Peter T Campbell

American Cancer Society, Atlanta, Georgia, United States

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Publications (111)892.89 Total impact

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    ABSTRACT: Background: Menopausal hormone therapy (MHT) use has been consistently associated with a decreased risk of colorectal cancer (CRC) in women. Our aim was to use a genome-wide gene-environment interaction analysis to identify genetic modifiers of CRC risk associated with use of MHT. Methods: We included 10 835 postmenopausal women (5419 cases and 5416 controls) from 10 studies. We evaluated use of any MHT, oestrogen-only (E-only) and combined oestrogen-progestogen (E+P) hormone preparations. To test for multiplicative interactions, we applied the empirical Bayes (EB) test as well as the Wald test in conventional case-control logistic regression as primary tests. The Cocktail test was used as secondary test. Results: The EB test identified a significant interaction between rs964293 at 20q13.2/CYP24A1 and E+P (interaction OR (95% CIs)=0.61 (0.52-0.72), P=4.8 × 10(-9)). The secondary analysis also identified this interaction (Cocktail test OR=0.64 (0.52-0.78), P=1.2 × 10(-5) (alpha threshold=3.1 × 10(-4)). The ORs for association between E+P and CRC risk by rs964293 genotype were as follows: C/C, 0.96 (0.61-1.50); A/C, 0.61 (0.39-0.95) and A/A, 0.40 (0.22-0.73), respectively. Conclusions: Our results indicate that rs964293 modifies the association between E+P and CRC risk. The variant is located near CYP24A1, which encodes an enzyme involved in vitamin D metabolism. This novel finding offers additional insight into downstream pathways of CRC etiopathogenesis.British Journal of Cancer advance online publication, 14 January 2016; doi:10.1038/bjc.2015.443
    No preview · Article · Jan 2016 · British Journal of Cancer
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    ABSTRACT: Genome-wide association studies have identified several germline single nucleotide polymorphisms (SNPs) significantly associated with colorectal cancer (CRC) incidence. Common germline genetic variation may also be related to CRC survival. We used a discovery-based approach to identify SNPs related to survival outcomes after CRC diagnosis. Genome-wide genotyping arrays were conducted for 3494 individuals with invasive CRC enrolled in six prospective cohort studies (median study-specific follow-up = 4.2–8.1 years). In pooled analyses, we used Cox regression to assess SNP-specific associations with CRC-specific and overall survival, with additional analyses stratified by stage at diagnosis. Top findings were followed-up in independent studies. A P value threshold of P < 5×10−8 in analyses combining discovery and follow-up studies was required for genome-wide significance. Among individuals with distant-metastatic CRC, several SNPs at 6p12.1, nearest the ELOVL5 gene, were statistically significantly associated with poorer survival, with the strongest associations noted for rs209489 [hazard ratio (HR) = 1.8, P = 7.6×10−10 and HR = 1.8, P = 3.7×10−9 for CRC-specific and overall survival, respectively). No SNPs were statistically significantly associated with survival among all cases combined or in cases without distant-metastases. SNPs in 6p12.1/ELOVL5 were associated with survival outcomes in individuals with distant-metastatic CRC, and merit further follow-up for functional significance. Findings from this genome-wide association study highlight the potential importance of genetic variation in CRC prognosis and provide clues to genomic regions of potential interest.
