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Frailty Defined in Older Adults Evidence for a Phenotype
  The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 56:M146-M157 (2001)
Linda P. Frieda, Catherine M. Tangenb, Jeremy Walstona, Anne B. Newmanc, Calvin Hirschd, John Gottdienere, Teresa Seemanf, Russell Tracyg, Willem J. Koph, Gregory Burkei and
Mary Ann McBurnie, for the Cardiovascular Health Study Collaborative Research Groupb
a The John Hopkins Medical Institutions, Baltimore, Maryland
b The University of Washington, Seattle
c The University of Pittsburgh, Pennsylvania
d The University of California at Davis, Sacramento
e St. Francis Hospital, Roslyn, New York
f The University of California at Los Angeles
g The University of Vermont, Burlington
h Uniformed Services University of the Health Sciences, Bethesda, Maryland
i Wake Forest University School of Medicine, Winston-Salem, North Carolina
Background. Frailty is considered highly prevalent in old age and to confer high risk for falls, disability, hospitalization, and mortality. Frailty has been considered synonymous with disability, comorbidity, and other characteristics, but it is recognized that it may have a biologic basis and be a distinct clinical syndrome. A standardized definition has not yet been established.
Methods. To develop and operationalize a phenotype of frailty in older adults and assess concurrent and predictive validity, the study used data from the Cardiovascular Health Study. Participants were 5,317 men and women 65 years and older (4,735 from an original cohort recruited in 1989-90 and 582 from an African American cohort recruited in 1992-93). Both cohorts received almost identical baseline evaluations and 7 and 4 years of follow-up, respectively, with annual examinations and surveillance for outcomes including incident disease, hospitalization, falls, disability, and mortality.
Results. Frailty was defined as a clinical syndrome in which three or more of the following criteria were present: unintentional weight loss (10 lbs in past year), self-reported exhaustion, weakness (grip strength), slow walking speed, and low physical activity. The overall prevalence of frailty in this community-dwelling population was 6.9%; it increased with age and was greater in women than men. Four-year incidence was 7.2%. Frailty was associated with being African American, having lower education and income, poorer health, and having higher rates of comorbid chronic diseases and disability. There was overlap, but not concordance, in the cooccurrence of frailty, comorbidity, and disability. This frailty phenotype was independently predictive (over 3 years) of incident falls, worsening mobility or ADL disability, hospitalization, and death, with hazard ratios ranging from 1.82 to 4.46, unadjusted, and 1.29-2.24, adjusted for a number of health, disease, and social characteristics predictive of 5-year mortality. Intermediate frailty status, as indicated by the presence of one or two criteria, showed intermediate risk of these outcomes as well as increased risk of becoming frail over 3-4 years of follow-up (odds ratios for incident frailty = 4.51 unadjusted and 2.63 adjusted for covariates, compared to those with no frailty criteria at baseline).
Conclusions. This study provides a potential standardized definition for frailty in community-dwelling older adults and offers concurrent and predictive validity for the definition. It also finds that there is an intermediate stage identifying those at high risk of frailty. Finally, it provides evidence that frailty is not synonymous with either comorbidity or disability, but comorbidity is an etiologic risk factor for, and disability is an outcome of, frailty. This provides a potential basis for clinical assessment for those who are frail or at risk, and for future research to develop interventions for frailty based on a standardized ascertainment of frailty.
FRAILTY is considered to be highly prevalent with increasing age and to confer high risk for adverse health outcomes, including mortality, institutionalization, falls, and hospitalization (1)(2)(3). Numerous geriatric interventions have been developed to improve clinical outcomes for frail older adults (3)(4)(5)(6)(7). A major obstacle to the success of such interventions has been the absence of a standardized and valid method for screening of those who are truly frail so as to effectively target care (1)(3).
Potential definitions of frailty abound, defining frailty as synonymous with disability (1)(8)(9), comorbidity (8), or advanced old age (3). Increasingly, geriatricians define frailty as a biologic syndrome of decreased reserve and resistance to stressors, resulting from cumulative declines across multiple physiologic systems, and causing vulnerability to adverse outcomes (9)(10)(11)(12)(13). This concept distinguishes frailty from disability (9)(10)(14)(15). There is a growing consensus that markers of frailty include age-associated declines in lean body mass, strength, endurance, balance, walking performance, and low activity (9)(10)(14)(15)(16)(17), and that multiple components must be present clinically to constitute frailty (9)(14). Many of these factors are related (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31) and can be unified, theoretically, into a cycle of frailty associated with declining energetics and reserve (Fig. 1). The core elements of this cycle are those commonly identified as clinical signs and symptoms of frailty (9)(10)(14)(15)(16). Frailty likely also involves declines in physiologic complexity or reserve in other systems, leading to loss of homeostatic capability to withstand stressors and resulting vulnerabilities (2)(9)(11)(12).
