Journal of General Internal Medicine

, Volume 29, Issue 4, pp 670–679 | Cite as

A Framework for Crafting Clinical Practice Guidelines that are Relevant to the Care and Management of People with Multimorbidity

  • Katrin Uhlig
  • Bruce Leff
  • David Kent
  • Sydney Dy
  • Klara Brunnhuber
  • Jako S. Burgers
  • Sheldon Greenfield
  • Gordon Guyatt
  • Kevin High
  • Rosanne Leipzig
  • Cynthia Mulrow
  • Kenneth Schmader
  • Holger Schunemann
  • Louise C. Walter
  • James Woodcock
  • Cynthia M. Boyd
Multimorbidity Symposium


Many patients of all ages have multiple conditions, yet clinicians often lack explicit guidance on how to approach clinical decision-making for such people. Most recommendations from clinical practice guidelines (CPGs) focus on the management of single diseases, and may be harmful or impractical for patients with multimorbidity. A major barrier to the development of guidance for people with multimorbidity stems from the fact that the evidence underlying CPGs derives from studies predominantly focused on the management of a single disease. In this paper, the investigators from the Improving Guidelines for Multimorbid Patients Study Group present consensus-based recommendations for guideline developers to make guidelines more useful for the care of people with multimorbidity. In an iterative process informed by review of key literature and experience, we drafted a list of issues and possible approaches for addressing important coexisting conditions in each step of the guideline development process, with a focus on considering relevant interactions between the conditions, their treatments and their outcomes. The recommended approaches address consideration of coexisting conditions at all major steps in CPG development, from nominating and scoping the topic, commissioning the work group, refining key questions, ranking importance of outcomes, conducting systematic reviews, assessing quality of evidence and applicability, summarizing benefits and harms, to formulating recommendations and grading their strength. The list of issues and recommendations was reviewed and refined iteratively by stakeholders. This framework acknowledges the challenges faced by CPG developers who must make complex judgments in the absence of high-quality or direct evidence. These recommendations require validation through implementation, evaluation and refinement.


guidelines multimorbidity comorbidity grading evidence 



The expert panel included Klara Brunnhuber, Jako S. Burgers, Sheldon Greenfield, Gordon Guyatt, Kevin High, Rosanne Leipzig, Cynthia Mulrow, Kenneth Schmader, Holger Schunemann, Louise C. Walter, and James Woodcock.

We acknowledge Anand Parekh and Kay Dickersin for their attendance for part of the ‘Improving Guidelines for Multimorbid Patients Stakeholder Conference.’

We acknowledge the Participants in the Guideline Breakout Groups who attended the ‘Improving Guidelines for Multimorbid Patients Stakeholder Conference’ (See below), Baltimore, Maryland, Fall 2010

Bass, Eric

Blaum, Caroline

Bruce, Stephanie

Hadley, Evan

Nici, Linda

Noronha, Gary

Green, Lee

Lewis, Sandra Zelman

Wolff, Tracy

Shiffman, Richard

Schmader, Ken

Walter, Louise

Barton, Mary

Greenfield, Sheldon

Grimshaw, Jeremy

High, Kevin

Lau, Joseph

Dolter, Kathryn

Mukherjee, Debjani

Nix, Mary

ZuWallack, Richard

Stokes, Tim

Schunemann, Holger


This work was funded by AHRQ R21 HS018597-01 (PI Boyd) and AHRQ R21 HS017653. Dr. Boyd’s effort was supported in part by the Johns Hopkins Bayview Center for Innovative Medicine, The Robert Wood Johnson Foundation Physician Faculty Scholars Program, and the Paul Beeson Career Development Award Program (NIA K23 AG032910, AFAR, The John A. Hartford Foundation, The Atlantic Philanthropies, The Starr Foundation, and an anonymous donor). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Dr. Walter’s effort was supported by the National Cancer Institute (grant number R01 CA134425) and the National Institute on Aging (grant number K24 AG041180).

Improving Guidelines for Multimorbid Patients Investigator Group

Cynthia Boyd, Johns Hopkins Medical Institutions (JHMI), Sydney Dy, Johns Hopkins Bloomberg School of Public Health (JHSPH), David M. Kent, Tufts Medical Center (TMC), Bruce Leff, JHMI, Jodi Segal (JHMI) Thomas A. Trikalinos, Brown University, Katrin Uhlig, TMC, Ravi Varadhan, JHMI, Carlos Weiss, JHMI.

