2 Q1 Body Size Indicators and Risk of Gallbladder 3 Cancer: Pooled Analysis of Individual-Level Data 4 Q2 from 19 Prospective Cohort Studies

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1 1 Research Article 2 Q1 Body Size Indicators and Risk of Gallbladder 3 Cancer: Pooled Analysis of Individual-Level Data 4 Q2 from 19 Prospective Cohort Studies 5 AU Peter T. Campbell 1, Christina C. Newton 1, Cari M. Kitahara 2, Alpa V. Patel 1, Patricia Hartge 2, 6 Jill Koshiol 2, Katherine McGlynn 2, Hans-Olov Adami 3,4, Amy Berrington 2, 7 Laura E. Beane Freeman 2, Leslie Bernstein 5, Julie E. Buring 3,6, Neal D. Freedman 2, 8 Yu-Tang Gao 7, Graham G. Giles 8, Marc J. Gunter 9, Mazda Jenab 9, Linda M. Liao 2, 9 Roger L. Milne 8, Kim Robien 10, Dale P. Sandler 11, Catherine Schairer 2, Howard D. Sesso 3,6, 10 Xiao-Ou Shu 12, Elisabete Weiderpass 4,13,14,15, Alicja Wolk 16, Yong-Bing Xiang 7, 11 Anne Zeleniuch-Jacquotte 17, Wei Zheng 12, and Susan M. Gapstur 1 Cancer Epidemiology, Biomarkers & Prevention 12 Abstract 13 Background: There are few established risk factors for gallblad- 14 der cancer beyond gallstones. Recent studies suggest a higher risk 15 with high body mass index (BMI), an indicator of general heavi- 16 ness, but evidence from other body size measures is lacking. 17 Methods: Associations of adult BMI, young adult BMI, height, 18 adult weight gain, waist circumference (WC), waist height ratio 19 (WHtR), hip circumference (HC), and waist hip ratio (WHR) 20 with gallbladder cancer risk were evaluated. Individual-level data 21 from 1,878,801 participants in 19 prospective cohort studies (14 22 studies had circumference measures) were harmonized and 23 included in this analysis. Multivariable Cox proportional hazards 24 regression estimated HRs and 95% confidence intervals (CI). 25 Results: After enrollment, 567 gallbladder cancer cases were 26 identified during 20.1 million person-years of observation, 27 including 361 cases with WC measures. Higher adult BMI (per 44 5 kg/m 2, HR: 1.24; 95% CI, ), young adult BMI (per 5 kg/m 2, HR: 1.12; 95% CI, ), adult weight gain (per 5 kg, HR: 1.07; 95% CI, ), height (per 5 cm, HR: 1.10; 95% CI, ), WC (per 5 cm, HR: 1.09; 95% CI, ), WHtR (per 0.1 unit, HR: 1.24; 95% CI, ), and HC (per 5 cm, HR: 1.13; 95% CI, ), but not WHR (per 0.1 unit, HR: 1.03; 95% CI, ), were associated with higher risks of gallbladder cancer, and results did not differ meaningfully by sex or other demographic/lifestyle factors. Conclusions: These findings indicate that measures of overall and central excess body weight are associated with higher gallbladder cancer risks. Impact: Excess body weight is an important, and potentially preventable, gallbladder cancer risk factor. Cancer Epidemiol Biomarkers Prev; Ó2016 AACR Introduction 46 Gallbladder cancer etiology is poorly understood with only a 47 few, mostly nonmodifiable, established risk factors, including 48 older age, female sex, abnormal pancreatic-biliary junction, and 49 history of cholesterol gallstones (1). Identifying modifiable risk 50 factors for gallbladder cancer is hindered by its rarity and poor prognosis. In more-developed areas, such as the United States, Australia, and Western Europe, incidence rates are 1 to 2 cases per 100,000 persons each year, whereas in certain high-risk populations, such as Mapuche Indians in South America, incidence rates exceed 20 per 100,000 (2). Overall 5-year relative survival is approximately 18% for U.S. adults diagnosed with gallbladder Q3 1 Epidemiology Research Program, American Cancer Society, Atlanta, Georgia. 2 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland. 3 Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, Massachusetts. 4 Department of Medical Epidemiology and Biostatistics, Karolinska Insitutet, Stockholm, Sweden. 5 Division of Cancer Etiology, Department of Population Sciences, Beckman Research Institute of the City of Hope, Los Angeles, California. 6 Divisions of Preventive Medicine and Aging, Brigham and Women's Hospital, Boston, Massachusetts. 