RE: Rational of using IOV

From: mats karlsson [mailto:[email protected]] Sent: Tuesday, November 02, 2010 11:31 AM To: 'Stephen Duffull'; 'Nick Holford'; '[email protected]' Subject: RE: [NMusers] Rational of using IOV Hi Steve, When you say BSV is not design-specific, do you with BSV mean the variability in parameter value between subjects at any given instance, or the variability in their average parameter value over 1 hour or over 1 year? With each of these definitions and in the presence of time-varying parameters, BSV is different. Whenever we have variability in parameters over time, our ability to capture and distinguish between random effects will be dependent on our design. If you have IIV, IOV and RV present, all three will become design-dependent in the sense I think you used the word. I would say that none of them are design-dependent, but the information in data and our ability in postulating appropriate models is under many situations not sufficient to capture all variability adequately. In particular parameter time-variation is difficult to both capture and model appropriately. I have no definition of nuisance parameters, I just tried to echo your use. With respect to your definition of them, I would say that no parameter has unlimited interest, but in a model I am interested in, no estimated parameter has no interest. (and now I'm quite sure I'm splitting hairs.) Best regards, Mats Mats Karlsson, PhD Professor of Pharmacometrics Dept of Pharmaceutical Biosciences Uppsala University Sweden Postal address: Box 591, 751 24 Uppsala, Sweden Phone +46 18 4714105 Fax + 46 18 4714003 From: Stephen Duffull [mailto:[email protected]] Sent: Tuesday, November 02, 2010 9:05 AM To: [email protected]; 'Nick Holford'; [email protected] Subject: RE: [NMusers] Rational of using IOV Hi Mats I agree that if a mechanistic quality can be used to determine BOV then I think this would provide a very strong argument for duration of the occasion. I believe that this falls into my overarching statement "The duration of the occasion would need to be indexed to the substantive inferences of the model to ensure that any influence that BOV has can be assessed in terms of model predictions.". My interpretation of nuisance parameter is perhaps slightly different from your use - I was using a more general sense to indicate a non-ignorable parameter for which the value was of limited or no interest. As a general rule, although I am sure there are exceptions, BSV and RUV are non-design specific. The ability to estimate these parameters accurately and reliably is of course related to the design. The value of BOV as well as the ability to estimate the value is design specific and hence I am more inclined to include BOV in the non-ignorable but (design specific) interest. I would not consider BSV to be nuisance, RUV is equivocal. I suspect I am splitting hairs at this stage. Regards Steve --