Weight Cycling and Cancer Incidence
Weight Cycling and Cancer Incidence
The participants of this study (86,402 men and 97,785 women) were from the CPS-II Nutrition Cohort, a prospective study of cancer incidence begun in 1992. The Nutrition Cohort, which is described in detail elsewhere, was formed as a subcohort of CPS-II, a prospective study of cancer mortality involving approximately 1.2 million Americans enrolled in 1982. Nutrition Cohort participants were recruited from CPS-II participants between the ages of 50 and 74 years who were living in 21 states. Participants completed a self-administered questionnaire at baseline in 1992–1993 that included questions on demographic, anthropometric, medical, and lifestyle information. Follow-up questionnaires to update exposure information and to ascertain newly diagnosed cancers were sent to living Nutrition Cohort members in 1997 and every 2 years since. The response rate on all of the follow-up questionnaires, among those cohort participants who were mailed surveys, was at least 85%. Follow-up time for this study was from the date of receipt of the baseline survey in 1992–1993 to the date of diagnosis of cancer, death, date of the last survey returned, or June 30, 2009, whichever came first. All aspects of the CPS-II Nutrition Cohort Study were approved by the Emory University Institutional Review Board (Atlanta, Georgia).
CPS-II participants were excluded from this analysis if they were lost to follow-up (3,141 men and 3,111 women), reported any prevalent cancer other than nonmelanoma skin cancer in 1982 or 1992–1993 (9,769 men and 13,094 women), self-reported a cancer that could not be verified (527 men and 354 women), or self-reported a cancer more than 6 months before the diagnosis date of that cancer (100 men and 48 women). Also excluded were participants with missing body mass index (BMI, expressed as weight (kg)/height (m)) or BMI <18.5 in 1982 or 1992 (2,161 men and 4,174 women), missing information on number of times a participant purposely lost ≥10 pounds (4.54 kg), or regained weight that was purposefully lost (1,098 men and 1,866 women), as well as those who reported never having purposefully lost ≥10 pounds but reported ≥10 pounds as the most weight ever purposefully lost (1,070 men and 936 women), and those who reported the number of times that weight was purposefully lost that differed from the number of times weight was regained by more than 2 (2,468 men and 3,004 women). The characteristics of the individuals excluded for missing or invalid weight loss and regain information are shown in Web Table 1 http://aje.oxfordjournals.org/content/182/5/394/suppl/DC1 available at http://aje.oxfordjournals.org/. Finally, because an undiagnosed cancer at baseline may have influenced weight patterns, the first 2 years of follow-up (1992–1994, 3,276 men and 1,678 women) were excluded from all analyses. For analyses of endometrial cancer, women who reported removal of their uterus or had unknown uterine status at baseline were also excluded (27,022 women). Likewise, for ovarian cancer analyses, women who reported removal of their ovaries or had unknown ovarian status at baseline were also excluded (15,811 women). Women who reported removal of their uterus or ovaries during follow-up were censored from analyses of these cancers at the time of receipt of the questionnaire on which the procedure was reported. Thus, the final analytical cohort for this study comprised 62,792 men and 69,520 women except for analyses of endometrial or ovarian cancer, where the analytical cohort was 42,498 or 53,709 women, respectively.
A total of 25,317 first cancers occurred in the analytical cohort between 1994 and 2009. Of these, 24,217 were self-reported on follow-up questionnaires and subsequently verified through medical records (n = 15,911) or linkage with state cancer registries (n = 8,306). An additional 1,100 cancers were identified through linkage to the National Death Index. For analyses of all cancers and specific cancers, all cases were the first diagnosed cancer for that individual. In situ diseases were not included for breast, prostate, colon, or rectal cancers. Aggressive prostate cancer was defined as a Gleason score ≥8, American Joint Committee on Cancer tumor stage T3 or T4, or lethal prostate cancer of unknown stage.
CPS-II Nutrition Cohort participants were asked 2 questions about weight cycling on the baseline questionnaire: "How many times in your life have you purposely lost 10 pounds or more?" and "How many times in your life have you regained as much as 10 pounds that you previously had lost?" A write-in answer was required for both questions with space for a range from 0 to 99. A weight cycle was defined as a combination of both an intentional loss and a subsequent regain. Thus, someone who reported 3 weight losses and 3 subsequent regains was assigned 3 weight cycles, whereas someone who reported 3 weight losses but only 2 regains was assigned 2 weight cycles. The individuals who reported weight cycling ("weight cyclers") were further categorized by the total number of cycles they reported: 1–4, 5–9, 10–19, and 20 or more weight cycles. Weight change pattern or trajectory was not considered in assigning weight cycling status or category.