7 Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China. 8 Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia; and Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia. 9 Section of Nutrition and Metabolism, International Association for Cancer Research, Lyons, France. 10 Department of Exercise and Nutrition Sciences, Milken Institute School of Public Health, George Washington University, Washington, DC. 11 Epidemiology Branch, National Institute of Environmental Health Sciences, NIH/DHHS, Research Triangle Park, North Carolina. 12 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee. 13 Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway. 14 Department of Research, Cancer Registry of Norway, Oslo, Norway. 15 Samfundet Folkh alsan, Helsinki, Finland. 16 Department of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. 17 Department of Population Health, New York University School of Medicine, New York City, New York. Note: Supplementary data for this article are available at Cancer Epidemiology, Biomarkers & Prevention Online ( Corresponding Author: Peter T. Campbell, American Cancer Society, 250 Williams Street NW, Atlanta, GA Phone: ; Fax: ; peter.campbell@cancer.org doi: / EPI Ó2016 American Association for Cancer Research. Q4 Q5 1

2 Campbell et al. 60 cancer, and the overall median survival time is 3 to 7 months (3). 61 The poor prognosis is due, in part, to the lack of specific symptoms 62 for the disease. Early-staged gallbladder cancers are uncommon 63 and are typically only detected incidentally during cholecystec- 64 tomy for gallstones, but only 1% to 3% of patients with gallstones 65 will ever develop gallbladder cancer (4). 66 Because excess body weight is a risk factor for gallstones and 67 several other digestive system cancers (e.g., colorectum, liver, and 68 pancreas; refs. 5 9), it is a plausible risk factor for gallbladder 69 cancer. The 2015 World Cancer Research Fund's Continuous 70 Update Project (CUP) on gallbladder cancer concluded that body 71 fatness, as defined by high body mass index (BMI), is a "probable" 72 risk factor for gallbladder cancer (10). The CUP identified eight 73 prospective cohort studies (11 18) that contributed to dose 74 response meta-analyses and reported that each 5 kg/m 2 increase 75 in BMI was associated with a 25% higher risk of gallbladder 76 cancer. Of those eight studies, four provided relative risks (RR) 77 for BMI that were not statistically significant (11, 12, 14, 15), and 78 two included biliary system cancer mortality as the main outcome 79 (14, 18). Waist circumference, an indicator of central adiposity 80 that might be more etiologically relevant to cancers of the diges- 81 tive system, has been evaluated by only one relatively small study 82 (76 cases) that reported higher risks with increasing waist circum- 83 ference (11). 84 Because the evidence base for overall body fatness (based on 85 BMI) and gallbladder cancer risk is considered probable and not 86 convincing, and because risk estimates for indicators of central 87 adiposity and other non-bmi measures of body size are especially 88 rare, we conducted a pooled analysis of data from 19 prospective 89 cohort studies based in the United States, Europe, Australia, and 90 Asia to investigate associations of BMI (at enrollment during 91 adulthood and recalled from young-adulthood), height, adult 92 weight gain, waist circumference, waist height ratio, hip circum- 93 ference, and waist hip ratio with gallbladder cancer risk. 94 Materials and Methods 95 Study population 96 All member studies of the NCI Cohort Consortium ( 97 grants.cancer.gov/consortia/cohort.html) with body size data 98 were invited to participate, and 19 prospective cohort studies 99 were included in this analysis: Physicians' Health Study (PHS); 100 NIH-AARP Diet and Health Study (NIH-AARP); Agricultural 101 Health Study (AHS); Breast Cancer Detection Demonstration 102 Project Follow-Up Study (BCDDP); Prostate, Lung, Colorectal 103 and Ovarian Cancer Screening Trial (PLCO); Women's Health 104 Study (WHS); New York University Women's Health Study 105 (NYUWHS); Cancer Prevention Study-II Nutrition Cohort 106 (CPS-II); Iowa Women's Health Study (IWHS); California 107 Teachers' Study (CTS); European Prospective Investigation into 108 Cancer and Nutrition (EPIC); Melbourne Collaborative Cohort 109 Study (MCCS); Cohort of Swedish Men (COSM); Swedish Mam- 110 mography Cohort (SMC); The Sister Study (SISTER); Shanghai 111 Men's Health Study (SMHS); Shanghai Women's Health Study 112 (SWHS); Vitamins and Lifestyle Study (VITAL); and Women's 113 Lifestyle and Health Study (WLH). Participants gave written, 114 informed consent at enrollment or consent was implied from 115 the return of questionnaires. All studies were approved by the 116 Institutional Review Boards of their host centers. 117 All studies submitted de-identified, participant-level data 118 from their entire cohort study to the data coordinating center. Data were centrally harmonized and pooled for analyses. Prior to exclusions, participant-level data were provided for 2,213,174 men and women. The following exclusions were applied: missing age at study entry, or baseline age less than 18 years, or older than 85 years (n ¼ 5,501); less than 1 year of follow-up time (n ¼ 51,399); missing BMI (n ¼ ); BMI less than 15 kg/m 2 or greater than 60 kg/m 2 (n ¼ 2,110); missing height (n ¼ 26,698); height less than 122 cm or greater than 244 cm (n ¼ 137); and prevalent cancer at baseline (n ¼ 100,976). Data from 1,878,801 participants comprised the analytic cohort. Gallbladder cancer diagnoses [International Classification of Diseases, 10 th version (ICD-10): C23.9; ref. 19] were verified after enrollment by linking to state/provincial/federal cancer or death registries and/or medical record abstraction. Exposures Height and weight were self-reported in most cohorts and directly measured in others (MCCS, SMHS, SWHS, EPIC, SIS- TER); BMI was calculated as weight (kg) divided by heightsquared (m 2 ) and categorized according to World Health Organization criteria (20): underweight (15 < 18.5 kg/m 2 ), normal weight (18.5 < 25 kg/m 2 ), overweight (25 < 30 kg/m 2 ), and obese (30 kg/m 2 ). Obesity was additionally stratified as classes I ( kg/m 2 ), II ( kg/m 2 ), and III (40 kg/ m 2 ). Young-adult BMI was available from 10 of the cohort studies(nih-aarp,ahs,cosm,cps-ii,iwhs,mccs,plco, SMC, VITAL, and WLH), derived from recalled weight at ages 18 to 21 years, and categorized as above for adult BMI. Height, in cm, was categorized into four groups for women (<160, 160 < 165, 165 < 170, and 170) and men (<170, 170 < 175, 175 < 180, and 180). Adult weight gain was estimated by subtracting young adult weight from baseline weight, both in kg, and categorized as: any weight loss, weight stable (0 kg change) or weight gain of 5, weight gain of 6 to 10, weight gain of 11 to 15, weight gain of 16 to 20, and weight gain of 21. Waist circumference and hip circumference were measured by trained staff (EPIC, MCCS, NYUWHS, SISTER, SMHS, SWHS) or self-measured by participants who were given instructions on the protocol [NIH-AARP, BCDDP, COSM, CTS, IWHS, CPS-II (waist circumference only), WLH, and SMC]. The remaining five cohort studies did not collect waist circumference or hip circumference data. Waist circumference and hip circumference were available at baseline enrollment for COSM, IWHS, MCCS, SISTER, SMC, SMHS, SWHS, and WLH, whereas NIH-AARP, BCDDP, CPS-II (waist circumference only), CTS, EPIC, and NYUWHS collected these data 1 to 8 years after baseline. Participants with waist or hip circumference measures below 50 cm or above 190 cm were excluded from the relevant analysis (n ¼ 1,329 and n ¼ 345 were excluded from waist and hip circumference analyses, respectively). Waist circumference, in cm, was categorized in four predefined groups (women: 50 <70, 70 <80, 80 <90, and 90 <191; men: 50 <90, 90 <100, 100 <110, and 110 <191). Hip circumference, in cm, was also categorized in four pre-defined groups (women: 50 <90, 90 <100, 100 <110, and 110 <191; men: 50 <95, 95 <105, 105 <115, and 115 <191). Waist height ratio was calculated by dividing waist by height, both in cm, and categorized as <0.45, 0.45 <0.50, 0.50 <0.55, and 0.55 for women and <0.50, 0.50 <0.55, 0.55 <0.60, and 0.60 for men. Waist hip ratio was calculated by dividing waist circumference by hip circumference, both in cm, and categorized into four groups Cancer Epidemiol Biomarkers Prev; 2017 Cancer Epidemiology, Biomarkers & Prevention

