AMERICAN JOURNAL OF EPIDEMIOLOGY Vol. 132, No.

4
Copyright © 1990 by The Johns Hopkins University School of Hygiene and Public Health Printed in U.S A.
All rights reserved

A META-ANALYSIS OF PHYSICAL ACTIVITY IN THE PREVENTION

OF CORONARY HEART DISEASE
JESSE A. BERLIN12 AND GRAHAM A. COLDITZ13

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Berlin, J. A. (U. of Pennsylvania School of Medicine, Clinical Epidemiology Unit,
Philadelphia, PA 19104-6095), and G. A. Colditz. A meta-analysis of physical
activity in the prevention of coronary heart disease. Am J Epidemiol 1990; 132:612-
28.
Evidence for an independent role of increased physical activity in the primary
prevention of coronary heart disease has grown in recent years. The authors
apply the techniques of meta-analysis to data extracted from the published
literature by Powell et al. (Ann Rev Public Health 1987;8:253-87), as well as more
recent studies addressing this relation, in order to make formal quantitative
statements and to explore features of study design that influence the observed
relation between physical activity and coronary heart disease risk. They find, for
example, a summary relative risk of death from coronary heart disease of 1.9
(95% confidence interval 1.6-2.2) for sedentary compared with active occupa-
tions. The authors also find that methodologically stronger studies tend to show
a larger benefit of physical activity than less well-designed studies.

coronary disease; exercise; meta-analysis

Evidence for an independent role of in- reviews (1-8) the authors have concluded
creased physical activity in the primary that physically active people are at lower
prevention of coronary heart disease has risk for coronary heart disease than those
grown in recent years. In most recent major who are inactive. Recently, Powell et al. (9)
produced a thorough review of this topic,
combining approaches that had been used
Received for publication February 17, 1989, and in in earlier reviews. In their review, they
final form March 7, 1990
1
Technology Assessment Group, Harvard School
present extensive tables that document
of Public Health, Boston, MA. study characteristics, including an overall
2
University of Pennsylvania School of Medicine, rating of study quality, and summarize the
Section of General Internal Medicine, Clinical Epi- relative risk information reported for each
demiology Unit, Philadelphia, PA.
3
Channing Laboratory, Harvard Medical School, of the studies. The authors stop short, how-
Boston, MA. ever, of using formal techniques of meta-
Reprint requests to Dr. Jesse A. Berlin, University analysis to make quantitative summary
of Pennsylvania School of Medicine, Clinical Epide-
miology Unit, 331 R Nursing Education Building, statements about the relation between
Philadelphia, PA 19104-6095. physical activity and the incidence of cor-
This work was supported by research grant onary heart disease. A subsequent work
HS05936 from the National Center for Health Ser-
vices Research and Health Care Technology Assess- (10), concluding that exercise is an econom-
ment and by HL 35464 from the National Institutes ically favorable risk-reduction strategy
of Health. when compared with other preventive or
The authors wish to thank Drs. Kenneth Powell,
Sander Greenland, and Moyses Szklo for helpful com- therapeutic interventions for coronary
ments on earlier versions of this paper. Unpublished heart disease, used a median relative risk
data were kindly provided by Ralph D'Agostino and presented by Powell et al. (9) in making
Albert Belanger for the Framingham Study and by calculations. In this paper, we apply the
Paul Sorlie for the Puerto Rico Heart Health Program.

