Jacob, I am guilty of having performed such a bootstrap (but didn't do any of the testing you describe). Anyway, here's an opinion: By using prior in nonmem you are trying to get an approximation of what the pooled data fit would be and get an OFV that is theoretically the same as if you did the pooled analysis. Similarly I would think that such a bootstrap gives a measure of uncertainty that is similar as would be found if you had pooled data - so if you increase uncertainty on the prior element, then I would imagine you would get increase in bootstrap uncertainty, the magnitude of which will vary depending on the relative contribution of the data and prior (and thereby tell you whether information is coming from the data or the prior). For this reason, I think without some exhaustive simulation exercise with lots of permutations of data and prior informativeness, there is probably no straight-forward answer as to how prior uncertainty affects bootstrap uncertainty, and would just try a couple of bootstraps with increased uncertainty in the priors of parameters that you think might be overly-influenced to see what happens. BW, Joe
Joseph F Standing MRC Fellow, UCL Institute of Child Health Antimicrobial Pharmacist, Great Ormond Street Hospital Honorary Lecturer, London School of Pharmacy Mobile: +44(0)7970 572435 ________________________________ From: owner-nmus...@globomaxnm.com [owner-nmus...@globomaxnm.com] On Behalf Of Brogren Jacob [jacob.brog...@mpa.se] Sent: 22 December 2011 12:58 To: nmusers@globomaxnm.com Subject: [NMusers] Bootstrap in combination with PRIOR? Dear nmusers, Merry Holiday! (you may change the variable ‘Holiday’ to an arbitrary value) First, accept my humble excuse – I can’t share any code for this example. I’m assessing a model where $PRIOR is used to stabilize the fit of an ‘old’ model to sparse data using NONMEM. It seems to be the only way forward. Using the final model the Applicant has then performed a non-parametric bootstrap (N=1000) to investigate i.a. robustness of the model parameter estimates. >From a non-scientific literature search (Google Scholar “NONMEM + PRIOR + >Bootstrap”) some examples show up where Bootstrap and PRIOR has been combined. I’m curious about if any nm-user has investigated how much and in what way the prior distribution of parameters affect the bootstrap estimates (eg. 2.5th, 50th and 97.5th percentiles)? I would guess that the stronger the prior the more it would affect the outcome of a bootstrap. Or is that a misconception? Cheers Jacob [cid:image003.jpg@01CCC0B1.D736A9D0] Medical Products Agency Jacob Brogren Assessor Efficacy and Safety 2 P.O. Box 26, SE-751 03 Uppsala, Sweden Visiting address: Dag Hammarskjölds väg 42 Phone: + 46 (0) 18 17 47 64, switchboard: + 46 (0) 18 17 46 00 Mobile: + 46 (0) xxx xx xx, Fax: + 46 (0) 18 54 85 66 www.lakemedelsverket.se<http://www.lakemedelsverket.se> ******************************************************************************************************************** This message may contain confidential information. If you are not the intended recipient please inform the sender that you have received the message in error before deleting it. Please do not disclose, copy or distribute information in this e-mail or take any action in reliance on its contents: to do so is strictly prohibited and may be unlawful. Thank you for your co-operation. NHSmail is the secure email and directory service available for all NHS staff in England and Scotland NHSmail is approved for exchanging patient data and other sensitive information with NHSmail and GSi recipients NHSmail provides an email address for your career in the NHS and can be accessed anywhere For more information and to find out how you can switch, visit www.connectingforhealth.nhs.uk/nhsmail ********************************************************************************************************************
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