Observational and genetic associations between cardiorespiratory fitness and cancer: a UK Biobank and international consortia study.

BACKGROUND: The association of fitness with cancer risk is not clear. METHODS: We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of lung, colorectal, endometrial, breast, and prostate cancer in a subset of UK Biobank participants who completed a submaximal fitness test in 2009-12 (N = 72,572). We also investigated relationships using two-sample Mendelian randomisation (MR), odds ratios (ORs) were estimated using the inverse-variance weighted method. RESULTS: After a median of 11 years of follow-up, 4290 cancers of interest were diagnosed. A 3.5 ml O2⋅min-1⋅kg-1 total-body mass increase in fitness (equivalent to 1 metabolic equivalent of task (MET), approximately 0.5 standard deviation (SD)) was associated with lower risks of endometrial (HR = 0.81, 95% CI: 0.73-0.89), colorectal (0.94, 0.90-0.99), and breast cancer (0.96, 0.92-0.99). In MR analyses, a 0.5 SD increase in genetically predicted O2⋅min-1⋅kg-1 fat-free mass was associated with a lower risk of breast cancer (OR = 0.92, 95% CI: 0.86-0.98). After adjusting for adiposity, both the observational and genetic associations were attenuated. DISCUSSION: Higher fitness levels may reduce risks of endometrial, colorectal, and breast cancer, though relationships with adiposity are complex and may mediate these relationships. Increasing fitness, including via changes in body composition, may be an effective strategy for cancer prevention.

Non-occupational physical activity and risk of cardiovascular disease, cancer and mortality outcomes: a dose-response meta-analysis of large prospective studies.

OBJECTIVE: To estimate the dose-response associations between non-occupational physical activity and several chronic disease and mortality outcomes in the general adult population. DESIGN: Systematic review and cohort-level dose-response meta-analysis. DATA SOURCES: PubMed, Scopus, Web of Science and reference lists of published studies. ELIGIBILITY CRITERIA: Prospective cohort studies with (1) general population samples >10 000 adults, (2) ≥3 physical activity categories, and (3) risk measures and CIs for all-cause mortality or incident total cardiovascular disease, coronary heart disease, stroke, heart failure, total cancer and site-specific cancers (head and neck, myeloid leukaemia, myeloma, gastric cardia, lung, liver, endometrium, colon, breast, bladder, rectum, oesophagus, prostate, kidney). RESULTS: 196 articles were included, covering 94 cohorts with >30 million participants. The evidence base was largest for all-cause mortality (50 separate results; 163 415 543 person-years, 811 616 events), and incidence of cardiovascular disease (37 results; 28 884 209 person-years, 74 757 events) and cancer (31 results; 35 500 867 person-years, 185 870 events). In general, higher activity levels were associated with lower risk of all outcomes. Differences in risk were greater between 0 and 8.75 marginal metabolic equivalent of task-hours per week (mMET-hours/week) (equivalent to the recommended 150 min/week of moderate-to-vigorous aerobic physical activity), with smaller marginal differences in risk above this level to 17.5 mMET-hours/week, beyond which additional differences were small and uncertain. Associations were stronger for all-cause (relative risk (RR) at 8.75 mMET-hours/week: 0.69, 95% CI 0.65 to 0.73) and cardiovascular disease (RR at 8.75 mMET-hours/week: 0.71, 95% CI 0.66 to 0.77) mortality than for cancer mortality (RR at 8.75 mMET-hours/week: 0.85, 95% CI 0.81 to 0.89). If all insufficiently active individuals had achieved 8.75 mMET-hours/week, 15.7% (95% CI 13.1 to 18.2) of all premature deaths would have been averted. CONCLUSIONS: Inverse non-linear dose-response associations suggest substantial protection against a range of chronic disease outcomes from small increases in non-occupational physical activity in inactive adults. PROSPERO registration number CRD42018095481.

Association of Accelerometer-Measured Sedentary Accumulation Patterns With Incident Cardiovascular Disease, Cancer, and All-Cause Mortality.