612
 META-ANALYSIS OF PHYSICAL ACTIVITY AND CORONARY HEART DISEASE
techniques of meta-analysis to the data col-
lected by Powell et al., as well as more
recent studies addressing this relation, in
order to make more formal quantitative
statements and to explore features of study
design that may influence the observed re-
lation between physical activity and coro-
nary heart disease.
Meta-analysis has been defined as "the
statistical analysis of a collection of ana-
lytic results for the purpose of integrating
the findings" (11). Although many of the
applications of meta-analysis have been in
the social sciences, it has gained greater
popularity as a tool for summarizing the
results of randomized controlled trials of
medical and surgical therapies (12).
MacMahon and Hutchison (13) used tech-
niques of meta-analysis to combine epide-
miologic data on intra-uterine exposure and
risk of leukemia in 1964. More recently,
meta-analytic methods have again been
used in the review of epidemiologic studies
of the relations between occupational ex-
posures or life-style characteristics and dis-
ease (14-16). We apply the techniques de-
veloped in these earlier quantitative
reviews to the analysis of the relative risk
information reported in studies of the re-
lation between physical activity and coro-
nary heart disease. Specifically, we address
the question of whether physical activity
relates to coronary heart disease and ex-
amine study characteristics that may influ-
ence conclusions on this question in indi-
vidual investigations.
METHODS
Several major sources of variability
among the studies of physical activity and
coronary heart disease must be addressed
before combining the published results.
Some studies involve activity levels at
work, and others focus on leisure-time ac-
tivity or a combination of work and leisure
activity levels. Using these different defi-
nitions of physical activity may be mea-
suring quite different levels of energy ex-
penditure over varying periods of time.
613
Such differences could have quite marked
physiologic effects. We therefore separate
these two general types of activity. We ad-
dress this issue in our primary analysis by
pooling results separately from studies of
work-related activity and studies of leisure-
time activity. The few studies that use both
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work and leisure activity are grouped with
the leisure studies, leaving the occupational
studies as a distinct group (9).
Even within a given type of activity, the
actual degree of activity, especially for the
so-called "physically active" group, varies
from study to study. Paffenbarger et al.
(17), in an earlier review, suggest that the
reason that some studies fail to show a
protective relation between activity and
coronary heart disease lies in insufficient
differences in actual activity level between
the "active" and "inactive" groups under
study.
This lack of differential activity levels
might be problematic when both active and
inactive groups are highly active or when
both groups are inactive. Some studies in-
cluded in the review by Powell et al. present
separate relative risk estimates for a "mod-
erate" activity comparison group and a
"sedentary" comparison group, with the
"highly active" group as the reference for
both. We provide summary relative risks,
therefore, for three sets of studies. In the
first summary, we combine the relative
risks from the comparisons of the vigorous
activity groups with the moderate activity
groups, for only those studies that present
separate relative risks for moderate and
sedentary comparison groups. In the second
summary, we combine the relative risks
from the studies that do not separate mod-
erate from sedentary comparison groups.
In the third summary, we combine the rel-
ative risks from the studies that separate
moderate and sedentary comparison
groups, using only the sedentary groups.
These separate analyses serve, in effect, as
an assessment of a dose-response relation
between activity level and risk for coronary
heart disease.
614 BERLIN AND COLDITZ
An additional obstacle to pooling the re-
sults from the individual studies is the va-
riety of coronary heart disease outcomes
reported from the previous studies. These
include coronary heart disease incidence,
coronary heart disease death, myocardial
infarction, myocardial infarction plus sud-
den death combined, angina pectoris, and
congestive heart failure (usually combined
with another category). For most studies
that report a relative risk for lack of phys-
ical activity with respect to total coronary
heart disease, the relative risk includes the
information on all of the separate outcomes
combined. The etiology of these different
categories of coronary disease may differ,
as may the contribution of physical activ-
ity. We address this issue by developing
separate summaries reflecting different lev-
els of disease severity: coronary heart dis-
ease incidence, coronary heart disease
death, myocardial infarction, myocardial
infarction and sudden death combined, and
angina pectoris.
Assessment of study quality
To explore the relation between study
quality and study outcome, we developed a
scoring system for quality. We based this
directly on data provided by Powell et al.
(9), who describe in detail their assessment
of the quality of three components of study
design: measurement of activity, measure-
ment of disease status, and epidemiologic
methods. For each article, these authors
described the quality of each component
and assign a quality of "unsatisfactory,"
"satisfactory," or "good." We assigned a
value of 0 to the rating unsatisfactory, 1 to
satisfactory, and 2 to good, for each of three
components, and summed the scores for
each study to produce a total quality score
which can range from 0 to 6. For example,
a study with ratings of unsatisfactory for
activity assessment and good for both other
components was given a score of 4 (0 + 2
+ 2 = 4) (e.g., references 18, 19).
We also developed a second, more objec-
tive, quality score, based on ratings of sep-
arate sub-components for each of the three
major components of quality. Powell et al.
describe seven separate desirable features
of a physical activity measure, four desir-
able components of a coronary heart dis-
ease measure, and five desirable aspects of
the epidemiologic methods, for a total of 16
components. The authors rated each com-
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ponent in each study as to its presence or
absence with a " •" for "no or uncertain," a
"+" for present "in part," and a "++" for
"yes." We awarded a single point for every
"+" appearing (thus, a "++" rating received
two points). The possible scores on this
scale, then, ranged from 0 to 32. It was not
uncommon for two studies with the same
objective score for a component to receive
different ratings from Powell et al. For
example, one study (20) reported on two
cohorts of workers in London: postal work-
ers and busmen. The subscores for the
physical activity measure on both cohorts
were 4 out of a possible 14, yet the measure
for the postal workers was rated unsatisfac-
tory while the measure for busmen was
rated satisfactory.
Statistical methods
To pool relative risks from several stud-
ies, we adapted a method developed for
combining event rate differences in clinical
trials (11). This method has previously
been used to combine standardized mortal-
ity ratios from occupational cohort studies
(15). Because the log scale is symmetric
and the variance of the log relative risk is
well understood, we first take the log of the
relative risk before combining results from
the individual studies.
The pooling method gives essentially a
weighted average of the log relative risks
from the individual studies, where the
weight depends, in part, on the inverse of
the variance of the log relative risk (11). In
effect, larger studies are given more impor-
tance in the summary measure than smaller
studies. This random effects method, how-
ever, allows for heterogeneity among study
results that may remain, even after strati-
 META-ANALYSIS OF PHYSICAL ACTIVITY AND CORONARY HEART DISEASE
fication on type of activity (work vs. lei-
syre), outcome (coronary heart disease, cor-
onary heart disease death, etc.), degree of
activity (moderate vs. sedentary), and qual-
ity score. That is, it does not assume ho-
mogeneity of relative risks across studies.
Heterogeneity may result, for example,
when study populations, activity levels (or
their measurement), or epidemiologic
methods vary extensively from study to
study. Substantial heterogeneity may re-
main, however, even after stratification on
important study attributes. The method we
use produces a relatively larger variance
(and, hence, wider confidence intervals) for
summary estimates of heterogeneous stud-
ies than for summaries of homogeneous
studies. This should seem intuitively rea-
sonable, since we would not expect to have
the same confidence in a summary of very
diverse results as we have in one of very
similar results. The technique is analogous
to the widely used Mantel-Haenszel
method (21) for combining odds ratios. An
exception is that the Mantel-Haenszel
method assumes homogeneous odds ratios
and does not compensate for heterogeneity
by building wider confidence intervals. We
perform and include results from a chi-
square test for heterogeneity along with all
summary estimates. It is important to be
aware that summarization in the presence
of extreme heterogeneity may be somewhat
misleading and certainly does not obviate
the need to explore the sources of the het-
erogeneity.
To examine further the hypotheses that
aspects of study design are related to study
results, we performed weighted least
squares, fixed effects regressions of the log
relative risk on several study attributes.
These were: whether the relative risk was
adjusted for at least age or not, whether the
study measured work or leisure activity
(both kinds of studies were included in a
single analysis), and each quality score,
subjective and objective, separately. We
also performed regressions using the sepa-
rate components of each of the quality
615
scores: assessment of disease, measurement
of activity, and epidemiologic methods. The
weight assigned to each study was the in-
verse of the variance of the log relative risk.
For each study, we chose only one out-
cqme to include in the regression model (so
as to maintain independence among obser-
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vations, which is one of the major assump-
tions of regression). In order of preference,
the outcome chosen from a study was cor-
onary heart disease, coronary heart disease
death, or myocardial infarction and sudden
death together. Studies that did not exam-
ine one of these three outcomes were not
included in this analysis. We estimated pa-
rameters for the model with all three main
effects terms, the three models with all
pairs of main effects, and the three univar-
iate models.
Several specific rules were adopted for
combining results. When more than one
published report was generated using the
same cohort and the same outcome, only
the most recently published results were
used. For example, two studies pf occupa-
tional activity both reported on the same
outcomes in the same cohort (20, 22). If
earlier studies reported on an outcome not
examined in a later study of the same co-
hort, the result from the earlier study was
used only for the relevant outcome (e.g.,
references 20 and 22, 23 and 24). To use as
much of the available information as pos-
sible, we included studies that reported on
women separately (25, 26). We recognize
that results for men and women may differ,
but the number of studies that included
only women was inadequate to examine
this hypothesis. For the studies of "various"
kinds of activity, we tried to approximate
"total activity" by using the combined
"work and leisure" results when these were
available from a study for a particular out-
come (26-28). For some studies and some
outcomes, the leisure results were used in
preference to the work activity results (26,
29). Since we had already performed a sep-
arate analysis of occupational activity, we
did not wish to be redundant.
616 BERLIN AND COLDITZ
In addition to these general rules, we also
adopted some technical rules. To convert
confidence intervals into estimates of the
variance of the log relative risk, we first
transformed the interval to the log scale.
The lower endpoint was subtracted from
the upper endpoint to compute the length
of the confidence interval. Under the (ad-
mittedly convenient but not always true)
assumption that the 95 percent confidence
interval had been constructed by adding
and subtracting 1.96 times the standard
error of the log relative risk, we divided the
interval length by 3.92 to obtain an approx-
imate standard error. This was then
squared to provide an estimate of variance.
This procedure was modified for the few
90 percent confidence intervals that were
provided.
For several studies, only a relative risk
and a p value were provided. The p value
was first converted to the corresponding
two-sided z statistic (from a table of stan-
dard normal variates). Assuming that the
log relative risk is approximately normally
distributed, we set the calculated z statistic
equal to the log relative risk divided by its
unreported standard error. The simple
equation could then be solved for the stan-
dard error. In cases where the p value was
reported, for example, as "p < 0.05," we
made the most conservative assumption
that the p value was equal to 0.05, and
would assign a z statistic of 1.96.
Some studies included in review by
Powell et al. (9) were excluded from our
analysis because they did not report a rel-
ative risk or a confidence interval or both.
This meant that we excluded the only two
studies (the Framingham Study and the
Puerto Rico Heart Health Program) in-
cluded by Powell et al. that would have
received a quality score of 6 (30, 31). We
were able to obtain unpublished data from
the authors of both of those studies for
inclusion in a separate analysis.
By using a MEDLINE search and by
checking the reference lists of those papers
already retrieved, we found several studies
of nonoccupational activity that have ap-
peared since the publication of Powell et
al. (9) and that met their inclusion criteria.
In a separate analysis, these studies were
combined for the appropriate outcomes.
Because we did not feel we could exactly
replicate the scoring system used by Powell
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et al., we did not include the most recent
studies in the stratified analyses involving
measurement of quality scores. These stud-
ies were, however, included in several
regression analyses by treating their quality
scores as missing data. An indicator vari-
able for presence of the quality score (0 =
absent, 1 = present) was entered, along
with a product term of this indicator and
the quality score, with no main effect for
quality score.
RESULTS
Summaries of the characteristics of and
findings from 27 cohorts in which the re-
lation between physical activity and coro-
nary heart disease was investigated appear
in table 1 (occupational activity) and table
2 (other forms of activity). The data in
these tables represent the unique results
reported from cohorts for which estimates
of the relative risk for lack of physical
activity were accompanied by either confi-
dence intervals or p values. The eight re-
cently published studies that we identified
are included in table 2 without quality
scores.
The quality scores of the studies of non-
occupational activity tend to be higher than
those of the occupational studies, particu-
larly with respect to the evaluation of ac-
tivity level. All of the nonoccupational
studies have either a good or satisfactory
rating for the activity evaluation; only six
of 18 occupational studies have such mea-
sures of activity. The objective quality score
was higher, on average, in the nonoccupa-
tional studies as well. Not surprisingly, be-
cause the presence of statistical adjustment
formed part of that rating scale, the objec-
tive quality score was higher for studies
 META-ANALYSIS OF PHYSICAL ACTIVITY AND CORONARY HEART DISEASE 617

