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Frailty in Older Adults - Evidence for a Phenotype

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Journal of Gerontology:



MEDICAL SCIENCES Copyright 2001 by The Gerontological Society of America

2001, Vol. 56A, No. 3, M146–M156

M146

Frailty in Older Adults: Evidence for a Phenotype

Linda P. Fried,

1

Catherine M. Tangen,

2

Jeremy Walston,

1

Anne B. Newman,

3

Calvin Hirsch,

4

John Gottdiener,

5

Teresa Seeman,

6

Russell Tracy,

7

Willem J. Kop,

8

Gregory Burke,

9

and Mary Ann McBurnie

2

for the Cardiovascular Health Study
Collaborative Research Group

1

The John Hopkins Medical Institutions, Baltimore, Maryland.

2

The University of Washington, Seattle.

3

The University of Pittsburgh, Pennsylvania.

4

The University of California at Davis, Sacramento.

5

St. Francis Hospital, Roslyn, New York.

6

The University of California at Los Angeles.

7

The University of Vermont, Burlington.

8

Uniformed Services University of the Health Sciences, Bethesda, Maryland.

9

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, hospitaliza-
tion, 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 mor-
tality.

Results.

Frailty was defined as a clinical syndrome in which three or more of the following criteria were present: un-
intentional 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 num-
ber 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

5

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 dis-
ability, 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.

RAILTY is considered to be highly prevalent with in-
creasing age and to confer high risk for adverse health
outcomes, including mortality, institutionalization, falls, and
hospitalization (1—3). Numerous geriatric interventions have
been developed to improve clinical outcomes for frail older
adults (3—7). A major obstacle to the success of such inter-
ventions has been the absence of a standardized and valid
method for screening of those who are truly frail so as to ef-
fectively target care (1,3).
Potential definitions of frailty abound, defining frailty as
synonymous with disability (1,8,9), comorbidity (8), or ad-
vanced old age (3). Increasingly, geriatricians define frailty
as a biologic syndrome of decreased reserve and resistance
to stressors, resulting from cumulative declines across mul-
tiple physiologic systems, and causing vulnerability to ad-
verse outcomes (9—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

F

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PHENOTYPE OF FRAILTY

M147

lean body mass, strength, endurance, balance, walking per-
formance, and low activity (9,10,14—17), and that multiple
components must be present clinically to constitute frailty
(9,14). Many of these factors are related (18—31) and can be
unified, theoretically, into a cycle of frailty associated with
declining energetics and reserve (Figure 1). The core ele-
ments of this cycle are those commonly identified as clini-
cal signs and symptoms of frailty (9,10,14—16). Frailty
likely also involves declines in physiologic complexity or
reserve in other systems, leading to loss of homeostatic ca-
pability to withstand stressors and resulting vulnerabilities
(2,9,11,12).
We hypothesized that the elements identified in Figure 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 (Figure 1), and, in a popula-
tion-based study of older adults, evaluated its prevalence
and incidence, cross-sectional correlates, and its validity in
terms of predicting the adverse outcomes geriatricians asso-
ciate with frail older adults.

M

ETHODS

Population

This study employed data from the Cardiovascular Health
Study, a prospective, observational study of men and women
65 years and older. The original cohort (

N



5

5201) was re-
cruited from four U.S. communities in 1989—90. An addi-
tional cohort of 687 African American men and women was
recruited in 1992—93 from three of these sites. Participants
were recruited from age- and gender-stratified samples of
the HCFA Medicare eligibility lists in: Sacramento County,
California; Washington County, Maryland; Forsyth County,
North Carolina, and Allegheny County (Pittsburgh), Penn-
sylvania (32,33). Both cohorts received identical baseline
evaluations (except that the latter did not receive spirometry
or echocardiograms at baseline) and follow-up with annual
examinations and semiannual telephone calls and surveil-
lance for outcomes including incident disease, hospitaliza-
tions, falls, disability, and mortality.

