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BMJ Open Is Committed to Open Peer Review. As Part of This Commitment We Make the Peer Review History of Every Article We Publish Publicly Available BMJ Open: first published as 10.1136/bmjopen-2020-039747 on 22 October 2020. Downloaded from BMJ Open is committed to open peer review. As part of this commitment we make the peer review history of every article we publish publicly available. When an article is published we post the peer reviewers’ comments and the authors’ responses online. We also post the versions of the paper that were used during peer review. These are the versions that the peer review comments apply to. The versions of the paper that follow are the versions that were submitted during the peer review process. They are not the versions of record or the final published versions. They should not be cited or distributed as the published version of this manuscript. BMJ Open is an open access journal and the full, final, typeset and author-corrected version of record of the manuscript is available on our site with no access controls, subscription charges or pay-per-view fees (http://bmjopen.bmj.com). If you have any questions on BMJ Open’s open peer review process please email [email protected] http://bmjopen.bmj.com/ on September 26, 2021 by guest. Protected copyright. BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-039747 on 22 October 2020. Downloaded from Development and internal validation of prognostic models to predict negative health outcomes in older patients with multimorbidity and polypharmacy in general practice ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2020-039747 Article Type: Original research Date Submitted by the 24-Apr-2020 Author: Complete List of Authors: Müller, Beate; Goethe University Frankfurt, Institute of General Practice Uhlmann, Lorenz ; University of Heidelberg, Institute of Medical Biometry and Informatics Ihle, Peter; University of Cologne, PMV Research Group, Faculty of Medicine and University Hospital Cologne Stock, Christian; University of Heidelberg, Institute of Medical Biometry and Informatics von Buedingen, Fiona; Goethe University Frankfurt, Institute of General Practice Beyer, Martin; Goethe University Frankfurt, Institute of General Practice Gerlach, Ferdinand; Goethe University Frankfurt, Institute of General Practice Perera, Rafael; University of Oxford, Nuffield Department of Primary http://bmjopen.bmj.com/ Care Health Sciences Valderas, Jose; University of Exeter Medical School, APEx Collaboration for Academic Primary Care Glasziou, Paul; Bond University, Centre for Research in Evidence-Based Practice, Faculty of Health Sciences and Medicine van den Akker, Marjan; Goethe University Frankfurt, Institute of General Practice; Maastricht University, Department of Family Medicine, School CAPHRI Muth, Christiane; Goethe University Frankfurt, Institute of General on September 26, 2021 by guest. Protected copyright. Practice PRIMARY CARE, THERAPEUTICS, GERIATRIC MEDICINE, HEALTH Keywords: SERVICES ADMINISTRATION & MANAGEMENT For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 48 BMJ Open 1 2 3 BMJ Open: first published as 10.1136/bmjopen-2020-039747 on 22 October 2020. Downloaded from 4 5 6 7 8 9 I, the Submitting Author has the right to grant and does grant on behalf of all authors of the Work (as defined 10 in the below author licence), an exclusive licence and/or a non-exclusive licence for contributions from authors 11 who are: i) UK Crown employees; ii) where BMJ has agreed a CC-BY licence shall apply, and/or iii) in accordance 12 with the terms applicable for US Federal Government officers or employees acting as part of their official 13 duties; on a worldwide, perpetual, irrevocable, royalty-free basis to BMJ Publishing Group Ltd (“BMJ”) its 14 licensees and where the relevant Journal is co-owned by BMJ to the co-owners of the Journal, to publish the 15 Work in this journal and any other BMJ products and to exploit all rights, as set out in our licence. 16 17 The Submitting Author accepts and understands that any supply made under these terms is made by BMJ to 18 the Submitting Author Forunless you peer are acting as review an employee on behalf only of your employer or a postgraduate 19 student of an affiliated institution which is paying any applicable article publishing charge (“APC”) for Open 20 Access articles. Where the Submitting Author wishes to make the Work available on an Open Access basis (and 21 intends to pay the relevant APC), the terms of reuse of such Open Access shall be governed by a Creative 22 Commons licence – details of these licences and which Creative Commons licence will apply to this Work are set 23 out in our licence referred to above. 