that used adjustment than for those that

did not.
We first pooled the relative risk for each
cardiovascular outcome for high activity
compared with moderate activity and for <U CO O

high activity compared with low activity

when comparison groups were separated by

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activity level in the original studies. In a t?
third analysis, we pooled the relative risks £3 8
CO
for those studies that presented only a sin-
gle comparison. We pooled studies sepa-
rately within the occupational and nonoc- Q)
C C a, B S B
<U Q)

O O So O O O
cupational activity categories (see tables
zz < zzz
3-5). In these tables, we report the chi-
square statistic from the test for heteroge-
neity of relative risks for each pooled rela-
tive risk.
•2
Several patterns emerge from the data. -S
o
Many of the pooled relative risks are sta- c
o
tistically significant and accordingly their
confidence intervals exclude 1.0. Statistical a) o> a>
2 §
significance is not generally apparent using 2 2 2

the moderate comparison groups for occu- al ss s §3

pational activity. The summaries of studies

reporting on angina pectoris are consist- 3 1
ently not statistically significant. The com-
bined results from comparisons with a mod- E S2
erate activity group give lower relative risks CO O c SS

than those produced by pooling studies

with sedentary or mixed comparison groups
for each cardiovascular outcome. These re-
sults are consistent with an inverse dose-
Q
response relation; increasing physical ac- X
o
tivity is associated with a decrease in risk
of coronary heart disease.
Several recent studies, not included in
Powell et al. (9), are included in the sum-
mary relative risks for coronary heart dis-
ease and coronary heart disease death in
table 5. The addition of a substantial num-
ber of new studies to these analyses does
not materially alter the pooled relative
civi serv
snq •