Baseline Evaluation

Standardized interviews ascertained self-assessed health,
demographics, health habits, weight loss, medications used,
and self-reported physician diagnosis of cardiovascular events,
emphysema, asthma, diabetes, arthritis, renal disease, can-
cer, and hearing and visual impairment. A version of the
Minnesota Leisure Time Activities Questionnaire (34) as-
certained physical activities in the prior 2 weeks, plus fre-
quency and duration. Physical function was ascertained by
asking about difficulty with 15 tasks of daily life, including
mobility, upper extremity, instrumental activities of daily
living (IADL) and activities of daily living (ADL) tasks
(35). Frequency of falls in the prior 6 months was assessed
by self-report. The modified 10-item Center for Epidemio-
logical Studies—Depression scale [CES—D; (36)] ascertained
depressive symptoms.
Cardiovascular diseases [myocardial infarction (MI), con-
gestive heart failure (CHF), angina, peripheral vascular dis-
ease, and stroke] were validated by ascertaining medications
used and through standardized examinations: electrocardio-
gram, echocardiogram, and posterior tibial—brachial artery
systolic (ankle—arm) blood pressure ratio (32,37,38). These
data and medical records were then reviewed by clinicians
for consensus-based adjudication of the presence of these
diseases, based on standardized algorithms (37).
Additional examinations ascertained weight; blood pres-
sure; carotid ultrasound measuring maximal stenosis of the
internal and common carotid arteries (39); phlebotomy,
under fasting conditions, with blood analyzed by the Labora-
tory for Clinical Biochemistry Research (University of
Vermont) for fasting glucose, serum albumin, creatinine,
Figure 1. Cycle of frailty hypothesized as consistent with demonstrated pairwise associations and clinical signs and symptoms of frailty. Re-
produced with permission from (14).

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M148

FRIED ET AL.

and fibrinogen (32). Fasting plasma lipid analyses were
performed, and low-density lipoprotein cholesterol was cal-
culated (32). Cognitive function was assessed with the
Mini-Mental State Examination (40) and the Digit Symbol
Substitution test (41). Standardized performance-based mea-
sures of physical function included time (seconds) to walk
15 feet at usual pace and maximal grip strength (kilograms)
in the dominant hand (3 measures averaged), using a Jamar
hand-held dynamometer (32).

Mortality

Deaths were identified at semi-annual contacts and con-
firmed through intensive surveillance (37,42). Mortality as-
certainment was 100% complete through the eighth year.

Operationalization of the frailty phenotype in CHS.—

Based on the scientific rationale above, a phenotype of frailty
was proposed to include the elements summarized in Table
1, column A. It was operationalized utilizing data collected
in CHS at baseline for Cohort 1 and years 3 (baseline for
Cohort 2) and 7 for both cohorts (Figure 2 and Table 1, col-
umn B). We specified that a phenotype of frailty was identi-
fied by the presence of three or more of the following com-
ponents (see Appendix) of the hypothesized cycle of frailty
(Figure 1):
1. Shrinking: weight loss, unintentional, of

$

10 pounds in
prior year or, at follow-up, of

$

5% of body weight in
prior year (by direct measurement of weight).
2. Weakness: grip strength in the lowest 20% at baseline,
adjusted for gender and body mass index.
3. Poor endurance and energy: as indicated by self-report of
exhaustion. Self-reported exhaustion, identified by two
questions from the CES—D scale (36), is associated with
stage of exercise reached in graded exercise testing, as an
indicator of O

2

max (43), and is predictive of cardio-
vascular disease (44).
4. Slowness: The slowest 20% of the population was de-
fined at baseline, based on time to walk 15 feet, adjusting
for gender and standing height.
5. Low physical activity level: A weighted score of kilocalo-
ries expended per week was calculated at baseline (34,45),
based on each participant s report. The lowest quintile of
physical activity was identified for each gender.
For measures that identified the lowest quintile, the level
established at baseline was applied to follow-up evalua-
tions. A critical mass of characteristics, defined as three or
more, had to be present for an individual to be considered
frail. Those with no characteristics were considered robust,
whereas those with one or two characteristics were hypothe-
sized to be in an intermediate, possibly prefrail, stage clini-
cally.

Data Analysis

Using CHS data, we identified the number of frailty char-
acteristics present, as per definitions above. Those consid-
ered evaluable for frailty had three or more nonmissing
frailty components among the five criteria (Table 1). We ex-
cluded those with a history of Parkinson s disease (

n



5

47),
stroke (

n



5

245), or Mini-Mental scores

,

18 (

n



5

84), and
those who were taking Sinemet, Aricept, or antidepressants
(

n



5

235), as these conditions could potentially present with
frailty characteristics as a consequence of a single disease.
There were 4,735 in the original and 582 in the African
American cohort who were eligible; the total baseline sam-
V
œ

Table 1. Operationalizing a Phenotype of Frailty

A.

Characteristics of Frailty

B.

Cardiovascular Health Study Measure

*
Shrinking: Weight loss
(unintentional)
Sarcopenia (loss
of muscle mass)
Baseline:

.

10 lbs lost unintentionally in
prior year
Weakness Grip strength: lowest 20% (by gender, body
mass index)
Poor endurance; Exhaustion Exhaustion (self-report)
Slowness Walking time/15 feet: slowest 20% (by
gender, height)
Low activity Kcals/week: lowest 20%
males:

,

383 Kcals/week
females:

,

270 Kcals/week
C.

Presence of Frailty

Positive for frailty phenotype:

$

3 criteria
present
Intermediate or prefrail: 1 or 2 criteria
present
*See Appendix.
Figure 2. Timing of assessments of frailty components for both cohorts in the Cardiovascular Health Study. *Note that Cohort 2 was recruited
and their baseline examination occurred 3 years after that of Cohort 1. Although clinic visits were done annually, frailty was evaluated less fre-
quently.

