Sci. Aging Knowl. Environ., 28 September 2005
Vol. 2005, Issue 39, p. pe29
[DOI: 10.1126/sageke.2005.39.pe29]


From Bedside to Bench: Research in Comorbidity and Aging

G. Darryl Wieland

The author is with the Geriatric Services Department at the Palmetto Health Richland Hospital, 3010 Farrow Road 300, Columbia, SC 29203, USA, and the Division of Geriatrics, University of South Carolina School of Medicine, Columbia, SC 29208, USA. E-mail:Darryl.Wieland{at}

Key Words: comorbidity • comorbid disease • multimorbidity • multiple morbidity


Clinicians involved in the everyday care of aging patients are increasingly being confronted by comorbidity: the presence of one or more diseases or disorders in addition to a primary or "index" disease. For specialists in fields such as oncology, management of the index disease (cancer) is frequently affected by other (comorbid) conditions or diseases (1). In primary care, it is not uncommon to see elderly patients with three or more distinct diseases (multiple morbidity or multimorbidity) requiring attention: Of all Medicare beneficiaries aged 65 or older, 43% have three or more major chronic conditions (2). Comorbidity thus poses considerable medical and public health and policy challenges. Numerous comorbidity indices demonstrate strong relationships between combinations of diagnosed disease and patient outcomes, such as mortality (3), length of hospitalization (4), disability (5), and perceived health (6). Medicare expenditures have been shown to increase with simple counts of diagnosed chronic diseases (Fig. 1) (2). This trend highlights both the salience of the underlying construct and the very contingent nature of its measurement: Most measures of comorbidity are based simply on diagnosed diseases, often obtained from chart review or billing records.

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Fig. 1. Impact of multiple morbidity on Medicare expenditures. [Adapted from (2)]

Gaps in Understanding Comorbidity

Despite this demonstrable social and economic burden, little conceptual work or empirical research on comorbidity and multimorbidity has entered the literature (aside from the efforts to develop adjusters or covariates for it). In fact, much clinical research explicitly excludes older people and others with significant comorbidity or multiple diseases. Thus, there is relatively little in the way of an evidence base for the medical management of elderly patients with more than one chronic condition. This is reflected in medical training, in which most of the major textbooks give short shrift to comorbidity in older patients, and in clinical guidelines, even those of scientific societies, in which comorbidity is hardly mentioned.

From the 1960s onward, gerontological research has managed to conceptually and empirically separate aging per se from disease, to clarify the modified expression of diseases and pathological processes in older patients, and to identify and describe common age-associated geriatric syndromes as they overlie such processes. This work underscores the need to clarify and refine comorbidity and multimorbidity constructs. We can still follow Feinstein (7) in defining comorbidities as any distinct additional clinical entities that have existed or may occur during the clinical course of a patient who has an index disease under study. The index-disease orientation in treatment and research contexts recognizes that coexisting problems affect clinical management, patient functioning and quality of life, and the public health consequences of the index condition. But, in our aging patients, what multiple pathological changes can be ascribed to a more-or-less single or unitary process? In contradistinction, what more-or-less discrete pathological processes can be triggered by multiple relatively independent risk factors? Aside from having some evidence that some particular conditions are more likely to co-occur than others, we lack clear answers to these very basic questions.

The co-occurrence of two or more active health conditions or diseases defines multimorbidity. This is a different perspective on co-occurring conditions that has special relevance in primary and geriatric care settings, where the total burden of disease on patient health is a burning issue. Relative to comorbidity, less research has been directly focused on understanding multimorbidity and the additional questions it raises: In addition to identifying clinically distinct (that is, more than one) entities, what entities are counted? Intuitively, it does not make sense that such entities/conditions be restricted to diagnosed diseases, yet adding pre- and subclinical pathological processes, organ system impairments, functional problems, and abnormal physiologic indictors leads to many complexities. For example, how do we study the relationship between multimorbid conditions and functional impairments, when functional impairments are among the criteria for defining some of these conditions?

Priorities for Comorbidity Research

Attention to comorbidity and multiple morbidity has increased, in some measure because of the efforts of the American Geriatrics Society (AGS) and the National Institutes of Health, particularly the National Institute on Aging (NIA). On behalf of NIA, Rosemary Yancik and Evan Hadley convened a Task Force on Comorbidity Research Issues in 2003-2004. Its objectives were to identify research opportunities regarding important interactive health issues affecting the elderly commonly faced by practitioners caring for older people; to propose research priorities to close the considerable knowledge gap on age-related comorbidity as it affects treatment efficacy and tolerance in older persons; and to identify research topics to improve diagnostic, prognostic, treatment, and prevention methods related to comorbidity.

Concurrently, AGS--with NIA support--convened a 2-day conference in March 2005 titled "Comorbid Disease and Multiple Morbidity in an Aging Society." This was the second in a series of conferences collectively known as "From Bedside to Bench," intended to focus research attention on understudied areas of concern in geriatric medicine (see Fried Perspective for an overview of the first conference in this series, on frailty). Beginning with a keynote address by Linda Fried, the conference considered the conceptual linkages between multimorbidity and disablement and frailty (see Lipsitz Perspective and Walston Perspective). Among many useful observations, Fried noted that the "action" in comorbidity research "is in the interactions." She suggested that some diseases or conditions, in addition to having greater or lesser likelihoods of co-occurrence, may be synergistic in their effects (Fig. 2). Citing earlier work by Ettinger et al. (8), she noted that, for the development of mobility disability, the risk posed by heart disease alone [odds ratio (OR) = 2.3], and the risk posed by osteoarthritis alone (OR = 4.3) are considerably less than the risk posed by the combination of the two (OR = 13.6). Are convergent mechanisms responsible for this, and if so, how? That is, does heart disease lead to mobility disability through the loss of exercise tolerance, and osteoarthritis through pain, disuse, muscle weakness, and the loss of exercise tolerance?