U
Q.
risks, although the confidence intervals g
spo

0)
tend to be narrower when more studies are 11 c to
c
o
pooled. When unpublished data from the « a
aj

Framingham and Puerto Rico studies are c s,

•§
c < 0}
included in the summary of coronary heart 3 V
CO

disease incidence, the pooled relative risks

are 1.1 (95 percent confidence interval (CI)
 TABLE 1—Continued
Occupational cohort studies used in the meta-analysis*
oo
High activity Low activity Subjective Objective
Cohort Cohort Relative risk
Outcomef Adjustments quality quality
(reference no.) size group group (95% CI$)
score§ score 1|
US railroad workers (34, 35) 191,609 CHD death Section men Switchmen 1.4 (1.1-1.7) Age 3 18
Clerks 2.0 (1.7-2.5)
CHD death Switchmen Sedentary clerks 1.2 (0.6-2.4) Age 5 21
MI, SD 1.1 (0.5-2.4) Age
AP 1.2 (0.7-1.9) Age
North Dakota residents (36) 20,000 MI, SD Farmers Nonfarmers 1.8 (1.2-2.7) Age 2 15
AP, coronary 1.3 (0.8-2.1)
insufficiency
Chicago Utility company em- 784 CHD, CHF Work, medium Sedentary 1.1 (0.6-2.2) Age 2 15
ployees (37) and light
Washington, DC postal work- 1,664 CHD death Letter carriers Postal clerks >5 2.8 (1.0-7.8) Age 4 19
ers (38) &5 years on years on job
job
Yugoslavia residents (39, 40) 1,371 CHD Work, heavy Moderate 1.4 (0.6-3.6) None 3 14
Sedentary 1.9 (0.9-4.0)
Italy residents (18, 19) 1,712 MI, SD Work, heavy Moderate 1.8 (0.8-4.1) None 4 16 3
Sedentary 3.1 (1.2-7.5) 50
Greek islands residents (41, 42) 1,215 CHD Work, heavy Moderate 1.2 (0.4-3.6) None 3 14 r
Sedentary 2.0 (0.6-6.0) z
Italian railroad employees (43) 172,459 CHD death Work, heavy Moderate 1.9 (1.3-2.8) Age 3 17 >
Sedentary 1.6 (1.2-2.1) Z
Israeli kibbutzim male resi- 5,288 AP Work, less than At least 80% 2.6 (1.8-3.6) Age 4 19 a
dents (25) MI 80% seated seated 2.5 (1.8-3.4) Age o
CHD death 2.0 (1.2-3.3) Age o
Israeli kibbutzim female resi- 5,229 AP Work, less than At least 80% 3.5 (2.1-6.0) Age D
dents (25) MI 80% seated seated 1.8 (0.6-5.1) Age
CHD death 3.0 (0.3-29.4) None
East Finland residents (44) 671 CHD death Work category 4 Category 3 0.7 (0.3-1.6) None 2 14
(most active) Category 1 1.1 (0.4-3.1)
West Finland residents (44) 721 Category 3 1.1 (0.2-8.4) None 2 14
Category 2 2.4 (0.3-18.5)
(none in cate-
gory 1)
San Francisco longshoremen 3,975 CHD death Work, heavy Moderate and 1 6 (1.2-2.2) Age 5 23
(45, 46) tasks requir- light tasks
ing >5 kcal/ (£5 kcal/min)
min
• Adapted from Powell et al. (9).
t Abbreviations: AP) angina pectoris; CHD, coronary heart disease; CHF, congestive heart failure; MI, myocardial infarction; SD, sudden death.
t CI, confidence interval.
§ Subjective quality scores were based on assessments of quality by Powell et al. (9) of three components of study design: measurement of activity, measurement of disease
status, and epidemiologic methods. Each component was rated as "unsatisfactory," "satisfactory," or "good" by these authors. We assigned numerical values of 0, 1, or 2 to
the three levels of quality, respectively. Thus, the subjective scores could range from 0 to 6.
|| Objective quality scores were based on ratings by Powell et al. (9) of separate subcomponents for each of the three major components of study design. Possible values
of the objective score ranged from 0 to 32.
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 Nonoccupational cohort studies used in themeta-analysis
Subjective Objective
Cohort Cohort High activity Relative risk quality
Outcomet Low activity group Adjustments§ quality
(reference no.) size group (95% CIt) score || scoreU
Chicago Western Electric 1,989 CHD Leisure, sport Nonparticipant 2.0 (1.3-3.0) None 3 14
employees (47) participant
Harvard alumni (24) 16,936 CHD >2,000 kcal/wk <2,000 kcal/wk 1.6 (1.2-2.1) Age 4 21
in leisure ac- s
tivity
CHD death >2,000 kcal/wk 500-1,999 kcal/wk 1.3 (1.0-1.7) Age, BP, SM
(ref. #23) in leisure ac-
tivity
CHD death >2,000 kcal/wk <500 kcal/wk 1.6 (1.2-2.2) Age, BP, SM >
(ref#23) in leisure ac- CO
tivity
Nonfatal >2,000 kcal/wk <2,000 kcal/wk 1.3 (1.0-1.7) Age O
MI in leisure ac-
tivity •n
"0
AP £2,000 kcal/wk <2,000 kcal/wk 1.9 (1.2-3.0) Age «<
CO
in leisure ac-
tivity
British civil servants (48, 49) 17,944 CHD death Vigorous exercise No vigorous exer- 2.6 (1.5-4.6) Age 5 23 O
sports cise sports
Los Angeles firemen and po- 2,779 MI, SD Above median Below median car- 2.4 (1.1-5.9) Age, BP, CH, SM, 5 23
licemen (50) cardiovascular diovascular fit- other o
fitness ness
Gothenberg, Sweden resi- 8,125 MI, SD Above median Below median car- 2.3 (1.4-4.0) Age, BP, CH, SM 3 22
dents (51) cardiovascular diovascular fit- >
fitness ness z
New York health insurance 61,000 CHD, CHF, Work and lei- 3 least active cate- 1.7 (1.3-2.2) Age 4 18
a
subscribers (27) conduction sure, 13 most gories o
o
defects active cate-
gories
AP Work and lei- 9 least active cate- 0.7 (0.5-1.1) Age 16
I>
sure, 7 most gories
active cate-
gories
San Francisco corporate em- 3,154 CHD Leisure, regular Occasional or no ac- 1.5 (1.1-2.1) Age 3 18 I
ployees (29) activities tivities
San Francisco Federal em- 1,741 CHD Multiple regression on total daily calo- 1.2 (0.9-1.7) Age, BP, CH, SM 4 18
ployees (29) ries from work and leisure CO