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PHENOTYPE OF FRAILTY

M149

ple size after applying the exclusion criteria was 5,317. For
the first cohort, frailty components were ascertained at base-
line, and then 3 years and 7 years into the study. The second
cohort, recruited 3 years after the initial cohort, had frailty
components ascertained 4 years later (corresponding to year
7 for the first cohort; Figure 2).
For associations of frailty with other factors, the trend

p

value based on the Cochran-Mantel-Haenszel (CMH) test
was used. Comorbidity was defined as the presence of two
or more of nine conditions: self-reported claudication, ar-
thritis, cancer, hypertension, chronic obstructive pulmonary
disease (COPD), and validated diabetes (ADA definition),
CHF, angina, or MI. A Venn diagram illustrates the overlap
of disability and comorbidity with frailty at baseline; per-
centages are based on all frail subjects.
Kaplan-Meier estimates were used to determine the per-
centage of subjects free of an event (e.g., hospitalization,
fall, death) at 3 years after study entry and 7 years after
study entry. Cohort 1 had a longer follow-up period (median
79 months, range 73—84) than Cohort 2 (median 38 months,
range 37—43), so estimates at 7 years were based only on
Cohort 1. The

p

values reported for the difference in sur-
vival curves between frailty phenotype groups were based
on the logrank test.

Predictive Validity

Cox proportional hazard models were used to assess the
independent contribution of baseline frailty status to inci-
dence of major geriatric outcomes over 3 and 7 years, in-
cluding: (a) incident falls (evaluated every 6 months); (b)
worsening mobility or ADL function (evaluated annually);
(c) incident hospitalization: from time of study entry to dis-
charge date for the first confirmed overnight hospitaliza-
tion; (d) death. Indicators for frail (3 or more frailty compo-
nents) and at-risk (1 or 2 frailty components) were created,
with the nonfrail group (0 frailty components) serving as the
reference group. Unadjusted instantaneous hazard ratios (re-
ferred to as relative risk [RR] estimates) were estimated for
each outcome. Covariate-adjusted Cox models were also fit,
utilizing baseline covariates shown to be predictive of mor-
tality in this cohort (42): age, gender, income, smoking sta-
tus, diuretic use without a history of hypertension or con-
gestive heart failure, fasting glucose, albumin, creatinine;
objective measures of subclinical disease, including: bra-
chial and tibial systolic blood pressure, abnormal left ven-
tricular ejection fraction (LVEF; by echocardiography), ma-
jor ECG abnormality, forced vital capacity (FVC), and
maximal stenosis of the internal carotid artery (by ultra-
sound), congestive heart failure (validated history), digit
symbol substitution score, depressive symptoms (CES—D
score excluding the two questions utilized in the frailty defi-
nition), and difficulty in

$

1 IADL. Weight and physical ac-
tivity were also found to be independent predictors of sur-
vival, but they were not included in the covariate-adjusted
models, as they are components of the overall frailty score.
Covariates selected were based on analyses performed on
the first cohort; external validation using the second cohort
showed good agreement. However, FVC and LVEF abnor-
mality were not available at study entry for the second co-
hort, so they were not included in the covariate-adjusted
frailty models. Adding these two covariates to models based
only on the first cohort did not alter the frailty results.
Finally, a logistic model was used to evaluate whether the
intermediate frailty group (1,2 criteria) was at higher risk of
incident frailty than those who were not frail (0 criteria) at
study entry. Only subjects who were alive, eligible (satis-
fied exclusion criteria), and evaluable (at least 3 nonmissing
frailty components) at the subsequent visit were included in
the analysis. The covariate-adjusted logistic model includes
the same covariates described for the proportional hazards
models (above).

