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JAMA Intern Med. Author manuscript; available in PMC 2016 June 01.
Published in final edited form as:
JAMA Intern Med. 2015 June 1; 175(6): 959–967. doi:10.1001/jamainternmed.2015.0533.

Leisure Time Physical Activity and Mortality: A Detailed Pooled
Analysis of the Dose-Response Relationship

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Hannah Arem, Ph.D.1, Steven C. Moore, Ph.D.1, Alpa Patel, Ph.D.2, Patricia Hartge, Sc.D.1,
Amy Berrington de Gonzalez, D.Phil1, Kala Visvanathan, M.B.B.S., M.P.H.3, Peter T.
Campbell, Ph.D.2, Michal Freedman, J.D., Ph.D.1, Elisabete Weiderpass, M.D., M.Sc., Ph.D.
4,5,6,7, Hans Olov Adami, M.D., Ph.D.4,8, Martha S. Linet, M.D.1, I-Min Lee, M.B.B.S., Sc. D.9,*,
and Charles E. Matthews, Ph.D.1,*
1National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, MD
2American Cancer Society, Atlanta, GA 3Johns Hopkins School of Public Health, Baltimore, MD
4Karolinska Institute, Department of Medical Epidemiology and Biostatistics, Stockholm, Sweden
5Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The

Arctic University of Norway, Tromsø, Norway 6Cancer Registry of Norway, Oslo, Norway
7Department of Genetic Epidemiology, Folkhälsan Research Center, Helsinki, Finland
8Department of Epidemiology, Harvard School of Public Health, Boston, MA 9Harvard Medical
School, Boston, MA

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Abstract
Importance—The 2008 Physical Activity Guidelines for Americans recommended a minimumof 75 vigorous-intensity or 150 moderate-intensity minutes per week (7.5 metabolic equivalent
hours per week (MET h/wk)) of aerobic activity for “substantial” health benefit, and suggested“additional” benefits by doing more than double this amount. However, the upper limit oflongevity benefit or possible harm with more physical activity is unclear.
Objective—To quantify the dose-response association between leisure-time physical activity andmortality, and to define the upper limit of benefit or harm associated with more physical activity.

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Design—We pooled data from six studies in the NCI Cohort Consortium (baseline 1992–2003).
We used Cox proportional hazards regression with cohort stratification to generate multivariableadjusted hazard ratios (HR) and 95% confidence intervals (CI). Median follow-up time was 14.2
years.
Setting—Population-based prospective cohorts in the U.S. and Europe with self-reported
physical activity.
Participants—661,137 men and women (116,686 deaths); median age 62 (range 21–98) years.
Exposure—Leisure-time moderate- to vigorous-intensity physical activity

Corresponding author: Hannah Arem, M.H.S., Ph.D. Aremhe2@mail.nih.gov, NCI Shady Grove, Division of Cancer Epidemiology
and Genetics 9609 Medical Center Drive Rm 6E314, MSC 9768 Bethesda, MD 20892-9768 phone: 240-276-7204 fax: 240-276-7837.
*Contributed equally to this manuscript

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Page 2Main Outcome—Mortality

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Results—Compared to those reporting no leisure-time physical activity, we observed a 20%
lower mortality risk among those performing less than the recommended 7.5 MET h/wk minimum(HR=0.80, 95% CI 0.78–0.82), a 31% lower risk at 1–2 times the recommended minimum (0.69,
0.67–0.70), and a 37% lower risk at 2–3 times the minimum (0.63, 0.62–0.65). An upper thresholdfor mortality benefit occurred at 3–5 times the physical activity recommendation (0.61, 0.59–0.62), but compared to the recommended minimum, the additional benefit was modest (31% vs.
39%). There was no evidence of harm at 10+ times the recommended minimum (0.68, 0.59–0.78).
A similar dose-response was observed for mortality due to cardiovascular disease and to cancer.

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Conclusions and Relevance—Meeting the Guideline minimum by either moderate- orvigorous-intensity activities was associated with nearly the maximum longevity benefit. We
observed a benefit threshold around 3–5 times the recommended leisure-time physical activity
minimum, and no excess risk at 10+ times the minimum. In regard to mortality, clinicians should
encourage inactive adults to perform leisure-time physical activity and do not need to discourage
adults who already participate in high activity levels.

Introduction

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Regular physical activity has consistently been associated with a reduced risk ofmortality 1–3. However, the 2008 Physical Activity Guidelines for Americans were the firstever recommendations published by the federal government to describe types and amountsof physical activity that offer health benefits. The 2008 Guidelines recommended 150–300
minutes of moderate-intensity or 75–150 minutes of vigorous-intensity aerobic activity
weekly for substantial health benefits 4. However, the Guidelines noted that the upper
threshold of benefit for aerobic activity and potential harms associated with very high levelsof activity were undefined.