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Fig. 2. Two concurrent diseases have synergistic effects. [Adapted from (8)]

Subsequent sessions of the conference provided overviews of current research on comorbidity in relation to specific index diseases or conditions in aging clinical populations. Amy Justice, for example, gave a presentation on her cohort study of aging veterans with HIV. Some sessions discussed specific conditions that complicate comorbidity and geriatric care, including a talk by Ira Katz about depression. Other presentations focused on conditions/diseases such as alcohol use, cancer, cardiovascular disease, and diabetes. A final session dealt with the burden of comorbidity on society and the health care system, delving into some of the policy issues raised at the beginning of this Perspective.


We cannot convey all of the diverse thoughts and insights of the conference's many speakers and participants, and it would be premature to review them all here. However, the first fruits of the comorbidity task force--a conceptual overview and four commissioned papers--are forthcoming as a supplement to The Journal of Gerontology: Medical Sciences. The papers address several of the challenges in comorbidity research, including problems of nosology (the classification of diseases) in the definition of index, comorbid, and multiple morbid conditions; the inadequate definition of severity as one of several dimensions of diseases/conditions (such as acuity, chronicity, and progression); and the need for improved research design and analytic methods to help move research forward. A review article on the AGS conference proceedings is also in preparation. We hope that these syntheses will help stimulate progress in this understudied area of aging research.

September 28, 2005
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  5. D. M. W. Kriegsman, D. J. H. Deeg, W. A. B. Stalman, Comorbidity of somatic chronic disease and decline in physical functioning: The Longitudinal Aging Study Amsterdam. J. Clin. Epidemiol. 57, 55-65 (2004).[CrossRef][Medline]
  6. C. D. Mulrow, M. B. Gerety, J. E. Cornell, V. A. Lawrence, D. N. Kanten, The relationship between disease and function and perceived health in very frail elders. J. Am. Geriatr. Soc. 42, 374-380 (1994). [Medline]
  7. A. R. Feinstein, The pretherapeutic classification of comorbidity in chronic disease. J. Chronic Dis. 23, 455-468 (1970). [CrossRef]
  8. W. H. Ettinger, M. A. Davis, J. M. Neuhaus, K. P. Mallon, Long-term physical functioning in persons with knee osteoarthritis from NHANES. I: Effects of comorbid medical conditions. J. Clin. Epidemiol. 47, 809-815 (1994).[CrossRef][Medline]
  9. The Task Force on Comorbidity Research Issues was organized by Rosemary Yancik, NIA, Bethesa, MD, USA, and co-chaired by Bill Hazzard, University of Washington, Seattle, WA, USA, and Harvey Cohen, Duke University, Durham, NC, USA. The following scientists also participated: Luigi Ferrucci, Jack Gurlanik, Evan Hadley, Susan Molchan, Susan Nayfield, and Judy Salerno, NIA, USA; Carrie Klabunde, National Cancer Institute, Bethesda, MD, USA; Claudette Varricchio, National Institute of Nursing Research, Bethesda, MD, USA; Bill Ershler, Institute for Advanced Studies in Aging and Geriatric Medicine, Washington, DC, USA; Martine Extermann, University of South Florida, Tampa, FL, USA; Linda Fried, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Cynthia Boyd, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Jerry Gurwitz, Meyers Primary Care Institute, Worcester, MA, USA; Jeff Halter, University of Michigan, Ann Arbor, MI, USA; Jeanne Mandelblatt, Georgetown University, Washington, DC, USA; Vince Mor and Terri Wetle, Brown University, Providence, RI, USA; Marco Pahor, University of Florida, Gainesville, FL, USA; David Reuben and Arun Karlamangla, University of California-Los Angeles, Los Angeles, CA, USA; Bill Satariano, University of Calfornia-Berkeley, Berkeley, CA, USA; Rebecca Silliman and Tim Lash, Boston University, Boston, MA, USA; Stephanie Studenski, University of Pittsburgh, Pittsburgh, PA, USA; Mary Tinetti, Yale University, New Haven, CT, USA; and Darryl Wieland, University of South Carolina, Columbia, SC, USA.
  10. Darryl Wieland chaired the comorbidity conference. Many of the other Task Force members were also involved in the conference as planners, speakers, or moderators. They were joined in these roles by Didi Kriegsman, Vrije University, Amsterdam, Netherlands; Amy Justice, Yale University, New Haven, CT, USA; Ira Katz, University of Pennsylvania, Philadelphia, PA, USA; Allison Moore, University of California-Los Angeles, Los Angeles, CA, USA; Anne Newman, University of Pittsburgh, Pittsburgh, PA, USA; Caroline Blaum, University of Michigan, Ann Arbor, MI, USA; Dan Berlowitz, Boston University, Boston, MA, USA; Jennifer Wolff, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; and Christine Ritchie, University of Alabama, Birmingham, AL, USA.
Citation: G. D. Wieland, From Bedside to Bench: Research in Comorbidity and Aging. Sci. Aging Knowl. Environ. 2005 (39), pe29 (2005).

Science of Aging Knowledge Environment. ISSN 1539-6150