North Karelia, Finland male 3,978 CHD death High leisure Low leisure 1.4 (0.9-2.2) Age, BP, CH, SM, 5 20
residents (26) other
a
MI High work and High/low or low/ 1.3 (1.0-1.7) Age 1
high leisure high
High work and Low/low 2.5 (1.8-3.7) Age
high leisure
North Karelia, Finland fe- 3,688 MI High work and High/low or low/ 1.8 (0.9-3.5) Age 5 20
male residents (26) high leisure high
Low/low 4.0 (2.1-7.8) Age
Western Finland residents 15,088 CHD Work and leisure Low activity 1.4 (1.1-1.7) Age, BP, SM, CH,
(52) high activity other
Fable continues I
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 TABLE 2—Continued
Nonoccupational cohort studies used in the meta-analysis*
Subjective Objective
Cohort Cohort High activity Relative risk quality
Outcomet Low activity group Adjustments? quality
(reference no.) size group (95% CI+) score || scorell
Lipid Research Clinics Prev- 4,276 CHD High physical Low fitness 2.7 (1.4-5.1) Age, BP, CH, SM,
alence Study Participants fitness based other
(53) on exercise
test
MRFIT trial participants 12,138 CHD death Upper tertile Lowest tertile 1.5 (1.09-2.04) Age, BP, CH, SM,
(54) MI physical fit- 1.2 (1.04-1.43) other
ness
Oslo, Norway residents (55) 2,014 CHD death Upper quartile of Lowest quartile 4.8 (2.2-10.7) Age
physical fit-
ness
Middle two quar- 1.5 (0.6-3.8) Age
tiles
US railroad workers (56) 3,043 CHD death Upper (fourth) Lowest quartile 1.28 (0.99-1.63) Age, BP, CH, SM
quartile of Third quartile 1.05 (1.00-1.11)
kcal/expendi-
ture w
Belgian physical fitness 2,363 CHD Upper quartile of Lowest quartile 0.69 (0.25-1.93) None
study participants (57) leisure activity
Middle two quar- 0.90 (0.40-2.04)
tiles
Finnish men (58) 636 CHD death High total Light and sedentary 1.3 (0.89-1.89) Age, BP, CH, SM, o
other o
Honolulu heart study partic- CHD Upper tertile of Lowest tertile Age, SM, other s
ipants (59) total activity Middle tertile
Ages 45-64 7,221 1.45 (1.14-1.89)
Ages 65+ 423 2.33 (1.01-5.26)
Framingham, Massachusetts 4,121 CHD Work and lei- Low activity 1.27 (1.01-1.61) Age, sex 6 26
residents (30, 60)** sure, high ac-
tivity
Moderate activity 1.20 (1.00-1.44)
Puerto Rico residents (31)tt 8,838 CHD Framingham ac- Lowest tertile 1 41 (1.04-1.91) Age 6 26
tivity indexes
upper tertile
Middle tertile 0.95 (0.67-1.37)
* Adapted from Powell et al. (9).
t Abbreviations: AP, angina pectoris; CHD, coronary heart disease; CHF, congestive heart failure; MI, myocardial infarction; SD, sudden death.
$ CI, confidence interval.
§ Abbreviations: BP, blood pressure; CH, cholesterol; SM, smoking.
|| Subjective quality scores were based on assessments of quality by Powell et al. (9) of three components of study design: measurement of activity, measurement of disease
status, and epidemiologic methods. Each component was rated as "unsatisfactory," "satisfactory," or "good" by these authors. We assigned numerical values of 0, 1, or 2 to
the three levels of quality, respectively. Thus, the subjective scores could range from values 0 to 6.
11 Objective quality scores were based on ratings by Powell et al. (9) of separate subcomponents for each of the three major components of study design. Possible values of
the objective score ranged from 0 to 32.
** Unpublished data provided by R. D'Agostino and A. Belanger and analyzed by the authors using logistic regression.
t t Unpublished data provided by P. Sorlie and analyzed by the authors using logistic regression.
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 META-ANALYSIS OF PHYSICAL ACTIVITY AND CORONARY HEART DISEASE 621
TABLE 3 risk of 1.6 for the five occupational activity
Pooled relative risks from studies of occupational studies with mixed comparison groups is
activity and risk of heart disease not very close to the null. If we compute
Outcome*
No. of Relative risk x'for the simple, inverse-variance weighted av-
studies (95% CI) heterogeneity} erages of the same five angina studies, ig-
A. Relative risks for high activity compared with noring heterogeneity, the pooled relative
moderate activity groups from studies that reported risk is 1.9 (95 percent CI 1.5-2.3). Because