    No preview · Article · Nov 2015 · Carcinogenesis

  • No preview · Article · Oct 2015 · Nature Communications
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    ABSTRACT: Over 50 loci associated with colorectal cancer (CRC) have been uncovered by genome-wide association studies (GWAS). Identifying additional loci has the potential to help elucidate aspects of the underlying biological processes leading to better understanding of the pathogenesis of the disease. We re-evaluated a GWAS by excluding controls that have family history of CRC or personal history of colorectal polyps, as we hypothesized that their inclusion reduces power to detect associations. This is supported empirically and through simulations. Two-phase GWAS analysis was performed in a total of 16,517 cases and 14,487 controls. We identified rs17094983, a SNP associated with risk of CRC [p = 2.5 × 10(-10); odds ratio estimated by re-including all controls (OR) = 0.87, 95 % confidence interval (CI) 0.83-0.91; minor allele frequency (MAF) = 13 %]. Results were replicated in samples of African descent (1894 cases and 4703 controls; p = 0.01; OR = 0.86, 95 % CI 0.77-0.97; MAF = 16 %). Gene expression data in 195 colon adenocarcinomas and 59 normal colon tissues from two different studies revealed that this locus has genotypes that are associated with RTN1 (Reticulon 1) expression (p = 0.001), a protein-coding gene involved in survival and proliferation of cancer cells which is highly expressed in normal colon tissues but has significantly reduced expression in tumor cells (p = 1.3 × 10(-8)).
    No preview · Article · Sep 2015 · Human Genetics
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    ABSTRACT: Chronic inflammation plays a pivotal role in the pathogenesis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), the two most common types of liver cancer. A number of prior experimental studies have suggested that non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin and ibuprofen, may potentially protect against liver cancer. However, no observational study has examined the association between aspirin duration and dose or other over-the-counter non-aspirin NSAIDs, such as ibuprofen, and liver cancer incidence. Furthermore, the association between NSAID use and risk of ICC is unclear. As part of the Liver Cancer Pooling Project, we harmonized data on 1,084,133 individuals (HCC=679, ICC=225) from ten US-based prospective cohort studies. Cox proportional hazards regression models were used to evaluate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Current aspirin use, versus nonuse, was inversely associated with HCC (HR=0.68, 95% CI=0.57-0.81), which persisted when restricted to individuals not using non-aspirin NSAIDs and in a 5 and 10-year lag analysis. The association between aspirin use and HCC risk was stronger for users who reported daily use, longer duration use, and lower dosage. Ibuprofen use was not associated with HCC risk. Aspirin use was associated with a reduced ICC risk in men (HR=0.64, 95% CI=0.42-0.98) but not women (HR=1.34, 95% CI=0.89-2.01, pinteraction=0.01). The observed inverse association between aspirin use and liver cancer in our study, together with previous data, suggest the merit of future intervention studies of aspirin and other agents that affect chronic inflammatory pathways for HCC and possibly ICC.
    No preview · Article · Sep 2015 · Cancer Prevention Research
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    ABSTRACT: Physical activity is hypothesized to lower the risk of ovarian cancer, but current evidence for an association is limited and inconclusive. The purpose of this study was to examine moderate-to-vigorous physical activity, walking, and leisure-time sitting in relation to incident ovarian cancer, overall and by histologic subtype. Moderate-vigorous recreational physical activity (MET-hours/week), recreational walking, and leisure-time sitting were examined in relation to epithelial ovarian cancer in the American Cancer Society Cancer Prevention Study II Nutrition Cohort, a US cohort followed for cancer incidence from 1992 to 2011. Exposure information was collected via self-administered questionnaires. Cox proportional hazards regression was used to estimate multivariable-adjusted relative risks (RRs) and 95 % confidence intervals (CIs) of total, serous, and nonserous ovarian cancer according to MET-hours/week, hours/week of walking, and hours/day of sitting. Among 63,972 postmenopausal women, 651 cases of ovarian cancer were identified during follow-up. Neither MET-hours/week nor walking was associated with risk. However, ≥6 h/day of sitting, compared to <3, was associated with higher risk of ovarian cancer (RR 1.44, 95 % CI 1.12-1.85), particularly for serous cancer (RR 1.52, 95 % CI 1.06-2.16), although statistical heterogeneity by histology was not detected (p = 0.36). Results from this study do not support an association between physical activity and ovarian cancer, whereas prolonged sitting may be associated with higher risk. Additional large studies are needed to further assess possible etiologic differences by histologic subtype.