3 Anthropometry and Gallbladder Cancer Risk 182 for women (<0.75, 0.75 <0.80, 0.80 <0.85, and 0.85) and men 183 (<0.90, 0.90 <0.95, 0.95 <1.00, and 1.00). 184 Smoking was defined according to baseline cigarette smoking 185 status and categorized as never, former, current, or missing. 186 Alcohol consumption was defined as non-drinker and, among 187 persons who consumed alcohol, in categories of grams per day 188 (grams/day: <10, 10 <20, 20 <30, and 30þ), or missing. Race 189 was self-identified and categorized as white, black/african Amer- 190 ican, and all other races including those who did not report race. 191 Physical activity was categorized into study-specific quintiles or 192 missing. Education was categorized as less than high school, high 193 school graduate, some college, college graduate or more, or 194 missing. Sex (men, women) and history of gallstones (yes, no) 195 were defined as binary variables. Missing data were treated with an 196 indicator variable. 197 Statistical analysis 198 Cox proportional hazards regression models estimated HRs 199 and 95% confidence intervals (CI) for the associations of body 200 size variables with gallbladder cancer risk. Follow-up time for 201 both BMI measures and height began on the date of enrollment 202 when height and weight were first reported, whereas follow-up 203 time for waist circumference, hip circumference, waist height 204 circumference, and waist hip ratio analyses began on the date 205 waist/hip circumference was evaluated. Cases that were diagnosed 206 after baseline but before the time of waist/hip circumference 207 assessment were excluded from those analyses. Studies that did 208 not collect waist/hip circumference data were omitted from the 209 respective analyses. All statistical models were analyzed from a 210 pooled cohort of the combined studies with individual-level data. 211 Initially, Cox models included only baseline age, study, and sex as 212 covariates. Subsequently, more comprehensive models included 213 age, study, sex, alcohol consumption, race, education, physical 214 activity, and smoking status. An additional more comprehen- 215 sively adjusted model also included personal history of gallstones. 216 Waist circumference, waist height ratio, hip circumference, and 217 waist hip ratio are presented with and without adjustment for 218 BMI. Adult weight gain statistical models included young adult 219 BMI. Linear models estimated associations of continuous body 220 size measures (per unit increase and per 1 SD) with gallbladder 221 cancer risk. Wald tests assessed linear trends. 222 Sensitivity analyses excluded gallbladder cancers that were 223 diagnosed in the first 2 and 5 years after baseline to evaluate 224 potential bias from prediagnosis weight loss due to disease 225 progression. Sensitivity analyses also evaluated the impact of 226 excluding participants who were diagnosed with gallstones at 227 baseline. Two-stage individual participant meta-analyses 228 explored potential heterogeneity of HRs across studies for con- 229 tinuous body size measures. Meta-analysis methods also evalu- 230 ated potential heterogeneity according to region of study origin 231 [i.e., North America (NIH-AARP, AHS, BCDDP, CPS-II, CTS, 232 NYUWHS, PHS, PLCO, SISTER, VITAL, and WHS), Europe (i.e., 233 COSM, EPIC, SMC, and WLH), Asia (i.e., SMHS and SWHS), and 234 Australia (i.e., MCCS)] and BMI-assessment method (i.e., self- 235 reported vs. directly measured weight and height) for the associ- 236 ation between adult BMI and gallbladder cancer risk. 237 Interaction terms with the main exposures (continuous