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both moderate and sedentary comparison groups this confidence interval excludes 1.0, we
CHD 4 1.1 (0.9-1.3) 2.79
CHD death 5 1.4 (1.2-1.8) 5.09 might draw much different qualitative con-
MI 1 1.3 (0.9-1.9) clusions from the pooling method that ig-
MI + SD 1 1.8(0.8-4.1) nores heterogeneity among studies. The in-
AP 1 0.6(0.4-0.9) clusion of 1.0 in the random effects
confidence interval implies only that the
B. Relative risks for high activity compared with low
activity groups from studies that did not separate
mean relative risk may be null, but it may
moderate and sedentary comparison groups still be implausible that all of the individual
CHD 2 1.4 (0.9-2.3) 1.10
CHD death 6 1.5 (1.1-2.0) 11.45 TABLE 4
MI 3 2.4 (1.8-3.2) 0.35
Pooled relative risks from studies of nonoccupational
MI + SD 2 1.6 (1.0-2.4) 1.20
AP 5 1.6 (0.9-2.7) 22.49 activity and risk of heart disease, including only those
studies reviewed by Powell et al. (9)
C. Relative risks for high activity compared with sed- No. of Relative risk x2 for
entary groups from studies that reported both moder- Outcome* studies (95% Clf) heterogeneity}
ate and sedentary comparison groups
A. Relative risks for high activity compared with
CHD 4 1.4 (1.0-1.8) 3.31 moderate activity groups from studies that reported
CHD death 5 1.9 (1.6-2.2) 2.89 both moderate and sedentary comparison groups
MI 1 1.4 (0.9-2.1) CHD No studies
MI + SD 1 3.1 (1.2-7.5) CHD death 1 1.3 (1.0-1.7)
AP 1 0.8(0.5-1.2) MI 2 1.4 (1.1-1.7) 0.77
* Abbreviations: AP, angina pectoris; CHD, coro- MI + SD No studies
nary heart disease; MI, myocardial infarction; SD, AP No studies
sudden death.
t CI, confidence interval. B. Relative risks for high activity compared with low
$ Degrees of freedom for x2 are one less than the activity groups from studies that did not separate
number of studies. moderate and sedentary comparison groups
CHD 5 1.6 (1.3-1.8) 4.47
CHD death 2 1.9 (1.0-3.4) 2.87
1.0-1.3) for moderate comparison groups MI 1 1.3 (1.0-1.7)
and 1.3 (95 percent CI 1.1-1.5) for seden- MI + SD 2 2.3 (1.5-3.6) 0.01
tary comparison groups. These studies were AP 2 1.1 (0.4-3.0) 11.90
not included in the analysis of the studies
reviewed by Powell et al. (9) because the C. Relative risks for high activity compared with sed-
entary groups from studies that reported both moder-
original published reports did not provide ate and sedentary comparison groups
the requisite data. CHD No studies
Heterogeneity among the studies that we CHD death 1 1.6 (1.2-2.2)
combined is fairly high for some analyses. MI 2 2.9 (1.9-4.5) 1.51
Extremely high heterogeneity is evident in MI + SD No studies
AP No studies
the two summaries of angina pectoris re-
sults that include more than one study. * Abbreviations: AP, angina pectoris; CHD, coro-
Both are characterized by highly significant nary heart disease; MI, myocardial infarction; SD,
sudden death.
heterogeneity and by confidence intervals t CI, confidence interval.
that include the null value of 1.0. This is of X Degrees of freedom for x 2 are one less than the
note since the point estimate of relative number of studies.
622 BERLIN AND COLDITZ
TABLE 5
Pooled relative risks from studies of nonoccupational
activity and risk of heart disease, including recent
studies not reviewed by Powell et al. (9) (only those
outcomes for which new studies were published are
summarized)
No. of Relative risk x2 for
Outcome*
studies (95% CIt) heterogeneity^
A. Relative risks for high activity compared with
moderate activity groups from studies that reported
both moderate and sedentary comparison groups
CHD 1 0.9 (0.4-2.0)
CHD death 3 1.1 (1.0-1.3) 2.94
B. Relative risks for high activity compared with low
activity groups from studies that did not separate
moderate and sedentary comparison groups
CHD 9 1.5(1.4-1.7) 9.32
CHD death 3 1.6(1.1-2.4) 4.31
C. Relative risks for high activity compared with sed-
entary groups from studies that reported both moder-
ate and sedentary comparison groups
CHD 1 0.7 (0.3-1.9)
CHD death 4 1.7 (1.2-2.3) 10.04
MI 3 2.1(1.1-4.4) 23.33
* Abbreviations: CHD, coronary heart disease; MI,
myocardial infarction.
t CI, confidence interval.
t Degrees of freedom for x2 a r e one less than the
number of studies.
effects are null. The fixed effect confidence
interval, which excludes 1.0, implies that it
is, in fact, unlikely that all of the study-
specific relative risks (the individual ran-
dom effects) are 1.0.
We next explored the impact of study
design on the relative risk observed by the
original investigators. We first categorized
the studies into two groups, higher quality
scores (from 3 to 5) and lower quality scores
(0 to 2). With only one exception, when we
pool occupational studies using coronary
heart disease, coronary heart disease death,
or angina pectoris separately according to
quality score, we observe higher relative
risk estimates for all outcomes among the
studies with higher quality scores than
among those with lower quality scores (ta-
ble 6). A further effect of separating studies
on the basis of quality score is a reduction
of the heterogeneity. For all of the pooled
relative risks for the coronary heart disease
outcomes, the heterogeneity is reduced to
very low levels, suggesting that some of the
heterogeneity of outcomes in the overall
pooled estimates resulted from an associa-
tion between quality score and outcome.
For angina pectoris, heterogeneity is low
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for the studies with lower quality scores
after stratification. The heterogeneity
among the higher quality score studies is
still quite high (x 2 for heterogeneity = 9.46,
2 degrees of freedom, p = 0.009), but it
might arguably be considered less statisti-
cally significant compared with the unstrat-
ified result (x 2 = 22.49 on 4 degrees of
freedom, p = 0.0002). Overall, the pooled
relative risks for strenous physical activity
compared with sedentary, for the studies of
coronary heart disease outcomes with
higher quality scores, are in the 1.8 range,
are statistically significant, and accordingly
exclude 1.0 from their confidence intervals.
In contrast, the pooled relative risks
against sedentary comparison groups, for
the coronary heart disease studies with
lower quality scores, are in the null range.
A similar pattern holds when moderate ac-
tivity groups are used in comparisons with
the strenuous activity groups, except that
the pooled risk ratios are not as large as
those for the sedentary comparison groups
(b and c in table 6).
Regression results
The regression of the log relative risk on
various study characteristics (relative risk
adjusted or not, occupational versus other
activity, and quality score) confirms the
impression that quality score relates to
study outcome. Although all three factors
were significant predictors of the log rela-
tive risk in univariate regressions (p <
0.05), the only significant predictor in any
of the multiple regressions was quality
score, using either the subjective or the
objective measure. In the multivariate
models, the parameter estimates for quality
score were not substantially changed in
magnitude by the inclusion of other vari-
 META-ANALYSIS OF PHYSICAL ACTIVITY AND CORONARY HEART DISEASE 623