    No preview · Article · Sep 2015 · Cancer Causes and Control
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    ABSTRACT: Weight cycling, which consists of repeated cycles of intentional weight loss and regain, is common among individuals who try to lose weight. Some evidence suggests that weight cycling may affect biological processes that could contribute to carcinogenesis, but whether it is associated with cancer risk is unclear. Using 62,792 men and 69,520 women enrolled in the Cancer Prevention Study II Nutrition Cohort in 1992, we examined the association between weight cycling and cancer incidence. Weight cycles were defined by using baseline questions that asked the number of times ≥10 pounds (4.54 kg) was purposely lost and later regained. Multivariable-adjusted hazard ratios and 95% confidence intervals for all cancer and 15 individual cancers were estimated by using Cox proportional hazards regression. During up to 17 years of follow-up, 15,333 men and 9,984 women developed cancer. Weight cycling was not associated with overall risk of cancer in men (hazard ratio = 0.96, 95% confidence interval: 0.83, 1.11 for ≥20 cycles vs. no weight cycles) or women (hazard ratio = 0.96, 95% confidence interval: 0.86, 1.08) in models that adjusted for body mass index and other covariates. Weight cycling was also not associated with any individual cancer investigated. These results suggest that weight cycling, independent of body weight, is unlikely to influence subsequent cancer risk. © The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail:
    No preview · Article · Jul 2015 · American journal of epidemiology
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    ABSTRACT: Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P<5.0E-08. These findings provide additional insight into the underlying biological mechanisms of colorectal cancer and demonstrate the scientific value of large consortia-based genetic epidemiology studies.
    No preview · Article · Jul 2015 · Nature Communications
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    ABSTRACT: Coffee consumption has been reported to be inversely associated with hepatocellular carcinoma (HCC), the most common type of liver cancer. Caffeine has chemopreventive properties, but whether caffeine is responsible for the coffee-HCC association is not well studied. In addition, few studies have examined the relationship by sex, and no studies have examined whether there is an association between coffee and intrahepatic cholangiocarcinoma (ICC), the second most common type of liver cancer. In the Liver Cancer Pooling Project, a consortium of U.S.-based cohort studies, data from 1,212,893 individuals (HCC n=860, ICC n=260) in nine cohorts were pooled. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression. Higher coffee consumption was associated with lower risk of HCC (HR>3 cups/day vs. non-drinker, 0.73; 95% CI, 0.53-0.99; ptrend cups/day=<0.0001). More notable reduced risk was seen among women than men (pinteraction=0.07). Women who consumed more than three cups of coffee per day were at a 54% lower risk of HCC (HR, 0.46; 95% CI, 0.26-0.81), whereas men had more modest reduced risk of HCC (HR, 0.93; 95% CI, 0.63-1.37). The associations were stronger for caffeinated coffee (HR>3 cups/day vs. non-drinker, 0.71, 95% CI, 0.50-1.01) than decaffeinated coffee (HR, 0.92; 95% CI, 0.55-1.54). There was no relationship between coffee consumption and ICC. These findings suggest that, in a U.S. population, coffee consumption is associated with reduced risk of HCC. Further research into specific coffee compounds and mechanisms that may account for these associations is needed. Copyright © 2015, American Association for Cancer Research.
    No preview · Article · Jun 2015 · Cancer Epidemiology Biomarkers & Prevention
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    ABSTRACT: Time spent sitting is distinctly different from accumulating too little physical activity and may have independent deleterious effects. Few studies have examined the association between sitting time and site-specific cancer incidence. Among 69,260 men and 77,462 women who were cancer-free and enrolled in the American Cancer Society Cancer Prevention Study II Nutrition Cohort, 18,555 men and 12,236 women were diagnosed with cancer between 1992 and 2009. Extended Cox proportional hazards regression was used to estimate multivariable-adjusted relative risks (RR) and 95% confidence intervals (CI) of leisure-time spent sitting with total and site-specific cancer incidence. Longer leisure-time spent sitting, after adjustment for physical activity, BMI and other factors, was associated with risk of total cancer in women (RR=1.10, 95% CI 1.04-1.17 for >6 hours vs. <3 hours per day), but not men (RR=1.00, 95% CI 0.96-1.05). In women, sitting time was associated with risk of multiple myeloma (RR=1.65, 95% CI 1.07-2.54), invasive breast cancer (RR=1.10, 95% CI 1.00-1.21), and ovarian cancer (RR=1.43, 95% CI 1.10-1.87). There were no associations between sitting time and site-specific cancers in men. Longer leisure-time spent sitting was associated with a higher risk of total cancer risk in women, and specifically with multiple myeloma, breast and ovarian cancers, but sitting time was not associated with cancer risk in men. Further research is warranted to better understand the differences in associations between men and women. For women, these findings support American Cancer Society guidelines for cancer prevention to reduce sitting time when possible. Copyright © 2015, American Association for Cancer Research.