Conflict of Interest

Dr. Boyd is a co-author of an article on multimorbidity for UpToDate.


  1. 1.
    Barnett K, Mercer SW, Norbury M, Watt G, Wyke S, Guthrie B. Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study. Lancet. 2012;380(9836):37–43.PubMedCrossRefGoogle Scholar
  2. 2.
    Patient-centered care for older adults with multiple chronic conditions: a stepwise approach from the american geriatrics society: american geriatrics society expert panel on the care of older adults with multimorbidity. J Am Geriatr Soc. 2012;60(10):1957–68.Google Scholar
  3. 3.
    Tinetti ME, Bogardus ST Jr, Agostini JV. Potential pitfalls of disease-specific guidelines for patients with multiple conditions. N Engl J Med. 2004;351(27):2870–4.PubMedCrossRefGoogle Scholar
  4. 4.
    Fabbri LM, Boyd C, Boschetto P, Rabe KF, Buist AS, Yawn B, et al. How to integrate multiple comorbidities in guideline development: article 10 in Integrating and coordinating efforts in COPD guideline development. An official ATS/ERS workshop report. Proc Am Thorac Soc. 2012;9(5):274–81.PubMedCrossRefGoogle Scholar
  5. 5.
    Boyd CM, Darer J, Boult C, Fried LP, Boult L, Wu AW. Clinical practice guidelines and quality of care for older patients with multiple comorbid diseases: implications for pay for performance. JAMA. 2005;294(6):716–24.PubMedCrossRefGoogle Scholar
  6. 6.
    Schoen C, Osborn R, Doty MM, Bishop M, Peugh J, Murukutla N. Toward higher-performance health systems: adults’ health care experiences in seven countries, 2007. Health Aff (Millwood). 2007;26(6):w717–34.CrossRefGoogle Scholar
  7. 7.
    Lugtenberg M, Burgers JS, Clancy C, Westert GP, Schneider EC. Current guidelines have limited applicability to patients with comorbid conditions: a systematic analysis of evidence-based guidelines. PLoS ONE. 2011;6(10):e25987.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Brown AF, Mangione CM, Saliba D, Sarkisian CA. Guidelines for improving the care of the older person with diabetes mellitus. J Am Geriatr Soc. 2003;51(5 Suppl Guidelines):S265–80.PubMedGoogle Scholar
  9. 9.
    Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuunemann HJ. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):7S–47S.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Department of Health and Human Services Strategic Framework on Multiple Chronic Conditions, 2010.Google Scholar
  11. 11.
    Weiss CO, Varadhan R, Puhan M, Vickers A, Bandeen-Roche K, Boyd C, et al. Multimorbidity and Evidence Generation. JGIM. 2013, doi: 10.1007/s11606-013-2555-5.
  12. 12.
    Van Spall HG, Toren A, Kiss A, Fowler RA. Eligibility criteria of randomized controlled trials published in high-impact general medical journals: a systematic sampling review. JAMA. 2007;297(11):1233–40.PubMedCrossRefGoogle Scholar
  13. 13.
    Nouwen A, Winkley K, Twisk J, Lloyd CE, Peyrot M, Ismail K, et al. Type 2 diabetes mellitus as a risk factor for the onset of depression: a systematic review and meta-analysis. Diabetologia. 2010;53(12):2480–6.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Braithwaite RS, Fiellin D, Justice AC. The payoff time: a flexible framework to help clinicians decide when patients with comorbid disease are not likely to benefit from practice guidelines. Med Care. 2009;47(6):610–7.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Braithwaite RS, Concato J, Chang CC, Roberts MS, Justice AC. A framework for tailoring clinical guidelines to comorbidity at the point of care. Arch Intern Med. 2007;167(21):2361–5.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Trikalinos T, Segal J, Boyd CM. Addressing Multimorbidity in Evidence Integration and Synthesis. JGIM. 2013, doi: 10.1007/s11606-013-2661-4.
  17. 17.
    Boyd C, Kent D. Evidence Based Medicine and the Hard Problem of Multimorbidity. JGIM. 2013, doi: 10.1007/s11606-013-2658-z.
  18. 18.
    Lunney JR, Lynn J, Foley DJ, Lipson S, Guralnik JM. Patterns of functional decline at the end of life. JAMA. 2003;289(18):2387–92.PubMedCrossRefGoogle Scholar
  19. 19.