terms) 238 and time tested the proportional hazards assumption of the Cox 239 models. No interactions were observed. Restricted cubic splines 240 evaluated potential nonlinearity of the associations for body size 241 measures with gallbladder cancer risk. All P values were two-sided; P values less than 0.05 were considered statistically significant. SAS software was used for all statistical analyses (SAS Institute, Inc., version 9.4). Results In this analysis of 1.88 million adults enrolled in 19 prospective cohort studies, 567 gallbladder cancers occurred during 20.1 million person-years of observation. For analyses of waist circumference/waist height ratio and hip circumference, 361 and 318 cases were identified, respectively. Table 1 shows baseline characteristics of participants: mean age was 56.7 years, mean BMI at baseline was 26.1 kg/m 2, mean waist circumference was 86.5 cm, 71% reported any alcohol intake, and 15.6% were current smokers. The overall and sex-specific associations between adult BMI and gallbladder cancer risk are shown in Table 2. Compared with a normal adult BMI at baseline, overweight, class I obesity, class II obesity, and class III obesity were associated with 27%, 53%, 86%, and 131% higher risks of gallbladder cancer, respectively, after adjusting for age, sex, study, race, physical activity,education,smoking,alcohol,andgallstones.therewas no indication that risks differed meaningfully by sex (P interaction, 0.89). There was no statistically significant evidence of between-study heterogeneity for adult BMI (I 2 :0%;Pvalue, 0.49; Supplementary Fig. S1). HRs for continuous adult BMI from both the pooled cohort approach (Table 2) and from the two-stage individual participant meta-analysis (Supplementary Fig. S1) yielded similar results. Restricted cubic spline analyses supported a linear association (Fig. 1; P value for linearity: <0.0001; P value for nonlinearity: 0.95). There was evidence supporting a positive association between young adult BMI (modeled as a continuous measure) and gallbladder cancer risk (HR, 1.12, per 5 kg/m 2 ), although the prevalence of obesity was lower than at baseline enrollment, as expected, and the sex-specific obese categories contained few cases (Table 2). Adult weight gain also was positively associated with risk (HR, 1.07, per 5 kg). The continuous model for height showed a 10% increased risk with each 5 cm increase. There was no evidence of statistically significant interactions for sex and young adult BMI, height or adult weight gain (all P values for interaction 0.23) or of between-study heterogeneity for young adult BMI (I 2 : 0%; P value: 0.72; Supplementary Fig. S2), height (I 2 : 28%; P value: 0.13; Supplementary Fig. S3), or adult weight gain (I 2 : 6%; P value: 0.39; Supplementary Fig. S4). Restricted cubic spline analyses confirmed linear associations of young adult BMI, adult weight gain, and height with gallbladder cancer risk and demonstrated no evidence of nonlinearity (all P values for linearity: <0.0001; all P values for nonlinearity: 0.30). Associations of waist circumference, waist height ratio, hip circumference, and waist hip ratio overall and by sex with gallbladder cancer risk are shown in Table 3. Although sample sizes were smaller for the waist- and hip-circumference related measures than for the weight- and height-related measures, statistically significant positive associations were identified for continuous measures of waist circumference (HR, 1.09, per 5 cm), waist height ratio (HR, 1.24, per 0.1), and hip circumference (HR, 1.13, per 5 cm). Waist hip ratio was not statistically significantly associated with risk. Associations were similar when stratified by sex (all P values for interaction: 0.34). There was no statistically significant evidence of between-study heterogeneity for waist Cancer Epidemiol Biomarkers Prev;