    Full-text · Article · Jun 2015 · Cancer Epidemiology Biomarkers & Prevention
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    ABSTRACT: Although genome-wide association studies have separately identified many genetic susceptibility loci for ulcerative colitis (UC), Crohn's disease (CD), and colorectal cancer (CRC), there has been no large-scale examination for pleiotropy, or shared genetic susceptibility, for these conditions. We used logistic regression modeling to examine the associations of 181 UC and CD susceptibility variants previously identified by GWAS with risk of CRC using data from the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. We also examined associations of significant variants with clinical and molecular characteristics in a subset of the studies.Among 11,794 CRC cases and 14,190 controls, rs11676348, the susceptibility SNP for UC, was significantly associated with reduced risk of CRC (p = 7E-05). The multivariate-adjusted odds ratio of CRC with each copy of the T allele was 0.93 (95% CI, 0.89-0.96). The association of the SNP with risk of CRC differed according to mucinous histological features (Pheterogeneity=0.008). In addition, the (T) allele was associated with lower risk of tumors with Crohn's-like reaction but not tumors without such immune infiltrate (Pheterogeneity=0.02) and microsatellite instability-high (MSI-high) but not microsatellite stable or MSI-low tumors (Pheterogeneity = 0.03). The minor allele (T) in SNP rs11676348, located downstream from CXCR2 that has been implicated in CRC progression, is associated with a lower risk of CRC, particularly tumors with a mucinous component, Crohn's-like reaction, and MSI-high. Our findings offer the promise of risk stratification of inflammatory bowel disease patients for complications such as CRC. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email:
    No preview · Article · Jun 2015 · Carcinogenesis
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    ABSTRACT: Identification of gene-environment interaction (G × E) is important in understanding the etiology of complex diseases. Based on our previously developed Set Based gene EnviRonment InterAction test (SBERIA), in this paper we propose a powerful framework for enhanced set-based G × E testing (eSBERIA). The major challenge of signal aggregation within a set is how to tell signals from noise. eSBERIA tackles this challenge by adaptively aggregating the interaction signals within a set weighted by the strength of the marginal and correlation screening signals. eSBERIA then combines the screening-informed aggregate test with a variance component test to account for the residual signals. Additionally, we develop a case-only extension for eSBERIA (coSBERIA) and an existing set-based method, which boosts the power not only by exploiting the G-E independence assumption but also by avoiding the need to specify main effects for a large number of variants in the set. Through extensive simulation, we show that coSBERIA and eSBERIA are considerably more powerful than existing methods within the case-only and the case-control method categories across a wide range of scenarios. We conduct a genome-wide G × E search by applying our methods to Illumina HumanExome Beadchip data of 10,446 colorectal cancer cases and 10,191 controls and identify two novel interactions between nonsteroidal anti-inflammatory drugs (NSAIDs) and MINK1 and PTCHD3. © 2015 WILEY PERIODICALS, INC.