BMI in 1982 and 1992 was calculated by using self-reported body weight on questionnaires completed at those times and height self-reported on the 1982 questionnaire. BMI at age 18 years was calculated by using weight at age 18 years recalled and reported on the 1992 questionnaire.
All statistical analyses were conducted with SAS, version 9.3, software (SAS Institute, Inc., Cary, North Carolina). Cox proportional hazards regression was used to determine the hazard ratios and 95% confidence intervals for the association of weight cycling with cancer incidence. The time scale for the analysis was time in study from cohort entry in 1992–1993. P values for linear trend were estimated by modeling weight cycles as a continuous variable and were derived by use of the Wald test. The Cox proportional hazards assumption was tested by modeling multiplicative interaction terms between weight cycling numbers and time. The statistical significance of the interaction term was assessed by using the likelihood ratio test, and no deviations from proportional hazards were found. Interactions between either BMI or age at baseline and weight cycling were tested by using the likelihood ratio test in which either variable was modeled categorically. All P values are 2 sided.
Cox models were adjusted for age by stratifying on exact year of age in 1992. Additional covariates included in the multivariable-adjusted models were race (white, black, or other/missing), education (some high school, high school graduate, some college, college graduate, or missing), smoking status (nonsmoker, former <20 years, former ≥20 years, current <40 years, current ≥40 years, ever/unclassifiable, or missing), physical activity in metabolic equivalents (<8, 8 to <17.5, 17.5 to <31.5, ≥31.5/week, or missing), use of aspirin or other nonsteroidal antiinflammatory drugs (not current user, 1–14 pills/month, 15–29 pills/month, 30–59 pills/month, ≥60 pills/month, or missing/unknown), and history of diabetes (yes, no). For analyses of women, postmenopausal hormone use (never, current estrogen, current combined hormone replacement therapy, former estrogen or combined hormone replacement therapy, or ever/other/unknown) was also included in the model. Included in analyses of prostate, breast, and colon and rectal cancer were history of prostate-specific antigen testing (starting in 1997), mammography (starting in 1992), and colorectal endoscopy (starting in 1997), respectively, and all were modeled as time-dependent variables. BMI in 1992 (continuous, modeled linearly) was also included in the models as indicated. The inclusion of alcohol intake as a covariate did not change the associations and was not included in the final multivariable-adjusted model.
Methods
Study Population
The participants of this study (86,402 men and 97,785 women) were from the CPS-II Nutrition Cohort, a prospective study of cancer incidence begun in 1992. The Nutrition Cohort, which is described in detail elsewhere, was formed as a subcohort of CPS-II, a prospective study of cancer mortality involving approximately 1.2 million Americans enrolled in 1982. Nutrition Cohort participants were recruited from CPS-II participants between the ages of 50 and 74 years who were living in 21 states. Participants completed a self-administered questionnaire at baseline in 1992–1993 that included questions on demographic, anthropometric, medical, and lifestyle information. Follow-up questionnaires to update exposure information and to ascertain newly diagnosed cancers were sent to living Nutrition Cohort members in 1997 and every 2 years since. The response rate on all of the follow-up questionnaires, among those cohort participants who were mailed surveys, was at least 85%. Follow-up time for this study was from the date of receipt of the baseline survey in 1992–1993 to the date of diagnosis of cancer, death, date of the last survey returned, or June 30, 2009, whichever came first. All aspects of the CPS-II Nutrition Cohort Study were approved by the Emory University Institutional Review Board (Atlanta, Georgia).
CPS-II participants were excluded from this analysis if they were lost to follow-up (3,141 men and 3,111 women), reported any prevalent cancer other than nonmelanoma skin cancer in 1982 or 1992–1993 (9,769 men and 13,094 women), self-reported a cancer that could not be verified (527 men and 354 women), or self-reported a cancer more than 6 months before the diagnosis date of that cancer (100 men and 48 women). Also excluded were participants with missing body mass index (BMI, expressed as weight (kg)/height (m)) or BMI <18.5 in 1982 or 1992 (2,161 men and 4,174 women), missing information on number of times a participant purposely lost ≥10 pounds (4.54 kg), or regained weight that was purposefully lost (1,098 men and 1,866 women), as well as those who reported never having purposefully lost ≥10 pounds but reported ≥10 pounds as the most weight ever purposefully lost (1,070 men and 936 women), and those who reported the number of times that weight was purposefully lost that differed from the number of times weight was regained by more than 2 (2,468 men and 3,004 women). The characteristics of the individuals excluded for missing or invalid weight loss and regain information are shown in Web Table 1 http://aje.oxfordjournals.org/content/182/5/394/suppl/DC1 available at http://aje.oxfordjournals.org/. Finally, because an undiagnosed cancer at baseline may have influenced weight patterns, the first 2 years of follow-up (1992–1994, 3,276 men and 1,678 women) were excluded from all analyses. For analyses of endometrial cancer, women who reported removal of their uterus or had unknown uterine status at baseline were also excluded (27,022 women). Likewise, for ovarian cancer analyses, women who reported removal of their ovaries or had unknown ovarian status at baseline were also excluded (15,811 women). Women who reported removal of their uterus or ovaries during follow-up were censored from analyses of these cancers at the time of receipt of the questionnaire on which the procedure was reported. Thus, the final analytical cohort for this study comprised 62,792 men and 69,520 women except for analyses of endometrial or ovarian cancer, where the analytical cohort was 42,498 or 53,709 women, respectively.