24 25 Other than as permitted in any relevant BMJ Author’s Self Archiving Policies, I confirm this Work has not been 26 accepted for publication elsewhere, is not being considered for publication elsewhere and does not duplicate 27 material already published. I confirm all authors consent to publication of this Work and authorise the granting 28 of this licence. 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 26, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 48 1 2 3 1 TITLE BMJ Open: first published as 10.1136/bmjopen-2020-039747 on 22 October 2020. Downloaded from 4 5 2 Development and internal validation of prognostic models to predict negative health 6 3 outcomes in older patients with multimorbidity and polypharmacy in general practice 7 4 8 9 5 Corresponding author 10 11 6 Beate S. Müller, Institute of General Practice, Goethe University, Frankfurt/Main, 12 7 Theodor-Stern-Kai 7, 60590 Frankfurt, Germany, [email protected] 13 8 frankfurt.de 14 15 9 16 10 Authors 17 11 1. Beate S. Müller, Institute of General Practice, Goethe University, Frankfurt/Main, 18 For peer review only 19 12 Germany 20 13 2. Lorenz Uhlmann, Institute of Medical Biometry and Informatics, University of 21 14 Heidelberg, Heidelberg, Germany 22 23 15 3. Peter Ihle, PMV Research Group, Faculty of Medicine and University Hospital 24 16 Cologne, University of Cologne, Köln, Germany 25 17 4. Christian Stock, Institute of Medical Biometry and Informatics, University of 26 27 18 Heidelberg, Heidelberg, Germany 28 19 5. Fiona v. Büdingen, Institute of General Practice, Goethe University, 29 20 Frankfurt/Main, Germany 30 31 21 6. Martin Beyer, Institute of General Practice, Goethe University, Frankfurt/Main, 32 22 Germany 33 23 7. Ferdinand M. Gerlach, Institute of General Practice, Goethe University, 34 35 24 Frankfurt/Main, Germany 36 25 8. Rafael Perera, Nuffield Department of Primary Care Health Sciences, University 37 26 of Oxford, Oxford, UK http://bmjopen.bmj.com/ 38 39 27 9. Jose M. Valderas, APEx Collaboration for Academic Primary Care, University of 40 28 Exeter Medical School, Exeter, UK 41 29 10.Paul P. Glasziou, Centre for Research in Evidence-Based Practice (CREBP), 42 43 30 Faculty of Health Sciences and Medicine, Bond University, Robina, Australia 44 31 11.Marjan van den Akker, (1) Institute of General Practice, Goethe University, 45 32 Frankfurt/Main, Germany, (2) Department of Family Medicine, School CAPHRI, on September 26, 2021 by guest. Protected copyright. 46 47 33 Maastricht University, Maastricht, Netherlands 48 34 12.Christiane Muth, Institute of General Practice, Goethe University, Frankfurt/Main, 49 35 Germany 50 51 36 52 37 Word count: 4,400 53 54 38 55 56 39 57 58 59 60 1 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 48 BMJ Open 1 2 3 40 ABSTRACT BMJ Open: first published as 10.1136/bmjopen-2020-039747 on 22 October 2020. Downloaded from 4 5 6 41 Background: Polypharmacy interventions are resource-intensive and should ideally 7 8 42 target those at risk of negative health outcomes. Our aim was to predict health- 9 10 43 related quality of life (HRQoL) and the combined outcome of falls, hospitalisation, 11 12 44 institutionalisation, and nursing care needs, in older patients with multimorbidity and 13 14 15 45 polypharmacy in general practices. 16 17 46 Methods: Design: two independent datasets, one comprising health insurance claims 18 For peer review only 19 47 data (N=592,456) and the other data from the PRIoritising MUltimedication in 20 21 22 48 Multimorbidity (PRIMUM) cluster-RCT (N=502). Population: ≥60 years, ≥5 drugs, ≥3 23 24 49 chronic diseases, excluding dementia. Outcomes: the combined outcome of falls, 25 26 50 hospitalisation, institutionalisation, and nursing care needs (after 6, 9 and 24 months) 27 28 (claims data); and HRQoL (after 6 and 9 months) (trial data). Predictor variables in 29 51 30 31 52 both datasets: age, sex, morbidity-related variables (e.g., disease count), medication- 32 33 53 related variables (e.g., EU-PIM), health service utilisation (e.g., number of involved 34 35 54 physicians). Predictor variables exclusively in trial data: additional socio- 36 37 http://bmjopen.bmj.com/ 38 55 demographics, morbidity-related variables (e.g., Cumulative Illness Rating Scale, 39 40 56 depression), Medication Appropriateness Index (MAI), lifestyle (e.g., smoking status), 41 42 57 functional status and HRQoL (EuroQol EQ5D-3L). Analysis: mixed regression 43 44 45 58 models, combined with stepwise variable selection, 10-fold cross validation and on September 26, 2021 by guest. Protected copyright. 46 47 59 sensitivity analyses. 48 49 60 Results: The most important predictors of EQ5D-3L at 6 months in the best model 50 51 (Nagelkerke’s R² 0.507) were depressive symptoms (-2.73 [95%CI: -3.56 to -1.91]), 52 61 53 54 62 MAI (-0.39 [-0.7 to -0.08]) and baseline EQ5D-3L (0.55 [95%CI: 0.47 to 0.64]).
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