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Few prospective cohorts have been able to examine the association between activity levels
above these recommendations and mortality due to few deaths among participants reporting
higher activity levels. However, in recent years endurance training has increased asindicated by a record 541,000 individuals in the U.S. completing a marathon in 2013 5 and
510,859 USA Triathlon members in 2012 6. Recent studies have suggested higher risk ofarrhythmias with prolonged endurance training 7 or sudden death due to electrical andmyocardial remodeling 8, raising concerns among individuals performing such activities andmaking health effects of very high levels of exercise a potential clinical concern. The 2008
Guidelines reviewed this evidence and concluded that while cardiac risk increases when an
individual becomes more active than usual (e.g. someone inactive undertakes vigorous
activities), these cardiac events are rare and individuals who are regularly physically active
have the lowest risk of cardiac events even while active 9.
While a previous publication using these six pooled cohort studies showed lower mortality
among those performing three times the recommended minimum10, in the present study,
with additional follow-up, we tackle the not previous addressed question of upper limit ofbenefit from physical activity. In this pooled analysis we have a sufficient number of deaths
to examine the shape of the mortality dose-response curve for adults performing more than

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the recommended physical activity minimum (i.e., 150 minutes/week of moderate- or 75
minutes/week of vigorous-intensity activity, or some combination expending equivalentenergy) and up to 10+ times the recommended minimum.
To fill the gap in scientific knowledge of the dose-response relation between leisure-time
physical activity and mortality, we aimed to quantify 1) the upper threshold for longevity
benefit from leisure-time physical activity, and 2) mortality risks associated with very highlevels of exercise. In secondary analyses, we also evaluated the mortality dose-response formoderate- and vigorous-intensity leisure-time physical activity separately.

Methods
Study population

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The six cohorts in our pooled analysis previously participated in the National Cancer
Institute (NCI) Cohort Consortium analyses of body mass index (BMI) or physical activity
and mortality 10,11. We used the same inclusion criteria as those previous studies: aprospective design, at least 5 years of follow-up, at least 1,000 deaths among non-Hispanic
white participants, baseline data collected in 1970 or later, and assessment of height, weightand smoking status, as well as leisure-time physical activity. Of the 19 studies in the BMI
and mortality analysis, eight had information on time spent in moderate or vigorousintensity leisure-time physical activity and five agreed to participate. The Cancer Prevention
Study II (CPII) later joined the consortium, met the criteria and agreed to participate. We
excluded individuals missing BMI or reporting a BMI <15 or >60 kg/m2. Each participating
study was approved by the institutional review board of the host institute.

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The included cohorts have been previously described. In short, the National Institutes of
Health (NIH)–AARP Diet and Health Study collected information on diet and health risk
factors among members of AARP 12. The CPS II assessed environmental and lifestylecancer risk factors among U.S. and Puerto Rican individuals 13. CLUE II investigatedcardiovascular and cancer risk factors among Washington County, Maryland, residents 14. In
the U.S. Radiologic Technologists (USRT) Study, radiologic technologists residing in the
U.S. and certified by the American Registry of Radiologic Technologists were recruited forthe study of cancer risk factors 15. The Women's Health Study (WHS) is a completed
randomized clinical trial testing low-dose aspirin and vitamin E for preventing
cardiovascular disease and cancer in female health professionals from 1992–2004, after
which participants were followed observationally 16–18. The Women's Lifestyle and HealthStudy (WLHS) is a population-based cohort study on disease risk among Swedish womensampled from the Uppsala Health Care Region 19.

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Exposure assessment
Physical activity construct validity and intensity levels are presented in eTable 1. In short,
CPS II, CLUE II, and WHS had 7–8 line items querying the average weekly time spent
performing the following activities over the prior year: walking, jogging/running,
swimming, tennis/racquetball, bicycling, aerobics and dance. The physical activity
questionnaires were adapted from the Nurses’ Health Study questionnaire, which has shown

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correlation coefficients ranging from 0.79–0.83 compared to recalls and from 0.59–0.62
compared to diaries20.

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NIH-AARP and WLHS used physical activity questionnaires that have not formally beenvalidated, but have shown expected associations between physical activity and mortality inprevious studies 12,21, and USRT has shown expected inverse associations with breast
cancer 15. The NIH-AARP Study included a single line item for all moderate- or vigorousintensity leisure time physical activities with categorical responses measured in hours per
week (h/wk). The WLHS questionnaire included separate line items about hours per day inleisure-time physical activity such as walking, horseback riding, or in strenuous activities,
and the U.S. Radiologic Technologists study had separate line items for h/wk spent walking
for exercise and exercising strenuously. For all six studies, we calculated energy expended
per activity by multiplying the estimated MET value 22 (multiple of resting metabolic rate)by the number of h/wk and summed across activities to estimate overall leisure-time
physical activity energy expenditure in MET h/wk.

