RE: estimating Ka from dataset combining rich sample study and sparse sampling study
Dear Ethan
I concur with Mats's comments below.
As a note, from a design perspective adding additional data to an experiment cannot result in less precise parameter estimates under the assumption that the individuals from the two data sets are exchangeable. Under this assumption therefore the Sparse data should merely add information to the Rich data. That the Sparse data is affecting the parameter estimates from the Rich data suggests that the two data sets are not exchangeable (different centre, different assay, different covariates ...).
Another possible way to investigate the differences between the two data sets would be to analyse them sequentially, perhaps with consideration for using the analysis from the Rich data as an informative prior for the analysis of the Sparse data and see where this leads you.
Kind regards
Steve
--
Professor Stephen Duffull
Chair of Clinical Pharmacy
School of Pharmacy
University of Otago
PO Box 913 Dunedin
New Zealand
E: stephen.duffull
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Quoted reply history
From: owner-nmusers
Behalf Of Mats Karlsson
Sent: Thursday, 18 June 2009 9:17 a.m.
To: 'Ribbing, Jakob'; 'Ethan Wu'; 'Jurgen Bulitta'; nmusers
Cc: 'Roger Jelliffe'; 'Neely, Michael'
Subject: RE: [NMusers] estimating Ka from dataset combining rich sample study and sparse sampling study
Dear Ethan,
Variances estimated to be zero may result from fixing off-diagonal variances to zero (i.e. not using BLOCKs in IIV). Here, however, it may be that there are systematic differences between the sparse and the rich data experiments. Maybe fasting/fed status or something else is different. If the fit to the rich data is markedly worse when including the rich data, at least one parameter is different between the two situations. I would explore what parameter(s) that would be. In addition to Jakob's suggestions below, the two data sets together may indicate a more complex structural model that a single profile indicated. Maybe you need to go to a two-compartment for example.
Best regards,
Mats
Mats Karlsson, PhD
Professor of Pharmacometrics
Dept of Pharmaceutical Biosciences
Uppsala University
Box 591
751 24 Uppsala Sweden
phone: +46 18 4714105
fax: +46 18 471 4003
From: owner-nmusers
Behalf Of Ribbing, Jakob
Sent: Wednesday, June 17, 2009 10:43 PM
To: Ethan Wu; Jurgen Bulitta; nmusers
Cc: Roger Jelliffe; Neely, Michael
Subject: RE: [NMusers] estimating Ka from dataset combining rich sample study and sparse sampling study
Hi Ethan,
If OMEGA(?) for KA is drastically reduced when including the sparse data, then something is wrong with your model and in this case it is not the estimation method or assumption on distribution of individual parameter). Eta-shrinkage would not drastically reduce the estimate of OMEGA, since this estimate is driven by the subjects/studies which contain information on the parameter.
If the sparse data is multiple dosing it may be that KA is variable between occasions, rather than between subjects (assuming the sparse data contain some information on KA). Or if the sparse data is from a less well-controlled study or a different population, it may be that increased IIV in other parts of the model (e.g. OMEGA on V) is making IIV in KA appear low for the rich study, when fitting the two studies together. If you get the covariate model in place this problem will be solved. For the simple model you have it should be quick to start out assuming that most parameters (THETAs and OMEGAs) are different between the two studies and then reduce down to a model which is stable and parsimonious. Obviously, if you eventually can explain the differences using more mechanistic covariates than study number that is of more use.
Cheers
Jakob