We hypothesized that the elements identified in Fig. 1 are core clinical presentations of frailty, and that a critical mass of phenotypic components in the cycle would, when present, identify the syndrome. We evaluated whether this phenotype identifies a subset at high risk of the adverse health outcomes clinically associated with frailty. To do this, we operationalized a definition of frailty, as suggested by prior research and clinical consensus (Fig. 1), and, in a population-based study of older adults, evaluated its prevalence and incidence, cross-sectional correlates, and its validity in terms of predicting the adverse outcomes geriatricians associate with frail older adults.
This work proposes a standardized phenotype of frailty in older adults and demonstrates predictive validity for the adverse outcomes that geriatricians identify frail older adults as being at risk for: falls, hospitalizations, disability, and death. Even after adjustment for measures of socioeconomic status, health status, subclinical and clinical disease, depressive symptoms, and disability status at baseline, frailty remained an independent predictor of risk of these adverse outcomes. The intermediate group with one or two frailty characteristics was at elevated, but intermediate, risk for these outcomes and at risk for subsequent frailty.
This study provides insight into frailty and its outcomes in a population-based sample of older adults who were neither institutionalized nor end-stage, characterizing both early presentation, correlates, and long-term outcomes. A standardized phenotype provides a basis for future comparison with other populations. The exact frequencies identified are a function of the definitions of each criterion selected, and would (obviously) change if definition shifted. However, the approach selected indicates that frailty is not rare in a community-dwelling population, and is a meaningful predictor when people are relatively functional.
Prior to this, frailty has primarily been evaluated in hospitalized or nursing home populations (3)(4)(7)(8)(24)(46)(47). Such studies, due to the selection process by which their participants arrive in these settings, are likely to characterize persons with late-stage frailty, after the occurrence of related adverse outcomes, and having highly selected correlates. One recent study in a community-dwelling population in The Netherlands used a subset of the phenotype studied here, inactivity and weight loss over 5 years of >4 kg (48). They found a similar prevalence of 6% (26/440), and similar unadjusted associations with mortality and disability, providing evidence for consistency of findings across population. The phenotype proposed here offers greater predictive validity, compared with using only two criteria.
The characterization of frailty offered here also provides new insights into potential etiologies. Frailty in this study was strongly associated with a number of major chronic diseases, including cardiovascular and pulmonary diseases and diabetes, suggestive of etiologic associations with these single diseases. However, there was a greater likelihood of frailty when two or more diseases were present than with any one. Conversely, the observation that a subset of those who were frail reported none of the diseases assessed supports the hypothesis that there may be two different pathways by which individuals become frail: one, a result of physiologic changes of aging that are not disease-based (e.g., aging-related sarcopenia [16] or anorexia of aging [(30),(31),(49),(50)]), and the other a final common pathway of severe disease or comorbidity, as suggested by the higher rates of poor health status and greater extent of subclinical physiologic changes in the frail group. Individual or comorbid diseases could potentially initiate frailty via any point on the hypothesized cycle (Fig. 1). These hypotheses remain to be confirmed.
The likelihood of frailty was also higher among women and/or those with lower socioeconomic status. Female gender could confer intrinsic risk of frailty due to women starting with lower lean mass and strength than age-matched men; thereafter, women losing lean body mass with aging might be more likely to cross a threshold necessary for frailty. Women could also have greater vulnerability to frailty via extrinsic effects on sarcopenia (e.g., because older women have a greater likelihood of inadequate nutritional intake, compared to men, due to living alone more often [19]).