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We used standardized categories to harmonize data between cohorts as follows: race/
ethnicity (black, white, other), education (did not finish high school, finished high school,
post-high school training, some college, finished college, missing), smoking status (never,former, current, missing), history of cancer (yes, no/missing), history of heart disease (yes,no/missing), alcohol consumption (0, >0-<15, 15-<30, 30+ grams/day), marital status(married, divorced, widowed, unmarried, missing) and BMI (<18.5, 18.5–25, 25-<30, 30<35, 35+ kg/m2). We imputed the value for alcohol using the median value because nondrinkers and true missing values were grouped differently between studies. In subsequent
analysis we tested associations using a missing category for alcohol instead of the imputed
value and found no change in our physical activity results (all hazard ratios were within 0.02
of previous estimates). Questionnaires did not distinguish between “missing” and “no” forhistory of heart disease and cancer history; thus individuals were dichotomized into groupsof yes or missing/no. Missing data was <5% for all covariates. We performed analyses
calculating follow-up time in two ways: first, using age at study entry to age at death or endof follow up and second, calculating time from baseline questionnaire to date of death or endof follow-up. Because results did not differ from analyses using age as the time metric orusing follow-up time and adjusting for age, in further analyses we used the latter method andadjusted for continuous age. The National Death Index, death certificates, or medical records
were used to ascertain date of death (eTable 1).
Statistical analysis

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We performed Cox proportional hazards regression stratified by cohort to generate hazard
ratios (HRs) and 95% confidence intervals (95% CIs) for leisure-time physical activity andmortality. Final models were adjusted for age, gender, race, education, smoking status,
cancer history, heart disease, alcohol consumption, marital status, and BMI. We created thefollowing MET h/wk categories: 0, 0.1-<7.5, 7.5-<15, 15-<22.5, 22.5-<40, 40-<75, and 75+.
These categories were created to reflect multiples of the federal physical activity
recommendations, ranging from 1–2 times the recommended minimum (7.5-<15 METh/wk) to up to 10+ times the recommended levels (75+ MET h/wk). We further examined

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intensity in the five cohorts with line items for individual activities (CLUE II, CPS II,
USRT, WHS and WLH) by separating moderate (3-<6 METs) and vigorous (6+ <METs)
intensity activities and creating mutually adjusted models. In intensity analyses, MET h/wk
categories were 0, 0.1-<7.5, 7.5-<15, 15-<30, and 30+ due to a lower range of MET h/wk
for each intensity and fewer deaths in the highest categories. We also examined heart diseaseand cancer-specific mortality. The proportional hazards assumption was tested by creating
an interaction term between continuous leisure-time physical activity and follow-up timeand using the Wald test for significance of the interaction term.

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To test for statistical significance of interaction we created interaction terms between
continuous leisure-time physical activity and the exposures of interest and used the Wald
test for dichotomous variables and the likelihood ratio test for multi-level variables. We also
created separate models by cohort and used random effects meta-analyses to generatesummary risk estimates and the I2 statistic for heterogeneity. To explore individual random
effects we created Cox proportional hazards frailty models. To further test influence byspecific cohorts, we performed analyses excluding one cohort at a time. We used a restrictedcubic spline to explore whether mortality risk increased at the highest leisure-time physicalactivity levels 23. We excluded individuals reporting >100 MET h/wk to test the influence ofoutliers and also restricted the dataset to those performing >15 MET h/wk to test the p-trend
for leisure-time physical activity and mortality at levels only among individuals reporting
more than double the recommended minimum. We also stratified by potential effectmodifiers age, sex, education, race, BMI, smoking status, heart disease and previous cancer.
All analyses were performed in SAS 9.3 other than the random effects meta-analysis(STATA 11). The figure was generated using GraphPad Prism 6.

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Results
Our pooled dataset included 661,137 participants (291,485 men and 369,652 women). Witha median 14.2 follow-up years (range 0–15.2), we observed 116,686 deaths. Descriptive
characteristics of the six cohorts are included eTable 2. Median age at study entry was 62
years and the median physical activity level was 8 MET h/wk (interquartile range 4–22).
Those performing the most leisure-time physical activity tended to be younger, neversmokers, have a lower BMI, be married and have fewer comorbidities (Table 1).

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Compared to no baseline leisure-time physical activity, any level of activity was associatedwith a significantly lower risk of mortality (Figure 1, eTable 3). Specifically, among those
performing less than the recommended leisure-time physical activity minimum (0.1-<7.5
MET h/wk), we observed 20% lower risk of mortality (HR=0.80, 95% CI 0.78–0.82). This
inverse association grew stronger among those performing 1–2 times the recommended
minimum (7.5-<15 MET h/wk HR=0.69, 95% CI 0.67–0.70) or 2–3 times the minimum (15<22.5 MET h/wk HR=0.63, 95% CI 0.62–0.65), but appeared to reach a threshold of a 39%
lower mortality risk among those performing 3–10 times the recommended minimum (22.5<40 MET h/wk HR=0.61, 95% CI 0.59–0.62; 40-<75 MET h/wk HR=0.61, 95% CI 0.58–0.64). We observed a still reduced, but not as strong 32% lower mortality risk for those
performing 10+ times the recommended minimum leisure-time physical activity levels (75+JAMA Intern Med. Author manuscript; available in PMC 2016 June 01.