    No preview · Article · Jun 2015 · Genetic Epidemiology
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    ABSTRACT: Microsatellite instability (MSI) and BRAF-mutation status are associated with colorectal cancer survival whereas the role of body mass index (BMI) is less clear. We evaluated the association between BMI and colorectal cancer survival, overall and by strata of MSI, BRAF-mutation, sex, and other factors. This study included 5,615 men and women diagnosed with invasive colorectal cancer who were followed for mortality (maximum: 14.7 years; mean: 5.9 years). Pre-diagnosis BMI was derived from self-reported weight approximately 1-year before diagnosis and height. Tumor MSI and BRAF-mutation status were available for 4,131 and 4,414 persons, respectively. Multivariable hazard ratios (HR) and 95% confidence intervals (CIs) were estimated from delayed-entry Cox proportional hazards models. In multivariable models, high pre-diagnosis BMI was associated with higher risk of all-cause mortality in both sexes (per 5-kg/m2, HR = 1.10; 95% CI = 1.06 to 1.15), with similar associations stratified by sex (p-interaction: 0.41), colon vs rectum (p-interaction: 0.86), MSI status (p-interaction: 0.84), and BRAF-mutation status (p-interaction: 0.28). In joint models, with MS-stable/MSI-low and normal BMI as the reference group, risk of death was higher for MS-stable/MSI-low and obese BMI (HR: 1.32; p-value: 0.0002), not statistically significantly lower for MSI-high and normal BMI (HR: 0.86; p-value: 0.29), and approximately the same for MSI-high and obese BMI (HR: 1.00; p-value: 0.98). High pre-diagnosis BMI was associated with increased mortality; this association was consistent across participant subgroups, including strata of tumor molecular phenotype. High BMI may attenuate the survival benefit otherwise observed with MSI-high tumors. Copyright © 2015, American Association for Cancer Research.
    No preview · Article · Jun 2015 · Cancer Epidemiology Biomarkers & Prevention
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    ABSTRACT: For men and women, taller height is associated with increased risk of all cancers combined. For colorectal cancer (CRC), it is unclear whether the differential association of height by sex is real or is due to confounding or bias inherent in observational studies. We performed a Mendelian randomization study to examine the association between height and CRC risk. To minimize confounding and bias, we derived a weighted genetic risk score predicting height (using 696 genetic variants associated with height) in 10 226 CRC cases and 10 286 controls. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for associations between height, genetically predicted height and CRC. Using conventional methods, increased height (per 10-cm increment) was associated with increased CRC risk (OR = 1.08, 95% CI = 1.02-1.15). In sex-specific analyses, height was associated with CRC risk for women (OR = 1.15, 95% CI = 1.05-1.26), but not men (OR = 0.98, 95% CI = 0.92-1.05). Consistent with these results, carrying greater numbers of (weighted) height-increasing alleles (per 1-unit increase) was associated with higher CRC risk for women and men combined (OR = 1.07, 95% CI = 1.01-1.14) and for women (OR = 1.09, 95% CI = 1.01-1.19). There was weaker evidence of an association for men (OR = 1.05, 95% CI = 0.96-1.15). We provide evidence for a causal association between height and CRC for women. The CRC-height association for men remains unclear and warrants further investigation in other large studies. © The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.
    No preview · Article · May 2015 · International Journal of Epidemiology
  • Peter T Campbell

    No preview · Article · May 2015 · The Lancet
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    ABSTRACT: Physical activity is associated with a lower incidence of colorectal cancer (CRC); however, the relationship of physical activity with CRC survival is not yet clear. We evaluated the association between pre-diagnostic physical activity and CRC survival, overall and accounting for tumor-markers associated with CRC survival: BRAF and KRAS mutation status and microsatellite instability (MSI) status. Participants were 20-74 year old CRC patients diagnosed between 1998 and 2007 from the population-based Seattle Colon Cancer Family Registry (S-CCFR). Self-reported physical activity in the years preceding CRC diagnosis was summarized as average metabolic equivalent-task hours per week (MET-h/week) (n=1309). Somatic BRAF and KRAS mutations and MSI status were evaluated on a subset of patients (n=1043). Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for overall and disease-specific survival after adjusting for relevant confounders. Stratified analyses were conducted across categories of BRAF, KRAS and MSI, as well as tumor stage and site. Higher pre-diagnostic recreational physical activity was associated with significantly more favorable overall survival (HR for highest vs. lowest category=0.70, 95% CI 0.52-0.96); associations were similar for CRC-specific survival. Results consistently indicated a favorable association with physical activity across strata defined by tumor characteristics. Individuals who were physically active prior to CRC diagnosis experienced better survival than those who were inactive or minimally active. Our results support existing physical activity recommendations for CRC patients and suggest that the beneficial effect of activity is not specific to a particular molecular phenotype of CRC. Copyright © 2015, American Association for Cancer Research.