R

ESULTS

The 5,317 people evaluated were 65 to 101 years of age;
58% were female and 15% African American, with a broad
range of socioeconomic, functional, and health status (Table
2, column A). Frailty markers present at baseline are shown
in Table 3. Overall, 7% of the cohort had

$

3 frailty criteria,
and 46% had none. Six percent of the initial cohort and 12%
of the African American cohort were frail. Prevalence of
frailty increased with each 5-year age group, and was up to
twofold higher for women than men by age group (Table 4).
The exception was those 90 years and older, where preva-
lence was lower in both subgroups of women and men in
the minority cohort.
Three-year incidence of frailty was 7% for years 0—3 and
was 7%, as well, for 4-year incidence of frailty from years
3—7, for the first cohort. The second cohort had a 4-year in-
cidence rate of 11%. These incidence rates are likely under-
estimates, as they do not include loss to mortality or those
who were not evaluable for frailty at follow-up due to miss-
ing data.
Those who were frail were older, more likely to be fe-
male and African American, and had less education, lower
income, poorer health, and higher rates of comorbid chronic
diseases and of disability than those who were not frail or
were in the intermediate group (

p



,

.05 for each compari-
son; Table 2). They also had significantly higher rates of
cardiovascular and pulmonary diseases, arthritis, and diabe-
tes. There was no significant difference in cancer, possibly a
result of recruitment criteria that excluded those under ac-
tive treatment for cancer. The intermediate frailty group was
intermediate between those who were frail and those not
frail in all of these measures (

p

for trend

,

.05 in each case
except cancer). Notably, 7% of those who were frail had
none of these chronic diseases, and 25% had just one; they
were: 56% arthritis, 25% hypertension, 8% diabetes, and
less than 5% each of angina, congestive heart failure, can-
cer, and pulmonary disease. Both lower cognition and
greater depressive symptomatology were associated with
frailty (despite exclusion of those being treated with antide-
pressants or with MMSE

,

18).
Further analyses explored the association between the
frailty phenotype and self-reported physical disability. In
Table 2, 72% and 60% of those who were frail reported dif-
ficulty in mobility tasks or IADLs, respectively, while only
27% of those who were frail had difficulty in ADLs. There
was a step-wise increase in disability with increasing frailty
status (

p

for trend

,

.001). Separately, among those with
disability in ADLs, often considered synonymous with

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M150

FRIED ET AL.

Table 2. Baseline Association of Demographic and Health Characteristics With Frailty, in Percentages: the Cardiovascular Health Study

Factor
A
Total
(5317)
B
Not Frail
(

n



5

2469)
C
Intermediate
(

n



5

2480)
D
Frail
(

n



5

368)
E
Trend

p

Value
F
Age Adjusted
Trend

p

Value
Age
65—74 67.3% 76.1% 62.9% 38.0%

,

.001
75—84 29.1 22.6 32.7 48.9
85

1

3.6 1.3 4.5 13.0
Sex
Female 57.9 56.4 57.7 68.5

,

.001

,

.001
Male 42.1 43.6 42.3 31.5
Race
Caucasian 84.5 89.7 81.1 71.7

,

.001

,

.001
African American 14.8 9.6 18.1 27.5
Other 0.7 0.7 0.8 0.8
Education

#

9th grade 18.2 12.7 22.2 28.3

,

.001

,

.001
10—11th grade 9.9 8.8 10.9 10.6
HS grad/GED 28.3 29.5 27.8 24.8

.

12 years 43.5 49.0 39.2 36.2
Income

,

12K 25.6 18.7 29.9 44.3

,

.001

,

.001
12—

,

24K 35.4 34.8 36.3 32.9
24—50K 25.7 30.0 23.3 13.4

.

50K 13.2 16.5 10.6 9.3
Self-Assessed Health
Excellent 14.3 19.5 10.7 3.5

,

.001

,

.001
Very good 25.2 31.1 21.3 11.4
Good 37.1 36.1 39.4 28.3
Fair 20.0 12.6 24.4 40.3
Poor 3.4 0.7 4.1 16.4
Live Alone 14.1 10.9 15.5 27.5