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MET h/wk HR=0.68, 95% CI 0.59–0.78) after adjustment for other known mortality risk
factors (comparing 40–75 to 75+ MET h/wk p=0.127).
To test for heterogeneity we modeled the association between leisure-time physical activity
and mortality by random-effects meta-analysis. We found similar patterns of association,suggesting a relative threshold for benefit among those meeting or exceeding the leisuretime physical activity recommended minimum (eTable 4). Heterogeneity between cohorts
was statistically significant for all leisure-time physical activity categories (p<0.05). We also
created separate models for each cohort to examine cohort-specific risk estimates. The
direction of association was inverse for all cohorts, and did not show evidence of additionalmortality benefit at the highest leisure-time physical activity levels (eTable 4). Excluding
cohorts from analysis one at a time to further test for influence showed results consistent
with the main findings (eTable 5).

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We also created separate moderate vs vigorous intensity categories ranging from 0–30+
MET h/wk and ran models mutually adjusted for both leisure-time physical activity
intensities. In this subset analysis of 348,725 individuals, while we observed some mortality
benefit with low levels of moderate-intensity activity (0.1–7.5 MET h/wk HR=0.80, 95% CI
0.78–0.83), the maximum observed mortality benefit accrued with meeting therecommended minimum of 7.5 MET h/wk (7.5-<15 MET h/wk HR=0.73, 95% CI 0.71–0.75), and higher moderate-intensity activity levels did not yield additional benefit (30+
MET h/wk HR=0.72, 95% CI 0.68–0.76) (Table 2). For vigorous-intensity leisure-time
physical activity, any level of activity even below the recommended minimum was
associated with an approximate 20% lower mortality risk. Associations were similar
between men and women.

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In analyses of leisure-time physical activity and cause-specific mortality we found amonotonic inverse trend for cancer deaths, with a 31% lower cancer mortality risk
(HR=0.69, 95% CI 0.55–0.87) among those performing 10+ times the recommended
minimum (75+ MET h/wk) compared to those reporting no activity (Table 3). For CVD
deaths, however, the upper threshold was observed among those reporting 3–5 times therecommended minimum (22.5-<40 MET h/wk HR=0.58, 95% CI 0.56–0.61). There was no
additional benefit for those reporting 5–10 or 10+ times the recommended minimum (HR,
95% CIs = 0.61, 0.55–0.67 and 0.71, 0.56–0.91, respectively); There was no statisticaldifference between these two highest physical activity categories (p=0.226).

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In stratified analyses we found that the upper limit of mortality benefit appeared to beconsistent across covariate strata, although we observed some variation in point estimates
where number of deaths was low (Table 4). While we found statistically significant
differences by age, sex, education, BMI, smoking status and heart disease possibly
attributable to the large sample sizes (p<0.001), examination of point estimates did not show
results contradictory to our main findings. When we tested differences between the twohighest physical activity categories that appeared to diverge (e.g. men reporting 40-<75 v.
75+ MET h/wk) the two categories were not statistically different (p=0.07).

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Excluding those reporting >100 MET h/wk from analyses to assess the influence of outliers
did not change our conclusions. We also performed an analysis limited to those reporting
15+ MET h/wk and using a continuous term to see whether the risk trend existed beyond the
15 MET h/wk threshold, we found that the p-trend for continuous physical activity was
highly significant (p< 0.001). Using a cubic spline showed that the association between
physical activity and mortality was not linear, but the patterns of risk observed in the splines
paralleled risk estimates in the categorical analyses (eFigure 1).

Discussion

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Our findings on the shape of the physical activity-mortality dose-response curve offer threeunique and important contributions to inform healthcare professionals and future Guidelines– 1) the currently recommended amounts of leisure-time physical activity provide themajority of longevity benefits, 2) the longevity benefit threshold appears around 3–5 times
the recommended physical activity minimum, and 3), there does not appear to be an elevatedmortality risk with leisure-time physical activity levels as high as 10+ times therecommended minimum. In our study population both moderate and vigorous-intensity
activities were associated with longevity benefit.

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Two recent studies quantified the minimal amounts of leisure-time physical activity for
longevity benefit but did not estimate mortality risk beyond ~3 times the recommended
minimum, and therefore were unable to quantify the upper threshold of benefit. A
Taiwanese study found that compared to those who were inactive, those who were meeting
U.S. federal physical activity recommendations had a 26% lower mortality risk (HR=0.74,
95% CI 0.70–0.77) 24. Our previous publication in these pooled cohorts, with a shorter
follow-up, showed major longevity benefits with leisure-time physical activity 3+ times therecommended minimum compared to none (HR=0.59, 95% CI 0.57–0.61), but did not detailmortality benefits for physical activity above 22.5+ MET h/wk or estimate separate risk
estimates by activity intensity 10. The present study confirms and extends previous researchby quantifying the upper threshold of benefit, which in turn demonstrates that adults who
perform leisure-time physical activity at recommended levels achieve the majority of themortality benefits.