    Guyatt GH, Oxman AD, Kunz R, Vist GE, Falck-Ytter Y, Schunemann HJ. What is "quality of evidence" and why is it important to clinicians? BMJ. 2008;336(7651):995–8.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924–6.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Schunemann HJ, Jaeschke R, Cook DJ, Bria WF, El-Solh AA, Ernst A, et al. An official ATS statement: grading the quality of evidence and strength of recommendations in ATS guidelines and recommendations. Am J Respir Crit Care Med. 2006;174(5):605–14.PubMedCrossRefGoogle Scholar
  22. 22.
    Barton MB, Miller T, Wolff T, Petitti D, LeFevre M, Sawaya G, et al. How to read the new recommendation statement: methods update from the U.S. Preventive Services Task Force. Ann Intern Med. 2007;147(2):123–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Petitti DB, Teutsch SM, Barton MB, Sawaya GF, Ockene JK, DeWitt T. Update on the methods of the U.S. Preventive Services Task Force: insufficient evidence. Ann Intern Med. 2009;150(3):199–205.PubMedCrossRefGoogle Scholar
  24. 24.
    Owens DK, Lohr KN, Atkins D, Treadwell JR, Reston JT, Bass EB, et al. AHRQ Series Paper 5: grading the strength of a body of evidence when comparing medical interventions—Agency for Healthcare Research and Quality and the Effective Health-Care Program. J Clin Epidemiol. 2010;63(5):513–23.PubMedCrossRefGoogle Scholar
  25. 25.
    Institute of Medicine. Clinical Practice Guidelines We Can Trust: The National Academies Press, 2011.Google Scholar
  26. 26.
    National Institute for Clinical Excellence. Guideline Development Methods: Information for National Collaborating Centres and Guideline Developers. London: National Institute for Clinical Excellence; 2004. Updated 2005.Google Scholar
  27. 27.
    U.S. Preventive Services Task Force (USPSTF) Procedure Manual., Accessed on November 1, 2013.
  28. 28.
    Gupta SK, Eustace JA, Winston JA, Boydstun II, Ahuja TS, Rodriguez RA, et al. Guidelines for the management of chronic kidney disease in HIV-infected patients: recommendations of the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2005;40(11):1559–85.PubMedCrossRefGoogle Scholar
  29. 29.
    KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. Am J Kidney Dis 2007;49(2 Suppl 2):S12–154.Google Scholar
  30. 30.
    Guyatt G, Akl EA, Hirsh J, Kearon C, Crowther M, Gutterman D, et al. The vexing problem of guidelines and conflict of interest: a potential solution. Ann Intern Med. 2010;152(11):738–41.PubMedCrossRefGoogle Scholar
  31. 31.
    Uhlig K, Boyd C. Guidelines for the older adult with CKD. Am J Kidney Dis. 2011;58(2):162–5.PubMedCrossRefGoogle Scholar
  32. 32.
    Parker MG, Atkins MB, Ucci AA, Levey AS. Rapidly progressive glomerulonephritis after immunotherapy for cancer. J Am Soc Nephrol. 1995;5(10):1740–4.PubMedGoogle Scholar
  33. 33.
    Giovannetti ER, Wolff JL, Xue QL, Weiss CO, Leff B, Boult C, et al. Difficulty assisting with health care tasks among caregivers of multimorbid older adults. J Gen Intern Med. 2012;27(1):37–44.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Barrett BJ, Parfrey PS. Clinical practice. Preventing nephropathy induced by contrast medium. N Engl J Med. 2006;354(4):379–86.PubMedCrossRefGoogle Scholar
  35. 35.
    Guyatt GH, Oxman AD, Kunz R, Atkins D, Brozek J, Vist G, et al. GRADE guidelines: 2. Framing the question and deciding on important outcomes. J Clin Epidemiol. 2011;64(4):395–400.PubMedCrossRefGoogle Scholar
  36. 36.
    KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl 2009(113):S1–130.Google Scholar
  37. 37.
    Rahn DD, Abed H, Sung VW, Matteson KA, Rogers RG, Morrill MY, et al. Systematic review highlights difficulty interpreting diverse clinical outcomes in abnormal uterine bleeding trials. J Clin Epidemiol. 2011;64(3):293–300.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Legare F, Boivin A, van der Weijden T, Pakenham C, Burgers J, Legare J, et al. Patient and public involvement in clinical practice guidelines: a knowledge synthesis of existing programs. Med Dec Making. 2011;31(6):E45–74.CrossRefGoogle Scholar
  39. 39.
    den Breejen EM, Nelen WL, Knijnenburg JM, Burgers JS, Hermens RP, Kremer JA. Feasibility of a wiki as a participatory tool for patients in clinical guideline development. J Med Internet Res. 2012;14(5):e138.CrossRefGoogle Scholar
  40. 40.
    MacLean S, Mulla S, Akl EA, Jankowski M, Vandvik PO, Ebrahim S, et al. Patient values and preferences in decision making for antithrombotic therapy: a systematic review: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e1S–23S.PubMedCentralPubMedGoogle Scholar