    No preview · Article · May 2015 · Cancer Epidemiology Biomarkers & Prevention
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    ABSTRACT: High body mass index (BMI) is consistently linked to increased risk of colorectal cancer (CRC) for men, whereas the association is less clear for women. As risk estimates from observational studies may be biased and/or confounded, we conducted a Mendelian randomization study to estimate the causal association between BMI and CRC. We used data from 10,226 CRC cases and 10,286 controls of European ancestry. The Mendelian randomization analysis used a weighted genetic risk score, derived from 77 genome-wide association study identified variants associated with higher BMI, as an instrumental variable (IV). We compared the IV odds ratio (IV-OR) with the OR obtained using a conventional covariate-adjusted analysis. Individuals carrying greater numbers of BMI-increasing alleles had higher CRC risk (per weighted allele OR, 1.31; 95% confidence interval [CI], 1.10-1.57). Our IV estimation results support the hypothesis that genetically influenced BMI is directly associated with risk for CRC (IV-OR per 5 kg/m2, 1.50; 95% CI, 1.13-2.01). In the sex-specific IV analyses higher BMI was associated with higher risk of CRC among women (IV-OR per 5 kg/m2, 1.82; 95% CI, 1.26-2.61). For men, genetically influenced BMI was not associated with CRC (IV-OR per 5 kg/m2, 1.18; 95% CI, 0.73-1.92). High BMI was associated with increased CRC risk for women. Whether abdominal obesity, rather than overall obesity, is a more important risk factor for men requires further investigation. Overall, conventional epidemiologic and Mendelian randomization studies suggest a strong association between obesity and the risk of CRC. Copyright © 2015, American Association for Cancer Research.
    No preview · Article · May 2015 · Cancer Epidemiology Biomarkers & Prevention
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    ABSTRACT: Disease classification system increasingly incorporates information on pathogenic mechanisms to predict clinical outcomes and response to therapy and intervention. Technological advancements to interrogate omics (genomics, epigenomics, transcriptomics, proteomics, metabolomics, metagenomics, interactomics, etc.) provide widely open opportunities in population-based research. Molecular pathological epidemiology (MPE) represents integrative science of molecular pathology and epidemiology. This unified paradigm requires multidisciplinary collaboration between pathology, epidemiology, biostatistics, bioinformatics, and computational biology. Integration of these fields enables better understanding of etiologic heterogeneity, disease continuum, causal inference, and the impact of environment, diet, lifestyle, host factors (including genetics and immunity), and their interactions on disease evolution. Hence, the Second International MPE Meeting was held in Boston in December 2014, with aims to: (1) develop conceptual and practical frameworks; (2) cultivate and expand opportunities; (3) address challenges; and (4) initiate the effort of specifying guidelines for MPE. The meeting mainly consisted of presentations of method developments and recent data in various malignant neoplasms and tumors (breast, prostate, ovarian and colorectal cancers, renal cell carcinoma, lymphoma, and leukemia), followed by open discussion sessions on challenges and future plans. In particular, we recognized need for efforts to further develop statistical methodologies. This meeting provided an unprecedented opportunity for interdisciplinary collaboration, consistent with the purposes of the Big Data to Knowledge, Genetic Associations and Mechanisms in Oncology, and Precision Medicine Initiative of the US National Institute of Health. The MPE meeting series can help advance transdisciplinary population science and optimize training and education systems for twenty-first century medicine and public health.