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Previous studies on associations between intensity-specific leisure-time physical activity(i.e. moderate vs. vigorous) and mortality have shown equivocal results. A study of leisuretime physical activity and mortality in middle-aged British men supported an association
between vigorous-intensity but not moderate-intensity physical activity and all-cause and
CVD mortality 25. Other studies have shown reductions in mortality rate from moderate
activities, but greater reductions associated with vigorous-intensity activities26. Few studies
examining MET expenditures and types of high-intensity activities have been reported
among older adults, and given the low prevalence of older individuals performing very highlevels of activity or high intensity on a population level, previous epidemiologic studies are
not available for comparison. On the other hand, comprehensive reviews of the literature on
physical activity and mortality report that overall volume of physical activity is associatedwith lower mortality risk, but report mixed findings on relative contributions of moderate vsvigorous-intensity activities 27,28. Other studies also support associations between moderate

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activities including walking and lower risk of coronary heart disease 29–31 or mortality 24,26.
While more research is needed on physical activity intensity vs. dose, our finding thatmoderate-intensity activities was associated with mortality benefit is consistent with the2008 Guidelines.
An analysis in the 2011 Behavioral Risk Factor Surveillance Survey (BRFSS) reported thatwalking contributed 47.4% of overall aerobic exercise, while running/jogging accounted for
13.4% and conditioning exercises (including stationary biking, Stairmaster/stair climbing or
active gaming) accounted for 8.5% and sports grouped together accounted for 9.2% ofactivity32. Walking for exercise was also the largest contributor to overall MET h/wk in our
analysis, which is consistent with the BRFSS findings. Thus, the major activities listed onthese questionnaires were prevalent both at time of data collection and at present.

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Possible harms previously associated with high levels of leisure-time physical activity may
be explained by cause of death. The 2008 Guidelines evaluation of harms stated that risk ofcardiac events was transiently increased during vigorous-intensity physical activity,
particularly among inactive individuals, but that on average physically active individuals
have a lower risk of adverse cardiac events 4. Recent studies have suggested cardiac
remodeling and higher CVD and mortality risk with extremely high physical activity
levels 7,33–38, but these studies were largely performed in athletic populations with ayounger median age. Our cohort was older, as average age for those <60 years old was still
52 years old. While our study is not poised to examine the risk during or immediately after
exercise or co-morbid cardiac conditions such as atrial fibrillation, our findings do notsupport the hypothesis for increased mortality risk at leisure-time physical activity levels of
10+ times the federal guidelines. The present findings align with other studies that haveshown lower risks of mortality among long-term, long distance runners 39 as well as Tour deFrance cyclists 40. Thus, current trends in increasing marathon or triathalon participation
should not cause alarm, at least with regard to mortality.
Strengths of our study include the prospective nature of the cohorts, extended follow-up
time and detailed covariate information. We were uniquely positioned to estimate thethreshold for longevity benefit from high leisure-time physical activity levels and potential
harms with respect to mortality because by pooling we had enough individuals reporting thishigh level of exercise. Our stratified results further strengthen our finding, indicating theupper threshold of benefit was consistent in men and women, different age groups, various
lifestyle factors and in those with and without cardiovascular disease and cancer. However,the smaller sample size in our highest physical activity category led to wider confidence
intervals in this category.

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Limitations of our study include the reliance on self-reported physical activity, reported atonly a single time point. We also did not examine non-leisure time activities or sedentarytime, both of which have shown associations with mortality. Also, although we attempted toadjust for confounding by history of disease or other known mortality risk factors,
unaccounted risk factors may have influenced our observed results. Validation studies were
not specifically designed for older adults performing very high levels of physical activity.
Still, self-reported activity has shown construct validity in our cohorts by showing expected

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associations with mortality and disease-specific outcomes (eTable 1). The prospective
design minimizes recall bias, but measurement error in self-reported leisure-time physicalactivity is likely to result in attenuation of the associations observed. Differences in thequestionnaires between cohorts, variation in baseline age, relative physical fitness, andlength of follow-up may explain some of the heterogeneity we observed between individual
study results. However, additional analyses excluding each individual cohort showed that
estimates were not unduly influenced by a single cohort. Our median reported leisure-time
physical activity levels were above average U.S. values, which may be due to the higher
education level of our study participants. Also, MET h/wk intensities were assigned using
absolute, compendium-derived values that may not account for inter-individual variation.
Lastly, we cannot completely exclude the possibility of inflation in upper physical activity
categories.

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In summary, meeting the recommended guidelines by either moderate or vigorous-intensity
activities was associated with nearly the maximum longevity benefit. We observed thisbenefit threshold around 3–5 times the recommended leisure-time physical activity
minimum, and no excess risk at 10+ times the recommended minimum. These findings are
informative for individuals at both ends of the physical activity spectrum: they provide
important evidence to inactive individuals by showing that modest amounts of activity
provide substantial benefit for postponing mortality, while at the same time reassuring very
active individuals of no exercise-associated increase in mortality risk. These data will be
useful to inform future updates on physical activity guidelines regarding appropriate amountof physical activity to recommend for longevity.