4 Campbell et al. Q6 Table 1. Summary of cohort studies included in the Rare Cancer Collaboration (gallbladder cancer) Baseline cohort sample size Gallbladder cancer case Baseline age Baseline BMI (kg/m 2 ) Baseline BMI 30 kg/m 2 WC (cm) a Baseline WC men: 110 cm women: 90 cm a Current cigarette smoker a Alcohol intake (g/day) Any alcohol History of among drinkers a intake a gallstones a Study name (acronym) Gender N N Mean (SD) Mean (SD) % Mean (SD) % % Mean (SD) % % NIH-AARP Diet and Health Study (NIH-AARP) Women 191, (5.4) 26.9 (5.6) (13.4) (20.9) Men 296, (5.4) 27.3 (4.2) (11.0) (51.1) Agricultural Health Study (AHS) Women 21, (12.0) 25.9 (4.9) (6.1) 55.6 Men 20, (13.0) 27.5 (4.1) (14.6) 67.5 The Breast Cancer Detection Women 37, (8.0) 25.1 (4.6) (11.8) (14.2) Demonstration Project (BCDDP) Cohort of Swedish Men (COSM) Men 42, (9.6) 25.8 (3.4) (10.1) (23.5) Cancer Prevention Study-II (CPS-II) Women 80, (6.6) 25.6 (4.7) (13.0) (13.1) Men 71, (6.1) 26.4 (3.7) (10.1) (21.6) California Teachers' Study (CTS) Women 103, (13.5) 24.8 (5.0) (13.0) (9.7) European Prospective Women 254, (10.7) 25.5 (4.6) (11.5) (12.0) Investigation into Cancer and Cancer and Nutrition (EPIC) Iowa Women's Health Study (IWHS) Men 143, (10.1) 26.5 (3.7) (10.3) (23.7) Women 37, (4.2) 26.1 (4.9) (10.9) (13.1) 43.6 Melbourne Collaborative Cohort Women 22, (8.6) 26.8 (4.9) (11.8) (14.2) Study (MCCS) Men 15, (8.8) 27.2 (3.6) (10.0) (25.3) New York University Women's Health Study (NYUWHS) Women 13, (8.7) 24.9 (4.6) (11.7) (14.4) Physicians' Health Study (PHS) Men 28, (9.7) 25.1 (3.0) Prostate, Lung, Colorectal, and Women 68, (5.4) 27.1 (5.5) (14.0) Ovarian Cancer Screening Trial (PLCO) Men 68, (5.3) 27.6 (4.2) (33.1) The Sister Study (SISTERS) Women 47, (9.0) 27.8 (6.2) (14.7) (10.0) Swedish Mammography Cohort Women 33, (9.1) 25.0 (4.0) (10.7) (10.2) (SMC) Shanghai Men's Health Study Men 60, (9.7) 23.7 (3.1) (8.7) (32.3) (SMHS) Shanghai Women's Health Study Women 74, (9.1) 24.0 (3.4) (8.8) (13.9) (SWHS) Vitamins and Lifestyle Study Women 30, (7.4) 27.2 (5.8) (13.1) 57.9 (VITAL) Men 30, (7.3) 27.6 (4.4) (21.8) 70.1 Women's Health Study (WHS) Women 38, (7.0) 26.0 (5.1) (11.1) Women's Lifestyle and Health Study (WLH) Women 44, (5.8) 23.5 (3.6) (9.3) (4.5) 86.2 All women Women 1,100, (10.7) 25.8 (5.0) (12.5) (14.0) N (%) missing All men Men 778, (9.0) 26.7 (4.0) (11.2) (38.6) N (%) missing All combined All 1,878, (10.1) 26.1 (4.7) (13.8) (28.4) N (%) missing a Among nonmissing responders. 4 Cancer Epidemiol Biomarkers Prev; 2017 Cancer Epidemiology, Biomarkers & Prevention

5 Anthropometry and Gallbladder Cancer Risk Table 2. Associations of BMI, adult weight gain, and height with gallbladder cancer All Women Men Minimally adjusted Multivariable-adjusted Multivariable-adjusted Minimally adjusted Multivariable-adjusted Multivariable-adjusted Minimally adjusted Multivariable-adjusted Multivariable-adjusted BMI (kg/m 2 ) Case a RR (95% CI) b RR1 (95% CI) c RR2 (95% CI) d Case a RR (95% CI) b RR1 (95% CI) c RR2 (95% CI) d Case a RR (95% CI) b RR1 (95% CI) c RR2 (95% CI) d Baseline BMI < ( ) 1.19 ( ) 1.21 ( ) ( ) 1.06 ( ) 1.07 ( ) ( ) 2.00 ( ) 2.03 ( ) 18.5 < (ref) 1.00 (ref) 1.00 (ref) (ref) 1.00 (ref) 1.00 (ref) (ref) 1.00 (ref) 1.00 (ref) 25 < ( ) 1.29 ( ) 1.27 ( ) ( ) 1.24 ( ) 1.21 ( ) ( ) 1.49 ( ) 1.46 ( ) 30 < ( ) 1.60 ( ) 1.53 ( ) ( ) 1.41 ( ) 1.35 ( ) ( ) 2.16 ( ) 2.11 ( ) 35-< ( ) 1.99 ( ) 1.86 ( ) ( ) 2.11 ( ) 1.97 ( ) ( ) 1.45 ( ) 1.39 ( ) ( ) 2.50 ( ) 2.31 ( ) ( ) 2.47 ( ) 2.28 ( ) ( ) 2.74 ( ) 2.61 ( ) < ( ) 1.19 ( ) 1.21 ( ) ( ) 1.06 ( ) 1.08 ( ) ( ) 2.00 ( ) 2.03 ( ) 18.5 < (ref) 1.00 (ref) 1.00 (ref) (ref) 1.00 (ref) 1.00 (ref) (ref) 1.00 (ref) 1.00 (ref) 25 < ( ) 1.29 ( ) 1.27 ( ) ( ) 1.24 ( ) 1.21 ( ) ( ) 1.49 ( ) 1.46 ( ) ( ) 1.72 ( ) 1.64 ( ) ( ) 1.62 ( ) 1.54 ( ) ( ) 2.08 ( ) 2.02 ( ) Per 5 kg/m 2e 1.31 ( ) 1.26 ( ) 1.24 ( ) 1.31 ( ) 1.27 ( ) 1.24 ( ) 1.31 ( ) 1.24 ( ) 1.22 ( ) P value for trend < < < < < < P interaction with sex Per Std Dev e 1.28 ( ) 1.24 ( ) 1.21 ( ) 1.29 ( ) 1.24 ( ) 1.22 ( ) 1.28 ( ) 1.22 ( ) 1.20 ( ) Young-adult BMI < ( ) 0.83 ( ) 0.83 ( ) ( ) 0.74 ( ) 0.74 ( ) ( ) 1.20 ( ) 1.20 ( ) 18.5 < (ref) 1.00 (ref) 1.00 (ref) (ref) 1.00 (ref) 1.00 (ref) (ref) 1.00 (ref) 1.00 (ref) 25 < ( ) 