correct structural model. I am thinking, for example, about a comparison between 2-cmpt vs 1-cmpt when the absorption is subject to substantial random delays. If BOV is not considered, this is equivalent to pooling the data from all occasions, with the potential result of having a cloud of points without much structure... And also, as a general rule, I would allow a parameter to move with an ETA, before I try to explain its changes with a covariate effect. In this way I can also test better if the covariate is explaining some of this variability. Ok, I've been once again way too lengthy, apologies. Any comments/thoughts? In other words, do you first brush your teeth or have breakfast? Please join the survey! ;) Greetings from Cape Town, Paolo PS Ich putze die Zähne immer NACH dem Frühstück... I can't enjoy coffee with that minty toothpaste after-taste... :) -- ------------------------------------------------ Paolo Denti, PhD Post-Doctoral Fellow Division of Clinical Pharmacology Department of Medicine University of Cape Town K45 Old Main Building Groote Schuur Hospital Observatory, Cape Town 7925 South Africa phone: +27 21 404 7719 fax: +27 21 448 1989 email: [email protected] ------------------------------------------------ ### UNIVERSITY OF CAPE TOWN This e-mail is subject to the UCT ICT policies and e-mail disclaimer published on our website at http://www.uct.ac.za/about/policies/emaildisclaimer/ or obtainable from +27 21 650 9111. This e-mail is intended only for the person(s) to whom it is addressed. If the e-mail has reached you in error, please notify the author. If you are not the intended recipient of the e-mail you may not use, disclose, copy, redirect or print the content. 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