Background Emerging evidence suggests accruing sedentary behavior (SB) in relatively more prolonged periods may convey additional cardiometabolic risks, but few studies have examined prospective outcomes. We examined the association of SB accumulation patterns with incident cardiovascular disease (CVD), cancer, and all-cause mortality (ACM). Methods and Results Data were from 7671 EPIC-Norfolk (European Prospective Investigation Into Cancer and Nutrition-Norfolk) cohort middle- to older-aged adults who wore accelerometers on the right hip for 4 to 7 days. Cox proportional hazards regression modeled associations between 2 measures of SB accumulation and incident CVD, cancer, and ACM. These were usual SB bout duration (the midpoint of each individual's SB accumulation curve, fitted using nonlinear regression) and alpha (hybrid measure of bout frequency and duration, with higher values indicating relatively shorter bouts and fewer long bouts). Models were adjusted for potential confounders, then further for 24-hour time-use compositions. During mean follow-up time of 6.4 years, 339 ACM, 1106 CVD, and 516 cancer events occurred. Elevated rates of incident cancer and ACM were seen with more prolonged SB accumulation (lower alpha, higher usual SB bout duration) but not CVD. For usual SB bout duration and alpha, respectively, the confounder-adjusted hazard ratios per SD of the exposure were 1.12 (95% CI, 1.02-1.23) and 0.88 (95% CI, 0.79-0.98) with incident cancer and 1.16 (95% CI, 1.07-1.26) and 0.80 (95% CI, 0.72-0.89) with ACM (all P<0.05). Further adjustment for 24-hour time use weakened associations with ACM for usual bout duration (hazard ratio, 1.06; 95% CI, 0.97-1.16; P=0.209) and partially for alpha (hazard ratio, 0.87; 95% CI, 0.77-0.99; P=0.029). Conclusions Accruing SB in longer bout durations was associated with higher rates of incident cancer and ACM but not with incident CVD, with some evidence of direct SB accumulation effects independent of 24-hour time use. Findings provide some support for considering SB accumulation as an adjunct target of messaging to "sit less and move more."

Cardiorespiratory fitness assessment using risk-stratified exercise testing and dose-response relationships with disease outcomes.

Cardiorespiratory fitness (CRF) is associated with mortality and cardiovascular disease, but assessing CRF in the population is challenging. Here we develop and validate a novel framework to estimate CRF (as maximal oxygen consumption, VO2max) from heart rate response to low-risk personalised exercise tests. We apply the method to examine associations between CRF and health outcomes in the UK Biobank study, one of the world's largest and most inclusive studies of CRF, showing that risk of all-cause mortality is 8% lower (95%CI 5-11%, 2670 deaths among 79,981 participants) and cardiovascular mortality is 9% lower (95%CI 4-14%, 854 deaths) per 1-metabolic equivalent difference in CRF. Associations obtained with the novel validated CRF estimation method are stronger than those obtained using previous methodology, suggesting previous methods may have underestimated the importance of fitness for human health.

Is occupational physical activity associated with mortality in UK Biobank?

BACKGROUND: Current physical activity guidelines do not distinguish between activity accumulated in different behavioural domains but some studies suggest that occupational physical activity (OPA) may not confer health benefits and could even be detrimental. The purpose of this study was to investigate associations between OPA and mortality outcomes. METHODS: From baseline (2006-2010), 460,901 UK Biobank participants (aged 40-69 years) were followed for a median 12.0 (IQR: 11.3-12.7) years. OPA was categorised by cross-tabulating degree of manual work and walking/standing work amongst those in paid employment (n = 267,765), and combined with categories of occupational status for those not in paid employment (n = 193,136). Cox proportional hazards models were used to estimate sex-stratified hazard ratios (HR) and 95% confidence intervals (CI) for mortality from all causes, CVD, and cancer by occupational group, and for working hours/week and non-occupational physical activity stratified by occupational group. Models included adjustment for age and a range of lifestyle, socio-economic and health-related covariates. RESULTS: During 5,449,989 person-years of follow-up, 28,740 deaths occurred. Compared to those reporting no heavy manual or walking/standing work (e.g. sedentary office workers) and adjusting for covariates, retirement was associated with lower mortality in women (HR = 0.62, CI: 0.53-0.72) and men (HR = 0.80, CI: 0.71-0.90), whereas unemployment was associated with higher mortality in men only (HR = 1.24, CI: 1.07-1.45). Within the working population, there was no evidence of differences in all-cause, CVD or cancer mortality by OPA group when comparing those reporting higher levels of OPA to the lowest OPA reference group for both women and men. Working < 35 h/week versus 35-40 h/week was associated with lower mortality in women (HR = 0.85, CI: 0.79-0.92) and men (HR = 0.83, CI: 0.78-0.89), with no interaction by OPA. Non-occupational physical activity was associated with lower mortality in working women (HR = 0.89 per 5 kJ/day/kg, CI: 0.84-0.95) and men (HR = 0.87 per 5 kJ/day/kg, CI: 0.84-0.91), with no interaction by OPA group. CONCLUSIONS: Jobs classified as higher levels of OPA may not be as active as reported, or the types of physical activity performed in those jobs are not health-enhancing. Irrespective of OPA category or employment status, non-occupational physical activity appears to provide health benefits.

Use of the prevented fraction for the population to determine deaths averted by existing prevalence of physical activity: a descriptive study.