  41. 41.
    Butler M, Talley KMC, Burns R, Ripley A, Rothman A, Johnson P, et al. Values of Older Adults Related to Primary and Secondary Prevention. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011.Google Scholar
  42. 42.
    Sun X, Briel M, Busse JW, You JJ, Akl EA, Mejza F, et al. Credibility of claims of subgroup effects in randomised controlled trials: systematic review. BMJ. 2012;344:e1553.PubMedCrossRefGoogle Scholar
  43. 43.
    Vollenweider D, Boyd CM, Puhan MA. High prevalence of potential biases threatens the interpretation of trials in patients with chronic disease. BMC Med. 2011;9:73.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Boyd CM, Vollenweider D, Puhan MA. Informing evidence-based decision-making for patients with comorbidity: availability of necessary information in clinical trials for chronic diseases. PLoS One. 2012;7(8):e41601.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M, et al. GRADE guidelines: 8. Rating the quality of evidence–indirectness. J Clin Epidemiol. 2011;64(12):1303–10.PubMedCrossRefGoogle Scholar
  46. 46.
    Guyatt GH, Helfand M, Kunz R. Comparing the USPSTF and GRADE approaches to recommendations. Ann Intern Med. 2009;151(5):363. author reply 63-4.PubMedCrossRefGoogle Scholar
  47. 47.
    Petitti DB, Teutsch SM, Barton MB, Sawaya GF, Ockene JK, DeWitt T. Comparing the USPSTF and GRADE Approaches to Recommendations. Ann Intern Med. 2009;151(5):363–64.CrossRefGoogle Scholar
  48. 48.
    Kent DM, Hayward RA. Limitations of applying summary results of clinical trials to individual patients: the need for risk stratification. JAMA. 2007;298(10):1209–12.PubMedCrossRefGoogle Scholar
  49. 49.
    Zulman DM, Sussman JB, Chen X, Cigolle CT, Blaum CS, Hayward RA. Examining the evidence: a systematic review of the inclusion and analysis of older adults in randomized controlled trials. J Gen Intern Med. 2011;26(7):783–90.PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Leipzig RM, Whitlock EP, Wolff TA, Barton MB, Michael YL, Harris R, et al. Reconsidering the approach to prevention recommendations for older adults. Ann Intern Med. 2010;153(12):809–14.PubMedCrossRefGoogle Scholar
  51. 51.
    Trikalinos TA, Kulasingam S, Lawrence WF. Chapter 10: deciding whether to complement a systematic review of medical tests with decision modeling. J Gen Intern Med. 2012;27(Suppl 1):S76–82.PubMedCrossRefGoogle Scholar
  52. 52.
    You JJ, Singer DE, Howard PA, Lane DA, Eckman MH, Fang MC, et al. Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e531S–75S.PubMedCentralPubMedGoogle Scholar
  53. 53.
    Kirkman MS, Briscoe VJ, Clark N, Florez H, Haas LB, Halter JB, et al. Diabetes in older adults. Diabetes Care. 2012;35(12):2650–64.PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Greenfield S, Billimek J, Pellegrini F, Franciosi M, De Berardis G, Nicolucci A, et al. Comorbidity affects the relationship between glycemic control and cardiovascular outcomes in diabetes: a cohort study. Ann Intern Med. 2009;151(12):854–60.PubMedCrossRefGoogle Scholar
  55. 55.
    Justice AC, McGinnis KA, Skanderson M, Chang CC, Gibert CL, Goetz MB, et al. Towards a combined prognostic index for survival in HIV infection: the role of 'non-HIV' biomarkers. HIV Med. 2010;11(2):143–51.PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Minne L, Ludikhuize J, de Rooij SE, Abu-Hanna A. Characterizing predictive models of mortality for older adults and their validation for use in clinical practice. J Am Geriatr Soc. 2011;59(6):1110–5.PubMedCrossRefGoogle Scholar
  57. 57.
    Yourman LC, Lee SJ, Schonberg MA, Widera EW, Smith AK. Prognostic indices for older adults: a systematic review. JAMA. 2012;307(2):182–92.PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Framingham Heart Study,, Accessed on September 17, 2013.
  59. 59.
    Kent DM, Rothwell PM, Ioannidis JP, Altman DG, Hayward RA. Assessing and reporting heterogeneity in treatment effects in clinical trials: a proposal. Trials. 2010;11:85.PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Tinetti ME, McAvay GJ, Chang SS, Newman AB, Fitzpatrick AL, Fried TR, et al. Contribution of multiple chronic conditions to universal health outcomes. J Am Geriatr Soc. 2011;59(9):1686–91.Google Scholar

