Study population

The NHSII enrolled 116,608 female nurses residing in the US aged 25–42 years in 1989, when participants completed a baseline self-administered questionnaire about lifestyle risk factors and diagnosed conditions. Since then, biennial questionnaires were sent to update this information, with response rates over 93%. More details about the NHSII are described elsewhere.16,17 The study protocol was approved by the institutional review boards of the Brigham and Women’s Hospital and the Harvard T.H. Chan School of Public Health, and those of participating registries as required.

Assessment of physical activity

The 1997 questionnaire inquired about physical activity during adolescence and early adulthood. Participants reported average hours a week (none, 1, 2–5, 6–10, 11–20, 21–40, 41–60, 61–90, 90+ h/week) of walking to and from school or work, moderate recreational activities (e.g., hiking, walking for exercise, casual cycling, yard work), and strenuous recreational activities (e.g., running, aerobics, lap swimming) during grades 7–8 (ages 12–13 years), grades 9–12 (ages 14–17 years), ages 18–22, 23–29, and 30–34 years. We assigned average metabolic equivalent of task (MET) for each of these activities to classify intensities (i.e., walking 3 MET, moderate 4.5 MET, and strenuous 7 MET) based on the compendium of physical activities.18,19 We summed MET-h/week in each of these activities to obtain total physical activity. The 1997 questionnaire also inquired about the time spent watching television [(TV) (none, 1, 2–5, 6–10, 11–20, 21–40, 41–60, 61–90, ≥ 91 h/week)] during adolescence and early adulthood. For this analysis, we calculated the average of total physical activity (MET-h/week) from ages 12 to 22 years.

Adult recreational physical activity (32–64 years old) was assessed in 1989, 1991, 1997, 2001, 2005, and 2009.16,20 Participants reported average time spent per week on a variety of recreational activities and hours per week spent watching TV. We previously showed that in the NHS time spent watching TV in adults predicted risk of type II diabetes better than other measures of sedentary behaviours.21,22

We assigned MET values for each of these activities to obtain average total physical activity (in MET-h/week) in each questionnaire cycle where physical activity was assessed.18,19 Measures of physical activity have been validated previously (for more detail on reproducibility and validity of the physical activity questionnaires refer to Supplemental Material and our previous publications.16,17,20,23,24,25,26) Cumulative average adult physical activity was calculated using all available data up to and including the questionnaire 2 years prior to the follow-up cycle at which the most recent endoscopy was reported. Total physical activity during adolescence and cumulative average adult physical activity were weakly correlated (Spearman r = 0.19; P < 0.001).

Assessment of dietary factors and other covariates

In 1991 and every 4 years thereafter, diet was assessed through a validated semi-quantitative food frequency questionnaire (FFQ).27,28 In addition, in 1998, 47,355 participants (55% of the cohort), at that time 34–51 years old, completed a validated FFQ inquiring about diet during high school.29 Previous analyses showed that the risk factor profiles of this subsample were similar to those who did not respond to the high school FFQ.8

Height and current weight were obtained on the 1989 baseline questionnaire which also included a 9-level pictogram on body shape to assess body fatness (1 = most lean body shape and 9 = most overweight body shape) at age 5, 10 and 20 years. Weight and other relevant covariates such as lifestyle factors (e.g., aspirin use, smoking status, alcohol intake, family history of CRC) were updated every 2 years.6

Outcome ascertainment

Polyps are often asymptomatic and detected during a lower bowel endoscopy (i.e., either sigmoidoscopy or colonoscopy). Between 1998 and 2011, participants were asked on their biennial follow-up questionnaire whether they underwent a lower bowel endoscopy, the reasons for endoscopy (symptoms or screening) and whether colorectal polyps were diagnosed. Participants who reported a diagnosis of colorectal polyp were mailed a consent form requesting permission to obtain and review their medical records. Study investigators who were blinded to exposure status (e.g., physical activity) reviewed medical records and recorded anatomical location (proximal, distal, and rectum), subtype (adenoma only, serrated lesions only, both adenoma and serrated lesions), and histology and size (advanced: defined as size ≥ 1 cm or any mention of villous histology or high-grade dysplasia; non-advanced: < 1 cm and tubular adenomas) of colorectal polyps. Serrated lesions included the following subtypes: hyperplastic polyp, sessile serrated adenoma/polyp, and traditional serrated adenoma.30

Statistical analysis

For this analysis, we included 28,250 women who responded to a) the 1997 questionnaire, which included information about physical activity during adolescence and adulthood, b) the 1998 FFQ high school questionnaire, and c) underwent at least one lower bowel endoscopy during our follow-up period, i.e., 1998 to 2011. To consider individuals who underwent multiple endoscopies between 1998 and 2011 and reduce potential bias due to time-varying exposure, we used an Anderson-Gill data set structure with a new record for each 2 year follow-up during which participants underwent an endoscopy.31 Therefore, participants who underwent multiple endoscopies during follow-up could have multiple observations in the dataset. Exposure and covariates were set at one cycle (2 years) prior the endoscopy. Once a participant was diagnosed with one or more polyps, that participant was censored for all subsequent follow-up cycles.