BACKGROUND: Disease and mortality burdens of unhealthy lifestyle behaviours are often reported. In contrast, the positive narrative around the burdens that an existing behaviour have averted is rarely acknowledged. We aimed to estimate the prevented fraction for the population (PFP) for premature mortality averted by physical activity on a global scale. METHODS: In this descriptive study, we obtained previously published data on physical activity prevalence (2001-16) and relative risks of all-cause mortality for 168 countries. We combined the data in Monte-Carlo simulations to estimate country-specific, mean PFP values, corresponding to percentage of mortality averted, and their 95% CIs. High prevented fractions indicated an increased proportion of deaths averted due to physical activity. Using mortality data for all people in a country aged 40-74 years, we estimated the number of premature deaths averted for all adults and by gender. We present the median and range of the prevented fractions globally, by WHO region, and by World Bank income classification. FINDINGS: The global median PFP was 15·0% (range 6·6-20·5), conservatively equating to 3·9 million (95% CI 2·5-5·6) premature deaths averted annually. The African region had the highest median prevented fraction (16·6% [range 12·1-20·5]) and the Americas had the lowest (13·1% [10·8-16·6]). Low-income countries tended to have higher prevented fractions (group median 17·9% [12·3-20·5]) than high-income countries (14·1% [6·6-17·8]). Globally, the median prevented fraction was higher for men (16·0% [7·8-20·7] than women (14·1% [5·0-20·4]). INTERPRETATION: Existing physical activity prevalence has contributed to averting premature mortality across all countries. PFP has utility as an advocacy tool to promote healthy lifestyle behaviours. By making the case of what has been achieved, the prevented fraction can show the value of current investment and services, which might be conducive to political support. FUNDING: UK Medical Research Council, British Heart Foundation, Cancer Research UK, Economic and Social Research Council, National Institute for Health Research, Wellcome Trust, Heart Foundation Australia.

Estimating physical activity from self-reported behaviours in large-scale population studies using network harmonisation: findings from UK Biobank and associations with disease outcomes.

BACKGROUND: UK Biobank is a large prospective cohort study containing accelerometer-based physical activity data with strong validity collected from 100,000 participants approximately 5 years after baseline. In contrast, the main cohort has multiple self-reported physical behaviours from > 500,000 participants with longer follow-up time, offering several epidemiological advantages. However, questionnaire methods typically suffer from greater measurement error, and at present there is no tested method for combining these diverse self-reported data to more comprehensively assess the overall dose of physical activity. This study aimed to use the accelerometry sub-cohort to calibrate the self-reported behavioural variables to produce a harmonised estimate of physical activity energy expenditure, and subsequently examine its reliability, validity, and associations with disease outcomes. METHODS: We calibrated 14 self-reported behavioural variables from the UK Biobank main cohort using the wrist accelerometry sub-cohort (n = 93,425), and used published equations to estimate physical activity energy expenditure (PAEESR). For comparison, we estimated physical activity based on the scoring criteria of the International Physical Activity Questionnaire, and by summing variables for occupational and leisure-time physical activity with no calibration. Test-retest reliability was assessed using data from the UK Biobank repeat assessment (n = 18,905) collected a mean of 4.3 years after baseline. Validity was assessed in an independent validation study (n = 98) with estimates based on doubly labelled water (PAEEDLW). In the main UK Biobank cohort (n = 374,352), Cox regression was used to estimate associations between PAEESR and fatal and non-fatal outcomes including all-cause, cardiovascular diseases, respiratory diseases, and cancers. RESULTS: PAEESR explained 27% variance in gold-standard PAEEDLW estimates, with no mean bias. However, error was strongly correlated with PAEEDLW (r = -.98; p < 0.001), and PAEESR had narrower range than the criterion. Test-retest reliability (Λ = .67) and relative validity (Spearman = .52) of PAEESR outperformed two common approaches for processing self-report data with no calibration. Predictive validity was demonstrated by associations with morbidity and mortality, e.g. 14% (95%CI: 11-17%) lower mortality for individuals meeting lower physical activity guidelines. CONCLUSIONS: The PAEESR variable has good reliability and validity for ranking individuals, with no mean bias but correlated error at individual-level. PAEESR outperformed uncalibrated estimates and showed stronger inverse associations with disease outcomes.

Impact of follow-up time and analytical approaches to account for reverse causality on the association between physical activity and health outcomes in UK Biobank.