Copyright information

© Society of General Internal Medicine 2014

Authors and Affiliations

  • Katrin Uhlig
    • 1
  • Bruce Leff
    • 2
    • 4
  • David Kent
    • 3
  • Sydney Dy
    • 4
  • Klara Brunnhuber
    • 5
  • Jako S. Burgers
    • 6
  • Sheldon Greenfield
    • 7
  • Gordon Guyatt
    • 8
  • Kevin High
    • 9
  • Rosanne Leipzig
    • 10
  • Cynthia Mulrow
    • 11
  • Kenneth Schmader
    • 12
  • Holger Schunemann
    • 8
  • Louise C. Walter
    • 13
  • James Woodcock
    • 14
  • Cynthia M. Boyd
    • 2
    • 4
  1. 1.Department of Medicine, Division of Nephrology, and Institute for Clinical Research and Health Policy Studies, Center for Clinical Evidence Synthesis, Tufts Medical CenterTufts University School of MedicineBostonUSA
  2. 2.Division of Geriatric Medicine and Gerontology, Department of MedicineJohns Hopkins University School of MedicineBaltimoreUSA
  3. 3.Institute for Clinical Research and Health Policy StudiesTufts Medical CenterBostonUSA
  4. 4.Department of Health Policy and ManagementJohns Hopkins Bloomberg School of Public HealthBaltimoreUSA
  5. 5.BMJ Evidence CentreLondonUK
  6. 6.Department of Guideline Development and ResearchDutch College of General PractitionersUtrechtThe Netherlands
  7. 7.Health Policy Research Institute, School of MedicineUniversity of California at IrvineIrvineUSA
  8. 8.Clinical Epidemiology & BiostatisticsMcMaster UniversityHamiltonCanada
  9. 9.Section on Infectious DiseasesWake Forest School of MedicineWinston-SalemUSA
  10. 10.Brookdale Department of Geriatrics and Palliative MedicineMount Sinai School of MedicineNew YorkUSA
  11. 11.University of Texas Health Science Center at San AntonioSan AntonioUSA
  12. 12.Kenneth E. Schmader, Division of Geriatrics, Department of MedicineDuke University Medical Center and GRECC, Durham VA Medical CenterDurhamUSA
  13. 13.Division of GeriatricsSan Francisco VA Medical Center and University of CaliforniaSan FranciscoUSA
  14. 14.UKCRC Centre for Diet and Activity Research (CEDAR), Institute of Public HealthUniversity of CambridgeCambridgeUK

Personalised recommendations