1.25 ( ) 1.24 ( ) ( ) 1.18 ( ) 1.18 ( ) ( ) 1.35 ( ) 1.34 ( ) ( ) 1.77 ( ) 1.75 ( ) ( ) 1.45 ( ) 1.44 ( ) ( ) 2.60 ( ) 2.57 ( ) Per 5 kg/m 2e 1.13 ( ) 1.12 ( ) 1.12 ( ) 1.18 ( ) 1.15 ( ) 1.15 ( ) 1.12 ( ) 1.12 ( ) 1.12 ( ) P value for trend P interaction with sex Per Std Dev e 1.07 ( ) 1.07 ( ) 1.07 ( ) 1.10 ( ) 1.08 ( ) 1.08 ( ) 1.06 ( ) 1.07 ( ) 1.07 ( ) Adult weight change (kg) f Lost weight ( ) 1.11 ( ) 1.12 ( ) ( ) 0.82 ( ) 0.82 ( ) ( ) 3.18 ( ) 3.18 ( ) Gained 0 to (ref) 1.00 (ref) 1.00 (ref) (ref) 1.00 (ref) 1.00 (ref) (ref) 1.00 (ref) 1.00 (ref) Gained 6 to ( ) 1.19 ( ) 1.19 ( ) ( ) 1.03 ( ) 1.03 ( ) ( ) 2.33 ( ) 2.33 ( ) Gained 10 to ( ) 1.04 ( ) 1.03 ( ) ( ) 0.93 ( ) 0.93 ( ) ( ) 1.84 ( ) 1.83 ( ) Gained 16 to ( ) 1.20 ( ) 1.19 ( ) ( ) 1.09 ( ) 1.08 ( ) ( ) 2.08 ( ) 2.06 ( ) Gained ( ) 1.50 ( ) 1.48 ( ) ( ) 1.22 ( ) 1.20 ( ) ( ) 3.17 ( ) 3.13 ( ) Per 5 kg 1.07 ( ) 1.07 ( ) 1.07 ( ) 1.07 ( ) 1.07 ( ) 1.07 ( ) 1.06 ( ) 1.05 ( ) 1.05 ( ) P value for trend P interaction with sex Per Std Dev e 1.19 ( ) 1.18 ( ) 1.18 ( ) 1.20 ( ) 1.19 ( ) 1.19 ( ) 1.16 ( ) 1.14 ( ) 1.13 ( ) Height (cm) M <170, W < (ref) 1.00 (ref) 1.00 (ref) (ref) 1.00 (ref) 1.00 (ref) (ref) 1.00 (ref) 1.00 (ref) M 170 <175, W 160 < ( ) 1.06 ( ) 1.06 ( ) ( ) 1.11 ( ) 1.12 ( ) ( ) 0.87 ( ) 0.86 ( ) M 175 <180, W 165 < ( ) 1.31 ( ) 1.31 ( ) ( ) 1.37 ( ) 1.38 ( ) ( ) 1.15 ( ) 1.14 ( ) M 180þ, W 170þ ( ) 1.37 ( ) 1.37 ( ) ( ) 1.32 ( ) 1.32 ( ) ( ) 1.36 ( ) 1.34 ( ) Per 5 cm 1.07 ( ) 1.10 ( ) 1.10 ( ) 1.04 ( ) 1.07 ( ) 1.07 ( ) 1.13 ( ) 1.14 ( ) 1.14 ( ) P value for trend P interaction with sex Per Std Dev e 1.13 ( ) 1.20 ( ) 1.20 ( ) 1.07 ( ) 1.15 ( ) 1.15 ( ) 1.26 ( ) 1.30 ( ) 1.30 ( ) Abbreviation: RR, relative risk. a Some counts do not add to totals because of missing data. b Adjusted for age, sex, and study. c Adjusted for age, sex, study, race, physical activity, education, smoking, and alcohol. d Adjusted for age, sex, study, race, physical activity, education, smoking, alcohol, and gallstones. e Continuous BMI models exclude those <18.5 kg/m 2. f All adult weight change models additionally adjust for young adult BMI. Cancer Epidemiol Biomarkers Prev;

6 Campbell et al Q7 Rate ra o Figure 1. Restricted cubic spline analysis of BMI and risk of gallbladder cancer in the Rare Cancer Collaboration. The solid line indicates the HR, whereas the dashed line indicates 95% CIs Body mass index (kg/m 2 ) circumference (I 2 : 9%; P value: 0.36; Supplementary Fig. S5), 305 waist height ratio (I 2 : 35%; P value: 0.11; Supplementary Fig. S6), 306 hip circumference (I 2 : 16%; P value: 0.29; Supplementary Fig. S7), 307 or waist hip ratio (I 2 : 0%; P value: 0.88; Supplementary Fig. S8). 308 Restricted cubic spline analyses supported linear associations of 309 waist circumference (Fig. 2; P value for linearity: <0.0001; P value 310 for nonlinearity: 0.62), waist height ratio (P value for linearity: 311 <0.0001; P value for nonlinearity: 0.76), hip circumference 312 (P value for linearity: <0.0001; P value for nonlinearity: 0.97), 313 and waist hip ratio (P value for linearity: <0.0001; P value for 314 nonlinearity: 0.13) with gallbladder cancer risk. 315 When analyses were restricted to studies and participants that 316 had both BMI and waist circumference in the individual-level data 317 that included all participants, gallbladder cancer risks were sim- 318 ilarly elevated for each 1 SD unit increase in waist circumference 319 (HR, 1.28; 95% CI, ) and BMI (HR, 1.21; 95% CI, ), when modeled separately. When BMI and waist circum- 321 ference were included in the same model, both HRs were atten- 322 uated and no longer statistically significant (waist circumference 323 HR, 1.21; 95% CI, ; BMI HR, 1.06; 95% CI, ). 