,

.001

,

.001
Prevalent Disease at Baseline
MI 9.1 7.3 10.3 13.3

,

.001

,

.001
Angina 18.5 14.5 21.0 28.8

,

.001

,

.001
CHF 4.0 2.0 4.5 13.6

,

.001

,

.001
PVD 2.2 1.5 2.7 3.8

,

.001 .002
Arthritis 51.2 44.8 54.7 70.6

,

.001

,

.001
Cancer 14.6 14.2 14.7 15.8 .42 1.00
Diabetes 15.8 12.1 18.2 25.0

,

.001

,

.001
Hypertension 42.9 38.8 45.9 50.8

,

.001

,

.001
COPD* 7.8 5.8 8.8 14.1

,

.001

,

.001
Number of Chronic Diseases
0 18.5 23.2 15.4 7.3

,

.001

,

.001
1 33.3 36.8 31.0 24.7
2 25.6 24.0 27.0 26.9
3—4 19.8 14.5 23.2 32.9

$

5 2.9 1.5 3.5 8.2
Self-Reported Disability

$

1 mobility task 28.7 16.0 35.2 71.7

,

.001

,

.001

$

1 IADL task 23.8 13.5 28.8 59.7

,

.001

,

.001

$

1 ADL task 6.8 2.2 8.5 27.4

,

.001

,

.001
Any Disability 36.8 23.5 44.1 76.4

,

.001

,

.001
Cognitive Function
(Mini-Mental score range: 0—30)
18—23 6.3 3.0 8.3 15.1

,

.001

,

.001

.23 93.7 97.0 91.7 84.9
Depressive Symptoms
CES—D $10 9.9 2.6 14.0 31.0 ,.001 ,.001
Note: MI 5 myocardial infarction; CHF 5 congestive heart failure; PVD 5 peripheral vascular disease; IADL 5 instrumental activity of daily living; ADL 5 ac-
tivity of daily living; CES—D 5 Center for Epidemiological Studies—Depression scale.
*Chronic emphysema, bronchitis, or asthma confirmed by doctor.

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frailty, only 28% were in the frail group (Table 5). Figure 3
displays the overlap between these characteristics, as well
as with the presence of two or more comorbid diseases.
There was only modest concordance between frailty and
disability. Of those who were frail, 46% had comorbid dis-
ease, 6% had ADL disability, 22% had both comorbid dis-
ease and ADL disability, and 27% had neither ADL disabil-
ity nor comorbidity.
Frailty is considered to be a high-risk state predictive of a
range of adverse health outcomes (9,10,14—16). The inci-
dence of each of these outcomes is displayed (Table 6) by
frailty status and length of follow-up. In those who met the
criteria for frailty at baseline, mortality was sixfold higher
(18%) than that for the nonfrail (3%) for 3-year cumulative
survival, and was over threefold higher (43% compared to
12%), compared to the nonfrail group, for 7-year survival.
Figure 4 provides the unadjusted survival curves for each
frailty group, over the 7-year interval. After 84 months,
43% of those who were frail had died, compared to 23% of
those who were intermediate and 12% of those who were
robust at baseline.
To assess whether three criteria predicted mortality sig-
nificantly better than two, Kaplan-Meier survival curves
(similar to Figure 4) were created, where each of the 10 pos-
sible combinations of three phenotype criteria were consid-
ered as the definition of frailty. The predictive power of
each combination of three criteria being present was con-
trasted with only two of these being present. In each of 10
survival analyses, each group with three components posi-
tive for frailty had significantly worse survival than those
with two components, or the no frailty groups ( p , .05;
data not shown). Based on these models, it was concluded
that criteria that were based on three, rather than two, com-
ponents, provided improved predictive power in identifying
mortality risk.
To assess the independent predictive validity of this
frailty phenotype, we evaluated its association, prospec-
tively, with five important adverse health outcomes ascer-
tained in prospective follow-up, using Cox proportional
hazards models. As seen in Table 7, the RR ratio estimate,
or hazard ratio, for the outcomes of interest over 3 and 7
years of follow-up is displayed for those who were in the in-
termediate and frail groups at baseline, each relative to
Table 3. Prevalence of Frailty Phenotype Components in
Percentages: Cardiovascular Health Study
Total
(N 5 5317)
Men
(n 5 3077)
Women
(n 5 2240)
Frequency of Frailty Components % % %
Exhaustion 17 19 12
Weight loss 6 6 6
Low activity (kcals) 22 20 20
Slow walk (s) 20 20 20
Grip strength (kg) 20 20 20
Number of Frailty Components Present
0464548
1323233
2151514
3666
4121
5 0.2 0.1 0.2
Table 4. Prevalence of Frailty at Baseline: Cardiovascular
Health Study
Original Cohort
(1989—1990)
Minority Cohort
(1992—1993)
Age Group (n)
Overall
% Frail
Women
(n 5 2710)
% Frail
Men
(n 5 2025)
% Frail
Women
(n 5 367)
% Frail
Men
(n 5 215)
% Frail
65—70 (2308) 3.2 3.0 1.6 11.0 5.8
71—74 (1271) 5.3 6.7 2.9 9.7 3.1
75—79 (1057) 9.5 11.5 5.5 13.8 17.9
80—84 (490) 16.3 16.3 14.2 30.6 15.4
85—89 (152) 25.7 31.3 15.5 60.0 25.0
901 (39) 23.1 12.5 36.8 0.0 0.0
Total (5317) 6.9 7.3 4.9 14.4 7.4
Table 5. Distribution of Frailty Status Among Those With a
Disability at Baseline
CHS Baseline: Both Cohorts
Not Frail Intermediate Frail
(n 5 2469)
%
(n 5 2480)
%
(n 5 368)
%
Distribution in population 46.4 46.6 6.9
Difficulty
$1 Mobility task 25.9 57.1 17.0
$1 IADL task 26.4 56.3 17.2
$1 ADL task 14.6 57.9 27.5
Note: CHS 5 Cardiovascular Health Study; ADL 5 activities of daily liv-
ing; IADL 5 instrumental activities of daily living.
Figure 3. Venn diagram displaying extent of overlap of frailty with
ADL disability and comorbidity ($2 diseases). Total represented:
2,762 subjects who had comorbidity and/or disability and/or frailty. n
of each subgroup indicated in parentheses. 1 Frail: overall n 5 368
frail subjects (both cohorts). *Comorbidity: overall n 5 2,576 with 2
or more out of the following 9 diseases: myocardial infarction, angina,
congestive heart failure, claudication, arthritis, cancer, diabetes, hy-
pertension, COPD. Of these, 249 were also frail. **Disabled: overall
n 5 363 with an ADL disability; of these, 100 were frail.