We used multivariable logistic regression (PROC GENMOD, SAS 9.4, SAS institute Inc., Cary, NC, USA) for clustered data (i.e., each participant was defined as a cluster, therefore accounting for multiple endoscopies) to estimate odds ratios (OR) and 95% confidence intervals for the association between total physical activity during adolescence (<21, 21 to 35.9, 36 to 47.9, 48 to 71.9, ≥ 72 MET-h/week) and risk of adenoma. Categories of physical activity were derived based on its distribution and informative cutoffs.23 We also estimated associations per 21 MET-h/week (i.e., equivalent to 1 h of moderate intensity physical activity every day, which is the recommended physical activity level for children and adolescents)32 and tested for trend via a Wald test by including the median of physical activity in each category as a single continuous exposure variable into the models.

We ran different multivariable models adjusting for several adolescent and adult covariates selected based on the literature on known or suspected risk factors for colorectal adenomas or cancer.1,5,6,7,8 The first model (age-adjusted) included age at baseline, time period of endoscopy, number of reported endoscopies, time in years since most recent endoscopy and reason for current endoscopy. The second multivariable model (Model 2) was additionally adjusted for height (continuous), body fatness (1, 2, 3, 4, 5, ≥ 6) at age 5 years (body shape at age 5 was the strongest predictor of adenoma6), dietary intake during adolescence [high school FFQ: total calories (quintiles), unprocessed red meat and processed meat (quintiles), total dairy (quintiles), and total fibre (quintiles)], current (adult) aspirin use (≥2 or <2 times/week), current (adult) alcohol intake (< 4.9, 5–9.9, 10–14.9, ≥ 15 g/d), current pack-years of smoking (never, 0–10, > 10–20, > 20–40, > 40 pack-years), and family history of CRC (yes/no). Associations were also examined after further adjustment for cumulative average adult physical activity (quintiles), adult body mass index (BMI, < 25, 25 to 29.9, ≥ 30 kg/m2), and time spent watching TV during adolescence (< 3.5, 3.5 to 6.9, 7 to 10.4, 10.5 to 13.9, ≥ 14 h/week). We examined other potential confounders (total folate intake, total calcium intake and western dietary pattern during adolescence, pack-years of smoking before age 20, BMI at age 18, postmenopausal hormone use, total fibre, red and processed meat intake during adulthood) by including these variables separately (i.e., one by one) to Model 2. Adjustment for these variables did not alter the magnitude of associations, therefore, we excluded them from the final model.

To assess interactions, we studied associations after stratification by family history of CRC, age at adenoma diagnosis (<50 years and ≥ 50 years), BMI at 18 years (<23 kg/m2 and ≥ 23 kg/m2), and smoking status (never and ever). Tests for interaction were performed by including the multiplicative term (cross-product term) of the exposure and each stratification variable in the model and using a Wald test to assess statistical significance.

During adolescence physical activity levels were on average higher (median 40.1 MET-h/week; interquartile range from 23.8 to 70.4) than during adulthood (median 26.4 MET-h/week; interquartile range from 8.7 to 28.6). To assess joint associations of physical activity during adolescence and adulthood with adenoma, we classified participants into four groups according to physical activity and stage of life defining high physical activity as highest tertile (≥53.3 MET-h/week for adolescence and ≥ 23.1 MET-h/week for adulthood) and low physical activity as the bottom two tertiles. Cut-offs were determined post hoc based on our observation that inverse associations between physical activity during age 12–22 years and adenoma were only seen with physical activity levels above 48 to < 72 MET-h/week. We used the highest tertile (≥ 53.3 MET-h/week) to define high physical activity during adolescence. Both subgroup and joint association analyses were adjusted for the same covariates included in Model 2.

We used SAS 9.4 for all analyses (SAS institute Inc., Cary, NC, USA). A two-sided P value of 0.05 was considered statistically significant.