TABLE 6
Summary relative risks from studies of occupational activity and risk of coronary heart disease
incidence and death

Satisfactory! Unsatisfactoryt
Outcome* N o of Relative risk x 2 for No. of Relative risk 2
x for
studies (95% CI$) heterogeneity? studies (95% CI$) heterogeneity?
A. Relative risks for high activity compared with moderate activity groups from studies that reported both

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moderate and sedentary comparison groups
CHD 2 1.3 (0.7-2.6) 0.05 2 0.9 (0.4-1.8) 2.40
CHD death 2 1.6(1.2-2.1) 1.88 3 1.2(0.8-1.8) 2.27

B. Relative risks for high activity compared with low activity groups from studies that did not separate
moderate and sedentary comparison groups
CHD 1 1.8 (0.9-3.3) - 1 1.1 (0.6-2.2)
CHD death 5 1.7 (1.3-2.2) 2.64 1 1.1 (0.9-1.2)
AP 3 2.2 (1.3-3.9) 9.46 2 0.9 (0.3-2.2) 3.39

C. Relative risks for high activity compared with sedentary groups from studies that reported both moderate
and sedentary comparison groups
CHD 2 1.9 (1.0-3.6) 0.00 2 1.0 (0.5-2.3) 1.77
CHD death 2 1.8(1.5-2.3) 1.66 3 1.9(1.4-2.6) 1.22
* Abbreviation: CHD, coronary heart disease; AP, angina pectoris.
t Satisfactory: subjective quality score >2. Unsatisfactory: subjective quality score 0-2. Subjective quality
scores were based on assessments of quality by Powell et al. (9) of three components of study design:
measurement of activity, measurement of disease status, and epidemiologic methods. Each component was
rated as "unsatisfactory," "satisfactory," or "good" by these authors. We assigned numerical values of 0, 1, or 2
to the three levels of quality, respectively. Thus the subjective scores could range from 0 to 6. Objective scores
were based on ratings by Powell et al. (9) of separate subcomponents for each of the three major components
of study design. Possible values of the objective score ranged from 0 to 32.
t CI, confidence interval.
§ Degrees of freedom for x 2 are one less than the number of studies.

ables in the model compared with the esti- The association also held for the objective
mate from the univariate model for quality quality score (slope = 0.0457, SE = 0.0123,
score. In addition, the coefficients for the p = 0.001). The relative risk predicted using
variables other than quality score were the objective quality score would be 0.7 for
small relative to the coefficient for quality a study with an objective score of zero and
score. The regression equation, based on 3.1 for a study with a perfect objective score
27 studies, for the most parsimonious of 32. It is of note, in terms of the degree
model is: of extrapolation involved in these predicted
risks that, among the published results, the
=
°° 2 9 2 + °' 1341 * (subjective highest observed subjective score was 5 out
of a possible 6, and the highest observed
The standard error of the slope for qual- objective score was only 23 out of a pos-
ity score is 0.0273 (p = 0.0001), suggesting sible 32.
a highly significant linear relation between In multiple regressions involving the in-
quality score and log relative risk. Using dividual components of the quality scores
this equation, the predicted relative risk for and the adjustment and activity type vari-
a study with a quality score of zero is 1.0 ables, only the quality score for epidemio-
(essentially no association between physi- logic methods was a statistically significant
cal activity and risk of coronary heart dis- predictor of the log relative risk. The cri-
ease), and for a study with a quality score teria for the evaluation of epidemiologic
of 6 the relative risk is predicted to be 2.3. methods used by Powell et al. (9) included
624 BERLIN AND COLDITZ
whether physical activity status clearly pre-
ceded the period observed for outcome
events, whether the analysis was adjusted
for covariates, and whether loss to follow-
up was less than 20 percent. The fact that
the quality score contained information on
the adjustment for covariates may partially
explain why the adjustment variable was
not predictive when the quality score was
also in the model.
We performed several regressions that
included the more recent studies that were
not reviewed by Powell et al., using a miss-
ing data algorithm to take into account the
absence of quality scores for the newer
studies. The qualitative conclusions about
which covariates were predictive of relative
risk were identical to those from the models
involving fewer studies, i.e., quality score
was the only significant predictor in the
multiple regression.
DISCUSSION
The results of this meta-analysis are con-
sistent with an association between lack of
physical activity and increased risk of cor-
onary heart disease. This association is
generally stronger when the "high activity"
group in a study is compared with a sed-
entary group rather than when the compar-
ison group has a moderate activity level.
This pattern of association supports a dose-
response relation between physical activity
and protection from coronary heart disease.
This quantitative dose-response relation
supports the argument by Paffenbarger et
al. (17) that the explanation for a lack of
association between increased activity and
decreased coronary heart disease risk in
some studies is the relatively low activity
level in the so-called "active" group. It
should be noted that a lack of apparent
difference between activity groups could
also stem from measurement error that is
large relative to among-person variability
in physical activity. Nevertheless, even per-
fect measurement of activity levels that are
close together could yield no association
between lack of activity and coronary heart
disease risk.
The data we combined from previous co-
hort studies indicate that the protective
effect of physical activity lies in prevention
of the occurrence of major cardiovascular
events, rather than in the reduction of the
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severity of events that do occur. If we pool
results only from studies with higher qual-
ity scores that either employ a sedentary
comparison group or do not specify the
activity level in the comparison group, the
relative risks for both coronary heart dis-
ease and coronary heart disease death fall
in the range of 1.8. If the effect of exercise
were only to reduce the severity of events
that do occur, we would expect to see a
higher relative risk for coronary heart dis-
ease death than for overall coronary heart
disease incidence, a pattern that we do not
observe for the studies with higher quality
scores.
In support of the claim made by Powell
et al. (9), we also found that studies with
higher quality scores tend to show higher
relative risks than those with lower quality
scores. The results of our regression anal-
yses suggest that the association may be
due primarily to an association between the
quality of the epidemiologic methods used
in the studies and the log relative risk. It is
also of note, however, that the pooled rel-
ative risk of angina pectoris, the most easily
misclassified of the outcomes examined, is
not significantly elevated in any group of
studies. This suggests that misclassifica-
tion of disease may also contribute to the
reduced relative risk observed in studies
with lower quality scores.
Powell et al. defined explicit criteria for
all of their measures of study quality. For
example, to be rated highly for epidemio-
logic methods, a study had to provide evi-
dence that the physical activity status was
determined for a period prior to the onset
of coronary heart disease. Several other
reasonably objective criteria for epidemio-
logic methods had to be met. In addition,
the more objective quality score was also
 META-ANALYSIS OF PHYSICAL ACTIVITY AND CORONARY HEART DISEASE 625