Identification of Cancer Cases
A total of 25,317 first cancers occurred in the analytical cohort between 1994 and 2009. Of these, 24,217 were self-reported on follow-up questionnaires and subsequently verified through medical records (n = 15,911) or linkage with state cancer registries (n = 8,306). An additional 1,100 cancers were identified through linkage to the National Death Index. For analyses of all cancers and specific cancers, all cases were the first diagnosed cancer for that individual. In situ diseases were not included for breast, prostate, colon, or rectal cancers. Aggressive prostate cancer was defined as a Gleason score ≥8, American Joint Committee on Cancer tumor stage T3 or T4, or lethal prostate cancer of unknown stage.
Characterization of Weight Cycling
CPS-II Nutrition Cohort participants were asked 2 questions about weight cycling on the baseline questionnaire: "How many times in your life have you purposely lost 10 pounds or more?" and "How many times in your life have you regained as much as 10 pounds that you previously had lost?" A write-in answer was required for both questions with space for a range from 0 to 99. A weight cycle was defined as a combination of both an intentional loss and a subsequent regain. Thus, someone who reported 3 weight losses and 3 subsequent regains was assigned 3 weight cycles, whereas someone who reported 3 weight losses but only 2 regains was assigned 2 weight cycles. The individuals who reported weight cycling ("weight cyclers") were further categorized by the total number of cycles they reported: 1–4, 5–9, 10–19, and 20 or more weight cycles. Weight change pattern or trajectory was not considered in assigning weight cycling status or category.
Statistical Analyses
BMI in 1982 and 1992 was calculated by using self-reported body weight on questionnaires completed at those times and height self-reported on the 1982 questionnaire. BMI at age 18 years was calculated by using weight at age 18 years recalled and reported on the 1992 questionnaire.
All statistical analyses were conducted with SAS, version 9.3, software (SAS Institute, Inc., Cary, North Carolina). Cox proportional hazards regression was used to determine the hazard ratios and 95% confidence intervals for the association of weight cycling with cancer incidence. The time scale for the analysis was time in study from cohort entry in 1992–1993. P values for linear trend were estimated by modeling weight cycles as a continuous variable and were derived by use of the Wald test. The Cox proportional hazards assumption was tested by modeling multiplicative interaction terms between weight cycling numbers and time. The statistical significance of the interaction term was assessed by using the likelihood ratio test, and no deviations from proportional hazards were found. Interactions between either BMI or age at baseline and weight cycling were tested by using the likelihood ratio test in which either variable was modeled categorically. All P values are 2 sided.
Cox models were adjusted for age by stratifying on exact year of age in 1992. Additional covariates included in the multivariable-adjusted models were race (white, black, or other/missing), education (some high school, high school graduate, some college, college graduate, or missing), smoking status (nonsmoker, former <20 years, former ≥20 years, current <40 years, current ≥40 years, ever/unclassifiable, or missing), physical activity in metabolic equivalents (<8, 8 to <17.5, 17.5 to <31.5, ≥31.5/week, or missing), use of aspirin or other nonsteroidal antiinflammatory drugs (not current user, 1–14 pills/month, 15–29 pills/month, 30–59 pills/month, ≥60 pills/month, or missing/unknown), and history of diabetes (yes, no). For analyses of women, postmenopausal hormone use (never, current estrogen, current combined hormone replacement therapy, former estrogen or combined hormone replacement therapy, or ever/other/unknown) was also included in the model. Included in analyses of prostate, breast, and colon and rectal cancer were history of prostate-specific antigen testing (starting in 1997), mammography (starting in 1992), and colorectal endoscopy (starting in 1997), respectively, and all were modeled as time-dependent variables. BMI in 1992 (continuous, modeled linearly) was also included in the models as indicated. The inclusion of alcohol intake as a covariate did not change the associations and was not included in the final multivariable-adjusted model.
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