BACKGROUND: The advent of very large cohort studies (n > 500 000) has given rise to prospective analyses of health outcomes being undertaken after short (<4 years) follow-up periods. However, these studies are potentially at risk of reverse causality bias. We investigated differences in the associations between self-reported physical activity and all-cause and cardiovascular disease (CVD) mortality, and incident CVD, using different follow-up time cut-offs and methods to account for reverse causality bias. METHODS: Data were from n = 452 933 UK Biobank participants, aged 38-73 years at baseline. Median available follow-up time was 7 years (for all-cause and CVD mortality) and 6.1 years (for incident CVD). We additionally analysed associations at 1-, 2- and 4-year cut-offs after baseline. We fit up to four models: (1) adjusting for prevalent CVD and cancer, (2) excluding prevalent disease, (3) and (4) Model 2 excluding incident cases in the first 12 and 24 months, respectively. RESULTS: The strength of associations decreased as follow-up time cut-off increased. For all-cause mortality, Model 1 hazard ratios were 0.73 (0.69-0.78) after 1 year and 0.86 (0.84-0.87) after 7 years. Associations were weaker with increasing control for possible reverse causality. After 7-years follow-up, the hazard ratios were 0.86 (0.84-0.87) and 0.88 (0.86-0.90) for Models 1 and 4, respectively. Associations with CVD outcomes followed similar trends. CONCLUSIONS: As analyses with longer follow-up times and increased control for reverse causality showed weaker associations, there are implications for the decision about when to analyse a cohort study with ongoing data collection, the interpretation of study results and their contribution to meta-analyses.

Specific physical activities, sedentary behaviours and sleep as long-term predictors of accelerometer-measured physical activity in 91,648 adults: a prospective cohort study.

BACKGROUND: The evidence for the prospective relationships between specific physical activities (PA), sedentary behaviours (SB) and sleep on subsequent total PA levels is scarce. The purpose of this study was to examine prospective associations of self-reported PA, SB and sleep, and changes in these with subsequent accelerometer-measured PA. METHODS: A sub-sample of 91,648 UK Biobank participants reported moderate-to-vigorous PA (MVPA), lifestyle activities, TV viewing, computer use and sleep through screen-based questionnaires at baseline (2006-2010), and provided valid accelerometry data (dominant wrist-worn for 7 days between 2013 and 2015). A further sub-sample of 7709 participants repeated the screen-based questionnaires between 2012 and 2013. RESULTS: In both women (n = 51,545) and men (n = 40,103), positive associations were observed between all self-reported measures of PA at baseline (MVPA, lifestyle/job-related activities, active transporting modes) and accelerometer-measured PA levels at follow-up (median 5.7 years); an exception was 'walking/standing at work' in women. Sedentary time at work, TV viewing and computer use were inversely associated with PA at follow-up. Sleeping either more or less than 7 h/day at baseline was associated with lower PA at follow-up (except for ≤6 h/day in men). In the repeat self-report sub-sample (median 4.3 years), relatively higher physical activity at follow-up was observed in those who maintained or achieved favourable levels of MVPA, walking for pleasure, strenuous sports, other exercises, heavy DIY (in women), heavy physical work, and walking/standing at work (in women), sedentary time at work, getting about methods (in women), commuting methods (in women), TV viewing, computer use or sleep. CONCLUSIONS: Initial levels of PA, SB and sleep, and changes in these variables were generally associated with subsequent accelerometer-measured PA in the expected directions, suggesting these specific behaviours all contribute to the total volume of physical activity over time and could thus be targets for intervention.

Self-rated walking pace and all-cause, cardiovascular disease and cancer mortality: individual participant pooled analysis of 50 225 walkers from 11 population British cohorts.

BACKGROUND/OBJECTIVES: Walking pace is associated with risk of premature mortality. However, whether this relationship is independent of total volume of physical activity and highest physical activity intensity remains unclear. We examined the associations between walking pace and cause-specific mortality, investigating the potential modifying effect of factors such as total physical activity volume, highest physical activity intensity, age, sex and body mass index (BMI). METHODS: Prospective pooled analysis of 11 population-based baseline surveys in England and Scotland between 1994 and2008 that were linked with mortality records. Multivariate-adjusted Cox proportional hazards models examined associations between walking pace (slow, average, brisk/fast) and all-cause, cancer and cardiovascular disease (CVD) mortality. RESULTS: 50 225 walkers were entered in the core analyses. Among participants who did not experience an event in the first 2 years of follow-up (n=49 731), walking at an average or brisk/fast pace was associated with a reduced risk of all-cause (20% (95% CI 12% to 28%) and 24% (95% CI 13% to 33%), respectively) and CVD mortality (24% (95% CI 9% to 36%) and 21% (95% CI 1% to 38%), respectively), compared with reporting walking at a slow pace. In stratified analyses, such associations were evident among those over 50 years, those not meeting the physical activity recommendations and those who did not undertake vigorous-intensity activity. There were no interactions by sex or BMI. No associations were seen between pace and cancer mortality. CONCLUSION: Walking benefits health. Assuming causality, these analyses suggest that increasing walking pace could reduce risk for all-cause and CVD mortality. Walking pace could be emphasised in public health messages, especially in situations when increase in walking volume or frequency is less feasible.