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M152 FRIED ET AL.
those who were nonfrail. Bivariate (unadjusted) associa-
tions were significant (p , .05) for the predictive associa-
tion of frailty and intermediate frailty status with incident
falls, worsened mobility or ADL disability, incident hospi-
talization, and death over 3 or 7 years, with hazard ratios
ranging from 1.82—4.46 and 1.28—2.10 for the frail and in-
termediate groups, respectively. After adjustment for cova-
riates (42), the frailty phenotype remained an independent
predictor of all adverse outcomes at both 3 and 7 years, with
7-year hazard ratios ranging from 1.23—1.79 (p , .05 for
all, except falls, where p 5 .06). The intermediate group
also significantly (p , .05) predicted all outcomes after ad-
justment, but with lower strengths of association. Results
for both 3 and 7 years follow-up were consistent. The pro-
portional hazards assumption was found reasonable for each
model.
Finally, we evaluated whether being in the intermediate
group identified increased risk of frailty. Adjusting for co-
variates, those who were intermediate at baseline were at
more than twice the risk of becoming frail over 3 years (or
over 4 years for cohort 2), relative to those subjects with no
frailty characteristics at baseline (odds ratio [OR] 5 2.63,
95% confidence interval [CI] 5 1.94, 3.56) (Table 8). The
results were nearly identical in separate analyses of just the
first cohort (which had a 1-year shorter initial follow-up in-
terval than the second cohort). Of incident frailty cases,
88% (254/290) came from the first cohort.
DISCUSSION
This work proposes a standardized phenotype of frailty in
older adults and demonstrates predictive validity for the ad-
verse 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, depres-
sive symptoms, and disability status at baseline, frailty re-
mained 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 compari-
son with other populations. The exact frequencies identified
Table 6. Incidence of Adverse Outcomes Associated With Frailty: Kaplan-Meier Estimates at 3 Years and 7 Years* After Study Entry for
Both of the Cohorts

(N 5 5317)
Died First Hospitalization First Fall Worsening ADL Disability Worsening Mobility Disability
Frailty Status at Baseline (n) 3 yr % 7 yr % 3 yr % 7 yr % 3 yr % 7 yr % 3 yr % 7 yr % 3 yr % 7 yr %
Not Frail (2469) 3 12 33 79 15 27 8 23 23 41
Intermediate (2480) 7 23 43 83 19 33 20 41 40 58
Frail (368) 18 43 59 96 28 41 39 63 51 71
p

,.0001 ,.0001 ,.0001 ,.0001 ,.0001
*7-year estimates are only available for the first cohort.

Only those evaluable for frailty are included.

p value is based on the 2 degree of freedom log rank test using all available follow-up.
Figure 4. Survival curve estimates (unadjusted) over 72 months of follow-up by frailty status at baseline: Frail (3 or more criteria present); In-
termediate (1 or 2 criteria present); Not frail (0 criteria present). (Data are from both cohorts.)

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PHENOTYPE OF FRAILTY M153
are a function of the definitions of each criterion selected,
and would (obviously) change if definition shifted. How-
ever, 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 hos-
pitalized 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 character-
ize persons with late-stage frailty, after the occurrence of re-
lated adverse outcomes, and having highly selected corre-
lates. 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 simi-
lar unadjusted associations with mortality and disability,
providing evidence for consistency of findings across popu-
lation. The phenotype proposed here offers greater predic-
tive 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 dis-
eases, including cardiovascular and pulmonary diseases and
diabetes, suggestive of etiologic associations with these sin-
gle 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 sup-
ports the hypothesis that there may be two different path-
ways 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 se-
vere disease or comorbidity, as suggested by the higher
Table 7. Baseline Frailty Status Predicting Falls, Disability, Hospitalizations, and Death in Both Cohorts of CHS With a Maximum
Follow-up Time of 7 Years for the First Cohort and 4 Years for the Minority Cohort
No Frailty
(reference)
Hazard Ratios Estimated Over 3 Years Hazard Ratios Estimated Over 7 Years
Intermediate Frail Intermediate Frail
Incident Fall
Unadjusted HR* 5 1.0 HR 5 1.36
CI 5 (1.18,1.56)
p , .0001
HR 5 2.06
CI 5 (1.64,2.59)
p , .0001
HR 5 1.28
CI 5 (1.15,1.43)
p , .0001
HR 5 1.82
CI 5 (1.50,2.21)
p , .0001
Covariate Adjusted HR 5 1.0 HR 5 1.16
CI 5 (1.00,1.34)
p 5 .056
HR 5 1.29
CI 5 (1.00,1.68)
p 5 .054
HR 5 1.12
CI 5 (1.00,1.26)
p 5 .045
HR 5 1.23
CI 5 (0.99,1.54)
p 5 .064
Worsening Mobility