Supplementary Material
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Refer to Web version on PubMed Central for supplementary material.

Acknowledgments
Funding: This study was supported [in part] by the Intramural Research Program in the Division of Cancer
Epidemiology and Genetics and the Division of Cancer Control and Population Sciences, both of the US National
Institutes of Health (NIH,) National Cancer Institute (NCI). The NIH-AARP Diet and Health study was supportedby the Intramural Research Program of the NCI. CLUE was supported by the National Institute of Aging, grant
number: U01 AG18033 and NCI, grant number: CA105069. CPS II was supported by the intramural research
program at the American Cancer Society (Atlanta, Georgia). The US Radiologic Technologists study was supportedby the Intramural Research Program, Division of Cancer Epidemiology and Genetics, NCI. The Women's HealthStudy was supported by grant numbers CA047988, HL043851, HL080467, and HL099355. The Swedish Women's
Lifestyle and Health study is supported by the Swedish Research Council (grant 521–2011–2955).The funders had
no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; andpreparation, review, or approval of the manuscript; nor in the decision to submit the manuscript for publication.

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H. Arem had full access to all the data in the study and takes responsibility for the integrity of the data and theaccuracy of the data analysis. We are indebted to all study participants for their outstanding cooperation. We also
would also like to acknowledge the contribution to this study from central cancer registries supported through theCenters for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supportedby the National Cancer Institute Surveillance Epidemiology and End Results program. Certain CLUE II data were
provided by the VSA, MD DHMH, Baltimore, MD. The DHMH disclaims responsibility for any analyses,interpretation or conclusions. We also thank Dr. Jerry Reid of the American Registry of Radiologic Technologists
for continued study support, Diane Kampa and Allison Iwan of the University of Minnesota for study managementand data collection, and Jeremy Miller of Information Management Services for biomedical computing.

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Figure 1. Hazard ratios (HRs) and 95% confidence intervals (CIs) for leisure time moderate- tovigorous-intensity physical activity and mortalitya-c

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The dose-response curve and category-specific hazard ratio estimates for leisure timemoderate- to vigorous-intensity physical activity and mortality. Crude and adjusted risk
estimates are presented in eTable3.
Exercise levels compared to the federally recommended minimum of 7.5 MET h/wk
aModels were stratified by cohort and use age as the underlying time scale. The model was
adjusted for gender, smoking (never, former, current, missing), alcohol (none, <15 grams/
day, 15–30 grams/day, 30+ grams/day), education (dropout, high school, post high school
education, some college, college graduate, post-college, missing), marital status (married,
divorced, widowed, single, missing), history of cancer, history of heart disease, and bodymass index (<18.5, 18.5–25, 25-<30, 30-<35, 35+ kg/m2).
bThe dotted line between categories illustrates an assumed dose-response rather than
individual data points.
cCrude and adjusted hazard ratios and 95% confidence intervals are presented in
Supplemental Table 3.

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277,193
256,713
119,988627,393
61,15846,35825-<3030+

WhiteHeart disease

CancerRace

Co-morbidities

Frequencies are column percentage.

a474,338

376,861

One drink/d<25

179,676

Non-drinker

Married74,977

Current

BMI, kg/m2

298,256

FormerMarital Status

275,388

Never

250,564

369,652

Women

54,063

291,485

Men

College Graduate

61,35670+

Two drinks/d307,556

60-<70

Education

Alcohol intake

Smoking Status

Gender276,418

<60

8

8

96

27

37

36

77

29

7

51

38

19

41

40

62

38

12

39

50

11,523Age, years

52,848116,686

0

8

9

96

23

39

38

77

37

7

56

30

13

44

43

58

42

10

45

45

33,511

172,2030.1-<7.5

7

9

97

18

40

42

77

41

8

59

26

11

46

43

56

44

10

48

43

28,957

170,563

7.5-<15

6

11

96

15

40

44

74

44

10

59

22

10

49

41

51

49

8

53

39

19,979118,169

15-<22.5

7

10

97

12

40

48

76

40

10

56

25

10

49

41

51

49

10

54

36

21,114

124,44622.5-<40

6

4

96

9

32

60

81

44

7

65

23

10

42

48

70

30

8

27

65

1,390

18,83140-<75

5

3

93

10

30

60

76

43

6

66

24

11

38

51

72

28

6

18

76

212

4,077

75+

LTPA level, MET h/wk (percentages in each category reported below)a661,137

Participants

Deaths, nCategory (%)

Participants, n

Characteristic

Descriptive characteristics of study participants according to leisure time physical activity (LTPA) categories (n=661,137)

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Table 1
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0.83 (0.79–0.88)

0.78 (0.75–0.82)

0.80 (0.78–0.83)

0.75 (0.73–0.78)

3,525

55,1600.85 (0.77–0.94)

0.69 (0.61–0.78)