    No preview · Article · May 2015 · Cancer Causes and Control
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    ABSTRACT: The 2008 Physical Activity Guidelines for Americans recommended a minimum of 75 vigorous-intensity or 150 moderate-intensity minutes per week (7.5 metabolic-equivalent hours per week) of aerobic activity for substantial health benefit and suggested additional benefits by doing more than double this amount. However, the upper limit of longevity benefit or possible harm with more physical activity is unclear. To quantify the dose-response association between leisure time physical activity and mortality and define the upper limit of benefit or harm associated with increased levels of physical activity. We pooled data from 6 studies in the National Cancer Institute Cohort Consortium (baseline 1992-2003). Population-based prospective cohorts in the United States and Europe with self-reported physical activity were analyzed in 2014. A total of 661 137 men and women (median age, 62 years; range, 21-98 years) and 116 686 deaths were included. We used Cox proportional hazards regression with cohort stratification to generate multivariable-adjusted hazard ratios (HRs) and 95% CIs. Median follow-up time was 14.2 years. Leisure time moderate- to vigorous-intensity physical activity. The upper limit of mortality benefit from high levels of leisure time physical activity. Compared with individuals reporting no leisure time physical activity, we observed a 20% lower mortality risk among those performing less than the recommended minimum of 7.5 metabolic-equivalent hours per week (HR, 0.80 [95% CI, 0.78-0.82]), a 31% lower risk at 1 to 2 times the recommended minimum (HR, 0.69 [95% CI, 0.67-0.70]), and a 37% lower risk at 2 to 3 times the minimum (HR, 0.63 [95% CI, 0.62-0.65]). An upper threshold for mortality benefit occurred at 3 to 5 times the physical activity recommendation (HR, 0.61 [95% CI, 0.59-0.62]); however, compared with the recommended minimum, the additional benefit was modest (31% vs 39%). There was no evidence of harm at 10 or more times the recommended minimum (HR, 0.69 [95% CI, 0.59-0.78]). A similar dose-response relationship was observed for mortality due to cardiovascular disease and to cancer. Meeting the 2008 Physical Activity Guidelines for Americans minimum by either moderate- or vigorous-intensity activities was associated with nearly the maximum longevity benefit. We observed a benefit threshold at approximately 3 to 5 times the recommended leisure time physical activity minimum and no excess risk at 10 or more times the minimum. In regard to mortality, health care professionals should encourage inactive adults to perform leisure time physical activity and do not need to discourage adults who already participate in high-activity levels.
    No preview · Article · Apr 2015 · JAMA Internal Medicine
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    Preview · Article · Apr 2015 · Journal of Clinical Oncology

Publication Stats

2k Citations
892.89 Total Impact Points


  • 2010-2015
    • American Cancer Society
      • Epidemiology Research Program
      Atlanta, Georgia, United States
    • Mayo Clinic - Rochester
      Рочестер, Minnesota, United States
    • National Cancer Institute (USA)
      • Division of Cancer Epidemiology and Genetics
      Bethesda, MD, United States
  • 2014
    • Duke University
      Durham, North Carolina, United States
    • Emory University
      • Winship Cancer Institute
      Atlanta, Georgia, United States
  • 2007-2014
    • Fred Hutchinson Cancer Research Center
      • • Division of Public Health Sciences
      • • Cancer Prevention Program
      Seattle, Washington, United States
    • University of Toronto
      Toronto, Ontario, Canada
    • Childcare Resource and Research Unit
      Toronto, Ontario, Canada
    • Samuel Lunenfeld Research Institute
      Toronto, Ontario, Canada
  • 2012
    • Memorial University of Newfoundland
      • Division of Community Health and Humanities
      St. John's, Newfoundland and Labrador, Canada
  • 2008
    • University of Washington Seattle
      Seattle, Washington, United States
  • 2004
    • Mount Sinai Hospital, Toronto
      Toronto, Ontario, Canada