Unadjusted HR 5 1 HR 5 1.94
CI 5 (1.75,2.15)
p , .0001
HR 5 2.68
CI 5 (2.26,3.18)
p , .0001
HR 5 1.72
CI 5 (1.58,1.87)
p , .0001
HR 5 2.45
CI 5 (2.11,2.85)
p , .0001
Covariate Adjusted HR 5 1 HR 5 1.58
CI 5 (1.41,1.76)
p , .0001
HR 5 1.50
CI 5 (1.23,1.82)
p , .0001
HR 5 1.41
CI 5 (1.29,1.54)
p , .0001
HR 5 1.36
CI 5 (1.15,1.62)
p 5 .0003
Worsening ADL

Disability
Unadjusted HR 5 1.0 HR 5 2.54
CI 5 (2.16,3.00)
p , .0001
HR 5 5.61
CI 5 (4.50,7.00)
p , .0001
HR 5 2.14
CI 5 (1.92,2.39)
p , .0001
HR 5 4.22
CI 5 (3.55,5.01)
p , .0001
Covariate Adjusted HR 5 1.0 HR 5 1.67
CI 5 (1.41,1.99)
p , .0001
HR 5 1.98
CI 5 (1.54,2.55)
p , .0001
HR 5 1.55
CI 5 (1.38,1.75)
p , .0001
HR 5 1.79
CI 5 (1.47,2.17)
p , .0001
First Hospitalization
Unadjusted HR 5 1.0 HR 5 1.38
CI 5 (1.26,1.51)
p , .0001
HR 5 2.25
CI 5 (1.94,2.62)
p , .0001
HR 5 1.34
CI 5 (1.25,1.43)
p , .0001
HR 5 2.14
CI 5 (1.89,2.42)
p , .0001
Covariate Adjusted HR 5 1.0 HR 5 1.13
CI 5 (1.03,1.25)
p 5 .014
HR 5 1.29
CI 5 (1.09,1.54)
p 5 .004
HR 5 1.11
CI 5 (1.03,1.19)
p 5 .005
HR 5 1.27
CI 5 (1.11,1.46)
p 5 .0008
Death
Unadjusted HR 5 1.0 HR 5 2.42
CI 5 (1.84,3.19)
p , .0001
HR 5 6.47
CI 5 (4.63,9.03)
p , .0001
HR 5 2.01
CI 5 (1.73,2.33)
p , .0001
HR 5 4.46
CI 5 (3.61,5.51)
p , .0001
Covariate Adjusted HR 5 1 HR 5 1.49
CI 5 (1.11,1.99)
p , .0001
HR 5 2.24
CI 5 (1.51,3.33)
p 5 .0001
HR 5 1.32
CI 5 (1.13,1.55)
p 5 .0006
HR 5 1.63
CI 5 (1.27,2.08)
p 5 .0001
Note: Covariate adjustment includes: age, gender, indicator for minority cohort, income, smoking status, brachial and tibial blood pressure, fasting glucose, albumin,
creatinine, carotid stenosis, history of CHF, cognitive function, major ECG abnormality, use of diuretics, problem with IADLs, self-report health measure, CES—D
modified depression measure.
*HR 5 hazard ratio, the ratio of risk of frailty group (either frail or intermediate) relative to the nonfrail group with regards to the event of interest (e.g., first fall, death).

Defined as an increase in 1 unit of mobility score relative to baseline.

Defined as an increase in 1 unit of ADL score relative to baseline.

