{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:11:12Z","timestamp":1768565472199,"version":"3.49.0"},"posted":{"date-parts":[[2024,7,3]]},"group-title":"Epidemiology","reference-count":55,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,7,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>To investigate whether the higher risks of certain cancers associated with high cardiorespiratory fitness can be explained by increased detection and unobserved confounders.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Design<\/jats:title>\n                  <jats:p>Nationwide sibling-controlled cohort study of adolescents.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Setting<\/jats:title>\n                  <jats:p>Sweden.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Participants<\/jats:title>\n                  <jats:p>1 124 049 men of which 477 453 were full siblings, who underwent mandatory military conscription examinations between 1972 and 1995 at a mean age of 18.3 years.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Main outcome measures<\/jats:title>\n                  <jats:p>Hazard ratios (HR) and 95% confidence intervals (CI) of overall cancer diagnosis and cancer mortality, and 14 site-specific cancers (diagnosis or death), as recorded in the Swedish National Patient Register or Cause of Death Register until 31 December 2023, modelled using flexible parametric regressions.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Participants were followed until a median (maximum) age of 55.9 (73.5) years, during which 98 410 were diagnosed with cancer and 16 789 had a cancer-related death (41 293 and 6908 among full siblings respectively). The most common cancers were non-melanoma skin (27 105 diagnoses &amp; 227 deaths) and prostate cancer (24 211 diagnoses &amp; 869 deaths). In cohort analysis, those in the highest quartile of cardiorespiratory fitness had a higher risk of prostate (adjusted HR 1.10; 95% CI: 1.05 to 1.16) and skin cancer (e.g., non-melanoma HR 1.44; 1.37 to 1.50) compared to those in the lowest quartile, which led to a higher risk of any type of cancer diagnosis (HR 1.08; 1.06 to 1.11). However, those in the highest quartile had a lower risk of cancer mortality (HR 0.71; 0.67 to 0.76). When comparing full siblings, and thereby controlling for all behavioural, environmental, and genetic factors they share, the excess risk of prostate (HR 1.01; 0.90 to 1.13) and skin cancer (e.g., non-melanoma HR 1.09; 0.99 to 1.20) attenuated to the null. In contrast, the lower risk of overall cancer mortality was still statistically significant after control for such shared confounders (HR 0.78; 0.68 to 0.89). For other site-specific cancers, the influence of such confounding tended to vary, but none showed the same excess risk as prostate and non-melanoma skin cancer.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>The association between high levels of adolescent cardiorespiratory fitness and excess risk of some cancers, such as prostate and non-melanoma skin cancer, appears to be fully explained by unobserved confounders shared between full siblings. However, the protective association with cancer mortality persists even after control for such confounding.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Summary box<\/jats:title>\n                  <jats:p>\n                    What is already known on this topic\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>Adolescent physical activity and cardiorespiratory fitness are considered important factors for the prevention of cancer based on evidence from observational studies.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Observational studies are, however, vulnerable to unobserved confounders and bias processes, including health-seeking behaviours and genetic and environmental confounders.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>These biases could explain why prior studies have found that high adolescent cardiorespiratory fitness is associated with higher risks of some cancers, typically low-mortality cancers such as prostate and non-melanoma skin cancer.<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                    What this study adds\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>This nationwide cohort study of 1.1 million male adolescents showed that while higher cardiorespiratory fitness was associated with excess risk of the most common cancers - prostate and non-melanoma skin - these associations attenuated to the null when accounting for behavioural, environmental, and genetic confounders shared between full siblings.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>In contrast, high adolescent cardiorespiratory fitness was associated with a lower risk of overall cancer mortality, which remained after controlling for unobserved confounders shared between full siblings.<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.07.01.24309761","type":"posted-content","created":{"date-parts":[[2024,7,3]],"date-time":"2024-07-03T18:10:32Z","timestamp":1720030232000},"source":"Crossref","is-referenced-by-count":0,"title":["Adolescent Cardiorespiratory Fitness and Risk of Cancer in Late Adulthood: Nationwide Sibling-Controlled Cohort Study"],"prefix":"10.64898","author":[{"given":"Marcel","family":"Ballin","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Berglind","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pontus","family":"Henriksson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Neovius","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Nordstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francisco B.","family":"Ortega","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elina","family":"Sillanp\u00e4\u00e4","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Nordstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Viktor H.","family":"Ahlqvist","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024070509350555000_2024.07.01.24309761v1.1","unstructured":"International Agency for Research on Cancer. 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