This study offers support for geriatricians' contention that frailty is a physiologic syndrome (9)(10)(11)(12)(13)(14)(15)(16), and it delineates frailty from comorbidity and disability\characteristics that are often treated as synonymous with frailty. Our findings support the hypothesis that frailty causes disability, independent of clinical and subclinical diseases (Table 7 ). The syndrome of frailty may be a physiologic precursor and etiologic factor in disability, due to its central features of weakness, decreased endurance, and slowed performance. The aspects of function likely affected by frailty are those dependent on energetics and speed of performance (e.g., mobility). It is notable that only 27% of those who were disabled in ADL tasks were also frail (Table 2 ), suggesting that frailty begins by affecting mobility tasks before causing difficulty in endstage function such as ADLs, or that there are additional pathways by which older adults can become disabled. For example, disability due to arthritis of the hands might very specifically affect ability to grasp or eat, without having any relationship to frailty. Thus, frailty does not appear to be synonymous with either disability or comorbidity. Given the findings here, the terms appear to apply to distinct, but related, entities and should not be used interchangeably.
The definition of frailty offered and validated here provides a standardized, physiologically based definition applicable to the spectrum of frailty presentations seen in community-dwelling older adults. The clear criteria (see Appendix) are relatively easy and inexpensive to apply, and offer a basis for standardized screening for frailty and risk of frailty in older adults. They can, potentially, be used to establish clinical risk of adverse outcomes. They also provide a phenotype applicable to future research on etiology and interventions to prevent or retard the progression of frailty.
The major limitation of this study is that the measures utilized to operationalize the phenotype of frailty were limited to those that were fortuitously collected 10 years ago for other purposes in this longitudinal study. In addition, weight loss prior to baseline was necessarily drawn from baseline self-report. On the other hand, few studies can offer the length of follow-up or the breadth of health and demographic characteristics available in this cohort for use in understanding frailty. A number of questions remain to be evaluated, including the role of frailty in health outcomes for different subgroups (e.g, African Americans and Caucasians). In this same issue, we separately examine the association of frailty with cardiovascular diseases (51).
Overall, these findings provide support for the hypotheses of a physiologic cycle of frailty (14) that serves as the basis for the phenotype considered here (Fig. 1). This incorporates prior research demonstrating pairwise associations between each two components in the cycle (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). This hypothesized cycle of frailty, representing an adverse, potentially downward spiral of energetics, is consistent with the clinical markers of frailty identified by geriatricians and gerontologists (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) and our findings and others' proposals (46)(52)(53) of an intermediate and later stage of frailty in community-dwelling older adults. A more advanced stage may be observed in more debilitated populations, such as in nursing homes. This phenotype may not, however, fully explain the more subtle biologic underpinnings of decreased reserves and ability to maintain homeostasis (11)(12)(13), which may be latent prior to an insult, but be a basis for vulnerability to stressors (10)(11)(14). Further understanding of the basis for risk associated with frailty may ultimately be found in the alterations in multisystem function, complexity, and reserve with aging (12). It is possible that early frailty, or progression from the intermediate stage to frailty, might have one set of etiologic factors, whereas progression of the frailty observed here to a more end-stage point might be associated with others, such as declines in weight, albumin, or cholesterol as consequences of malnutrition or catabolism. This end stage has been reported to be irreversible and presage death (19)(24)(52)(53).
Table a. Criteria Used to Define Frailty
- Weight loss: "In the last year, have you lost more than 10 pounds unintentionally (i.e., not due to dieting or exercise)?" If yes, then frail for weight loss criterion. At follow-up, weight loss was calculated as: (Weight in previous year - current measured weight)/(weight in previous year) = K. If K >= 0.05 and the subject does not report that he/she was trying to lose weight (i.e., unintentional weight loss of at least 5% of previous year's body weight), then frail for weight loss = Yes.
- Exhaustion: Using the CES-D Depression Scale, the following two statements are read. (a) I felt that everything I did was an effort; (b) I could not get going. The question is asked "How often in the last week did you feel this way?" 0 = rarely or none of the time (<1 day), 1 = some or a little of the time (1-2 days), 2 = a moderate amount of the time (3-4 days), or 3 = most of the time. Subjects answering "2" or "3" to either of these questions are categorized as frail by the exhaustion criterion.
- Physical Activity: Based on the short version of the Minnesota Leisure Time Activity questionnaire, asking about walking, chores (moderately strenuous), mowing the lawn, raking, gardening, hiking, jogging, biking, exercise cycling, dancing, aerobics, bowling, golf, singles tennis, doubles tennis, racquetball, calisthenics, swimming. Kcals per week expended are calculated using standardized algorithm. This variable is stratified by gender.
Men: Those with Kcals of physical activity per week <383 are frail.
Women: Those with Kcals per week <270 are frail.
- Walk Time, stratified by gender and height (gender-specific cutoff a medium height).


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