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M154 FRIED ET AL.
rates of poor health status and greater extent of subclinical
physiologic changes in the frail group. Individual or comor-
bid diseases could potentially initiate frailty via any point
on the hypothesized cycle (Figure 1). These hypotheses re-
main to be confirmed.
The likelihood of frailty was also higher among women
and/or those with lower socioeconomic status. Female gen-
der could confer intrinsic risk of frailty due to women start-
ing 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 nutri-
tional intake, compared to men, due to living alone more of-
ten [19]).
This study offers support for geriatricians contention
that frailty is a physiologic syndrome (9—16), and it delin-
eates frailty from comorbidity and disability characteris-
tics 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 dis-
abled in ADL tasks were also frail (Table 2), suggesting that
frailty begins by affecting mobility tasks before causing dif-
ficulty in endstage function such as ADLs, or that there are
additional pathways by which older adults can become dis-
abled. 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 ap-
pear to be synonymous with either disability or comorbid-
ity. Given the findings here, the terms appear to apply to
distinct, but related, entities and should not be used inter-
changeably.
The definition of frailty offered and validated here pro-
vides a standardized, physiologically based definition appli-
cable to the spectrum of frailty presentations seen in commu-
nity-dwelling older adults. The clear criteria (see Appendix)
are relatively easy and inexpensive to apply, and offer a ba-
sis for standardized screening for frailty and risk of frailty in
older adults. They can, potentially, be used to establish clini-
cal 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 uti-
lized 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 demo-
graphic characteristics available in this cohort for use in un-
derstanding 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 Cauca-
sians). In this same issue, we separately examine the associ-
ation of frailty with cardiovascular diseases (51).
Overall, these findings provide support for the hypothe-
ses of a physiologic cycle of frailty (14) that serves as the
basis for the phenotype considered here (Figure 1). This in-
corporates prior research demonstrating pairwise associa-
tions between each two components in the cycle (18—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—16) and our findings and others propos-
als (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 ex-
plain the more subtle biologic underpinnings of decreased
reserves and ability to maintain homeostasis (11—13), which
may be latent prior to an insult, but be a basis for vulnerabil-
ity to stressors (10,11,14). Further understanding of the ba-
sis 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 as-
sociated 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).
Acknowledgments
This study was supported by contracts N01-HC-85079, N01-HC-85080,
N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-
HC-85085, N01-HC-85086, and N01-HC-15103 from the National Heart,
Lung, and Blood Institute (NIH), Bethesda, MD.
The authors thank Ray Burchfield for manuscript preparation and Carol
Han for her assistance in development of figures. The opinions and asser-
tions expressed herein are those of the authors and should not be construed
as reflecting those of the Uniformed Services University of the Health Sci-
ences or of the U.S. Department of Defense.
Table 8. Association of Intermediate Status at Baseline With
Frailty Status at Follow-up*
Baseline Status
Intermediate vs No Frailty
Using Both Cohorts
(n 5 3882)
Intermediate vs No Frailty
Only Cohort 1
(n 5 3546)Incident Frailty
Unadjusted OR 5 4.51
CI 5 (3.39,6.00)
p , .0001
OR 5 4.29
CI 5 (3.19,5.78)
p , .0001
Covariate Adjusted

OR 5 2.63
CI 5 (1.94,3.56)
p , .0001
OR 5 2.42
CI 5 (1.76,3.32)
p , .0001
Note: OR 5 odds ratio of intermediate frailty group (at baseline) becoming
frail, relative to the not frail group; CI 5 confidence interval.
*Logistic regression predicting frailty, assessing subjects from both cohorts
who were alive and evaluable at follow-up. Follow-up was after 3 years for Co-
hort 1 and 4 years for Cohort 2.

Adjusting for covariates (described in Methods and bottom of Table 7).

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Address correspondence to Dr. Linda P. Fried, Director, Center on Ag-
ing and Health, The Johns Hopkins Medical Institutions, 2024 East Monument
Street, Suite 2-700, Baltimore, MD 21205. E-mail: lfried@welch.jhu.edu
Address correspondence to Dr. Richard Kronmal, CHS Coordinating
Center, Century Square Building, 1501 4th Avenue, Suite 2105, Seattle,
WA 98101.
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Received June 30, 2000
Accepted September 19, 2000
Decision Editor: John E. Morley, MB, BCh
Appendix
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) 5 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 5 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 5 rarely or none of the time (,1 day), 1 5 some or a little of the time (1—2 days), 2 5 a
moderate amount of the time (3—4 days), or 3 5 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).
Men Cutoff for Time to Walk 15 feet criterion for frailty
Height # 173 cm $7 seconds
Height . 173 cm $6 seconds
Women
Height # 159 cm $7 seconds
Height . 159 cm $6 seconds
¥ Grip Strength, stratified by gender and body mass index (BMI) quartiles:
Men Cutoff for grip strength (Kg) criterion for frailty
BMI # 24 #29
BMI 24.1—26 #30
BMI 26.1—28 #30
BMI . 28 #32
Women
BMI # 23 #17
BMI 23.1—26 #17.3
BMI 26.1—29 #18
BMI . 29 #21

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PHENOTYPE OF FRAILTY M157

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