predictive of study outcome. Bias in the can be explained by available covariates.

classification of coronary heart disease in Nevertheless, the random effects summary
the original studies is unlikely to explain can be appropriate for taking into account
the observed results because the associa- excess variability that remains even after
tions did not increase in magnitude with stratification on important covariates.
decreasing objectivity of the categorization The results we present, in fact, highlight
of severity of coronary heart disease (i.e., another of the strengths of meta-analysis,

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from coronary death to angina pectoris). that is, the ability to explore the sources of
Many of the studies of physical activity heterogeneity. Both stratification of studies
and heart disease, particularly the studies into those with "higher" and "lower" qual-
of occupational activity, did not or could ity scores and regression analyses in which
not adjust results for confounding variables we included components of quality score,
other than age. In several studies, however, adjustment of the data during analysis, and
results are presented with adjustment for type of physical activity, show the influence
age alone, and for age with other covariates, of quality score not only on the relative risk
including cholesterol (e.g., references 50, observed but also on the level of heteroge-
52, 54, and 56). In these studies, multivar- neity. For coronary heart disease, coronary
iate adjustment using regression methods heart disease death, and angina pectoris,
has only a small impact on either the mag- pooled results from both the "higher" and
nitude or the statistical significance of the "lower" quality studies show lower varia-
regression term for physical activity, and bility among studies than when we com-
physical activity remains an independent bined all results. The regression of log rel-
predictor of the risk of coronary heart dis- ative risk on quality score further indicates
ease even after multivariate adjustment for that the relation between quality score and
other risk factors. Thus, while it may not relative risk is both systematic and quan-
be possible to make a definitive statement tifiable.
about the role of adjustment for risk factors It is possible that the results we have
other than age, this adjustment does not observed are influenced by the selective
appear to alter our conclusions about the publication of statistically significant or ep-
protective effect of physical activity againstidemiologically popular results showing a
coronary heart disease. relation between lack of physical activity
Our analysis demonstrates the impor- and coronary heart disease. This phenom-
tance of not ignoring heterogeneity of re- enon, known as publication bias, has been
sults among component studies of a meta- discussed in the social sciences (61, 62) and
analysis. Results for several summaries, has been demonstrated to be a potentially
particularly angina pectoris, are highly het- serious problem in the reporting of cancer
erogeneous. With such high heterogeneity, clinical trials (63, 64). While it is difficult
it is clearly not advisable to use a summary to rule out publication bias in the current
estimate that assumes homogeneity of rel- situation, several factors argue against this
ative risks across studies. This is a point bias being serious:
made in most advanced epidemiologic text-
books. The angina studies conflict as to 1) Many of the studies included in the meta-
analysis, although showing relative risks favor-
whether physical activity is protective or ing exercise as a preventive measure, are not
not, a point that is apparent even without statistically significant.
statistics. Thus, even the use of a random 2) Begg and Berlin (65) show that publication
bias is more extreme for nonrandomized trials
effects summary may be deceptive in the than for randomized trials. If we believe that
case of the angina studies. Any summary part of the bias is related to poorer study quality
could be considered deceptive to the extent and the consequent reluctance by both authors
and editors to publish nonsignificant results, we
that it masks important heterogeneity that should see an inverse relation between quality
626 BERLIN AND COLDITZ
score and size of the observed relative risk. In-
stead, we see the opposite association.
3) A scatter plot of study weights against log
relative risks (not shown), similar to the "funnel
plot" that has been suggested (66) as a qualita-
tive assessment of publication bias, does not
reveal any striking evidence of publication bias.
The association between lack of physical
activity and risk of heart disease implies
that sedentary life-styles could be having a
considerable public health impact. Cardio-
vascular disease is the leading cause of
death in the United States (67). Among
adults over age 34, one study estimates that
over 60 percent are sedentary (68). This
combination of a common disease and a
common exposure suggests that a substan-
tial number of deaths from cardiovascular
disease might be avoidable.
We have presented convincing evidence
that physical activity has a protective effect
against coronary heart disease. This can
and should have great importance in setting
public health priorities and goals for future
research. We have not demonstrated that
the benefits of physical activity are inde-
pendent of levels of other risk factors for
coronary heart disease. There is evidence,
for example, presented by Paffenbarger et
al. (23), that those at low risk (e.g., college
alumni who had low systolic blood pres-
sure) may not derive as much benefit from
exercise as those at high risk. It is possible
that physical activity may modify the
harmful effects of other risk factors. Such
a subgroup analysis was not possible in this
meta-analysis because the data necessary
were not available in published reports.
Based on these data, we conclude that lack
of physical activity is a potentially modifi-
able risk factor for coronary heart disease
that should receive greater emphasis in the
current efforts to reduce the impact of dis-
ease on society.
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