0.77 (0.71–0.84)

0.72 (0.67–0.78)

638

23,7920.68 (0.65–0.71)

0.86 (0.78–0.94)

0.72 (0.66–0.79)

0.78 (0.73–0.83)

0.71 (0.67–0.76)

892

10,8160.67 (0.63–0.70)

0.73 (0.71–0.76)

0.71 (0.68–0.73)

0.63 (0.61–0.65)

8,054

59,30415-<300.81 (0.72–0.91)

0.77 (0.70–0.85)

0.79 (0.73–0.85)

0.72 (0.67–0.78)

695

15,3590.69 (0.64–0.75)

0.74 (0.69–0.79)

0.72 (0.68–0.76)

0.63 (0.60–0.67)

1,696

12,83630+

Models are stratified by cohort, are adjusted for age and are mutually adjusted for both moderate and vigorous-intensity activities.

JAMA Intern Med. Author manuscript; available in PMC 2016 June 01.

where indicated, body mass index (<18.5, 18.5–25, 25-<30, 30-<35, 35+ kg/m2).

cModels are additionally adjusted for gender (in non-stratified models), smoking (never, former, current, missing), alcohol (none, <15 grams/day, 15–30 grams/day, 30+ grams/day), education (dropout,high school, post high school education, some college, college graduate, post-college, missing), marital status (married, divorced, widowed, single, missing), history of cancer, history of heart disease, and

b

1.00

1.00

Fully adjusted HR (95% CI)c
1.00

1.00

Age-adjusted HR (95% CI)b

Women

40,229DeathsMen

243,598

Participants

0.76 (0.73–0.80)

0.77 (0.74–0.80)

0.73 (0.71–0.75)

0.62(0.60–0.64)

11,667

100,687

7.5-<15

AARP was not included in this analysis because the questionnaire did not distinguish between moderate and vigorous-intensity activities.

a

Women

Vigorous-intensity activity

0.80 (0.78–0.83)

1.00

1.00

Fully adjusted HR (95% CI)c0.70 (0.68–0.72)

0.84 (0.81–0.87)

1.00

Age-adjusted HR (95% CI)b

16,203

122,5220.1-<7.5

1.00

8,359

Men

53,376

Deaths0Participants

Moderate-intensity activity

MET h/wk

n=239,823 women)aHazard ratios (HRs) and 95% confidence intervals (CIs) for leisure time physical activity and mortality, by activity intensity (n=108,902 men andAuthor Manuscript

Table 2
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8,584
0.87 (0.83–0.90)
7,952

3,143
1.00
3238
1.00

Cancer deaths, n

HR (95% CI)a

CVD deaths, n

HR (95% CI)a0.67 (0.65–0.70)

6,316

0.79 (0.75–0.82)

7,375

170,563

7.5-<15

0.59 (0.57–0.63)

3,293

0.75 (0.72–0.79)

4,373

118,169

15-<22.5

0.58 (0.56–0.61)

4,044

0.74 (0.71–0.77)

5,187

124,44622.5-<40

0.61 (0.55–0.67)457

0.72 (0.66–0.79)

557

18,83140-<750.71 (0.56–0.91)69

0.69 (0.55–0.87)

75

4,077

75+

heart disease, and body mass index (<18.5, 18.5–25, 25-<30, 30-<35, 35+ kg/m2).

Multivariable-adjusted models with stratification by cohort were adjusted for age, gender, smoking (never, former, current, missing), alcohol (none, <15 grams/day, 15–30 grams/day, 30+ grams/day),education (dropout, high school, post high school education, some college, college graduate, post-college, missing), marital status (married, divorced, widowed, single, missing), history of cancer, history ofa172,203

52,848

Participants, n0.80 (0.77–0.84)

0.1-<7.5

0

MET h/wk

Hazard ratios (HRs) and 95% confidence intervals (CIs) for moderate to vigorous-intensity physical activity and cause-specific mortality (n=661,137)

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1.00

60-<701.00

Female1.00
1.00

Some college or post-high school

College graduate

1.00

African American

1.00

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1.00

No

1.00

1.00

Yes

Previous cancer

1.00

No

Heart disease

0.80 (0.78–0.82)

0.79 (0.75–0.83)

0.80 (0.78–0.82)

0.85 (0.81–0.89)

1.00

FormerCurrent

0.77 (0.75–0.79)

1.00

Never

Smoking status0.80 (0.76–0.83)

0.83 (0.79–0.86)

1.00

30+

0.79 (0.76–0.82)

1.00

25-<300.78 (0.75–0.81)

0.80 (0.71–0.91)

0.79 (0.78–0.81)

0.75 (0.72–0.79)

0.74 (0.71–0.77)

0.78 (0.76–0.81)

0.77 (0.74–0.79)

0.82 (0.80–0.85)

0.77 (0.74–0.81)

0.81 (0.78–0.83)

0.78 (0.74–0.83)

0.73 (0.61–0.87)

0.1-<7.5

18.5-<25

BMI (kg/m2)

1.00

Non-Hispanic white

Race

1.00

High school or less

Education

1.00

Male

Sex

1.00

1.00

50-<60

70+

1.00

0

<50

Age (years)

MET h/wk

0.69 (0.68–0.71)

0.65 (0.62–0.68)

0.70 (0.68–0.72)

0.77 (0.73–0.81)

0.65 (0.63–0.67)

0.69 (0.66–0.72)

0.72 (0.68–0.75)

0.70 (0.67–0.72)

0.66 (0.63–0.68)

0.66 (0.58–0.76)

0.68 (0.67–0.70)

0.63 (0.61–0.66)

0.63 (0.61–0.65)

0.65 (0.63–0.68)

0.67 (0.64–0.69)

0.71 (0.69–0.73)

0.65 (0.62–0.68)

0.70 (0.68–0.72)

0.67 (0.64–0.71)

0.75 (0.62–0.90)

7.5-<150.64 (0.62–0.65)

0.58 (0.55–0.61)

0.65 (0.63–0.66)

0.72 (0.68–0.76)

0.59 (0.57–0.61)

0.66 (0.63–0.69)

0.67 (0.64–0.71)

0.64 (0.61–0.66)

0.59 (0.57–0.62)

0.70 (0.61–0.81)

0.62 (0.61–0.64)

0.57 (0.54–0.59)

0.56 (0.54–0.59)

0.61 (0.59–0.64)

0.64 (0.61–0.66)

0.63 (0.61–0.65)

0.62 (0.59–0.65)

0.63 (0.61–0.65)

0.66 (0.62–0.70)

0.81 (0.65–1.01)

15-<22.5

0.61 (0.59–0.63)

0.55 (0.52–0.58)

0.62 (0.60–0.64)

0.69 (0.65–0.72)

0.56 (0.54–0.58)

0.64 (0.61–0.67)

0.66 (0.63–0.69)

0.62 (0.59–0.64)

0.56 (0.54–0.58)

0.60 (0.51–0.69)

0.60 (0.59–0.61)

0.56 (0.53–0.58)

0.53 (0.51–0.55)

0.58 (0.56–0.61)

0.60 (0.57–0.62)

0.61 (0.59–0.63)

0.60 (0.57–0.62)

0.59 (0.57–0.61)

0.65 (0.61–0.69)

0.70 (0.56–0.89)

22.5-<40

0.63 (0.59–0.67)

0.56 (0.48–0.65)

0.62 (0.58–0.66)

0.72 (0.61–0.84)

0.55 (0.51–0.59)

0.67 (0.61–0.74)

0.72 (0.61–0.85)

0.67 (0.62–0.74)

0.54 (0.50–0.59)

0.57 (0.38–0.85)

0.61 (0.57–0.64)

0.55 (0.50–0.60)

0.53 (0.48–0.59)

0.58 (0.52–0.66)

0.59 (0.54–0.65)

0.62 (0.58–0.67)

0.54 (0.49––0.60)

0.61 (0.56–0.66)

0.63 (0.54–0.72)

0.80 (0.61–1.03)

40-<75Stratified hazard ratios and 95% confidence intervals for leisure time physical activity and mortality

0.70 (0.61–0.82)

0.66 (0.45–0.98)

0.69 (0.60–0.80)

0.83 (0.59–1.18)

0.61 (0.51–0.74)

0.67 (0.53–0.86)

0.62 (0.39–1.01)

0.76 (0.60–0.95)

0.63 (0.52–0.76)

0.80 (0.42–1.52)

0.68 (0.59–0.78)

0.68 (0.55–0.83)

0.56 (0.43–0.71)

0.58 (0.40–0.85)

0.61 (0.49–0.75)

0.74 (0.62–0.89)

0.67 (0.52–0.85)

0.70 (0.57–0.86)

0.60 (0.43–0.84)

0.72 (0.47–1.11)

75+

0.217

<0.001<0.001<0.001

0.237

0.087

0.002

<0.001p-interact

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1.00

0.79(0.75–0.83)

0.66 (0.63–0.70)

0.61 (0.57–0.65)

15-<22.5
0.58 (0.54–0.61)

22.5-<40
0.54 (0.47–0.62)

40-<750.59 (0.41–0.84)75+

p-interact

Interaction was tested using a continuous leisure-time physical activity term and the exposure of interest, using a Wald test for dichotomous variables and a likelihood ratio test for multi-level variables.

body mass index (<18.5, 18.5–25, 25-<30, 30-<35, 35+ kg/m2). The variable used for stratification was not included in the given model.

Multivariable models are stratified by cohort, and adjusted for age, gender, smoking (never, former, current, missing), alcohol (none, <15 grams/day, 15–30 grams/day, 30+ grams/day), education (dropout,high school, post high school education, some college, college graduate, post-college, missing), marital status (married, divorced, widowed, single, missing), history of cancer, history of heart disease, andYes

7.5-<15

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0.1-<7.5

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MET h/wk

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