324 In sensitivity analyses, the main study findings were not mate- 325 rially different after excluding gallbladder cancers that occurred in 326 the first 2 and 5 years after baseline and after excluding partici- 327 pants who reported history of gallstones (data not shown). No 328 strong evidence for geographic heterogeneity was detected for 329 continuous adult BMI and gallbladder cancer risk (i.e., North 330 America: HR, 1.25; 95% CI, ; Europe: HR, 1.12; 95% CI, ; Asia: HR, 1.18; 95% CI, ; Australia: HR, 1.85; % CI, ; P value for heterogeneity: 0.09). Studies with 333 self-reported versus directly measured height and weight yielded 334 relatively similar results (i.e., self-reported BMI, per 5 kg/m 2, HR, ; 95% CI, ; directly measured BMI, per 5 kg/m 2, HR, ; 95% CI, ; P value for heterogeneity: 0.53). 337 Discussion 338 In this large prospective analysis of 1.88 million adults enrolled 339 in 19 cohort studies, greater BMI (both at middle age and during young adulthood), adult weight gain, height, waist circumference, waist height ratio, and hip circumference were all consistently associated with higher risks of gallbladder cancer. Results for waist hip ratio generally suggested an increased risk, consistent with the other anthropometric measures, but the results were not statistically significant. Restricted cubic spline analyses supported linear associations for all anthropometric measures with gallbladder cancer risk, indicating dose response associations throughout the ranges of body size measures observed in this study. The main study results were consistent when stratified by sex, and they were not materially different in statistical models that included many confirmed and potential risk factors for gallbladder cancer, including sex, smoking, alcohol, race, education, and history of cholesterol gallstones. The main study results were robust after a series of sensitivity analyses, including individual participant meta-analyses and when excluding cases that occurred in the first 5 years of follow-up. Studies regarding BMI and gallbladder cancer risk have been generally hampered by small numbers of outcomes and the related issues of limited statistical power and imprecise risk estimates: of the 12 prospective cohort studies on this topic in the literature (11 13, 15 17, 21 26), six identified fewer than 100 cases (11, 12, 17, 22, 23, 25), and while most studies reported HRs above one, many studies were not statistically significant (11, 12, 15, 23, 25). With data from 567 gallbladder cancer cases, this study makes an important contribution toward confirming the association between high BMI and this rare and highly fatal cancer. The HR identified in this study for obese BMI and gallbladder cancer risk (HR, 1.64) is similar in magnitude to results from individual large, prospective cohort studies (13, 16, 21, 26), and to results from a recent meta-analysis (HR, 1.62; ref. 27). In addition, this study identified similar HRs for linear BMI and gallbladder cancer risk when stratified by sex, similar to the conclusion reached by the recent CUP (10), but somewhat in contrast to earlier reports that suggested the association was higher for women than men (27 29). Because gallbladder cancer is more common in women than in men (by approximately 2-fold, typically), it is plausible that the earlier studies compared Cancer Epidemiol Biomarkers Prev; 2017 Cancer Epidemiology, Biomarkers & Prevention

7 Anthropometry and Gallbladder Cancer Risk Table 3. Associations of waist circumference, waist to height ratio, hip circumference, and waist to hip ratio with gallbladder cancer All Women Men Minimally adjusted Multivariable-adjusted Multivariable-adjusted Minimally adjusted Multivariable-adjusted Multivariable-adjusted Minimally adjusted Multivariable-adjusted Multivariable-adjusted Case a RR (95% CI) b RR1 (95% CI) c RR2 (95% CI) d Case a RR (95% CI) b RR1 (95% CI) c RR2 (95% CI) d Case a RR (95% CI) b RR1 (95% CI) c RR2 (95% CI) d Waist circumference (cm) M <90, W < (ref) 1.00 (ref) 1.00 (ref) (ref) 1.00 (ref) 1.00 (ref) (ref) 1.00 (ref) 1.00 (ref) M 90 <100, W 70 < ( ) 1.26 ( ) 1.25 ( ) ( ) 1.37 ( ) 1.38 ( ) ( ) 1.04 ( ) 0.78 ( ) M 100 <110, W 80 < ( ) 1.72 ( ) 1.68 ( ) ( ) 1.73 ( ) 1.77 ( ) ( ) 1.69 ( ) 1.17 ( ) M 110þ, W 90þ ( ) 2.08 ( ) 2.03 ( ) ( ) 2.02 ( ) 2.09 ( ) ( ) 2.46 ( ) 1.83 ( ) Per 5 cm 1.12 ( ) 1.10 ( ) 1.09 ( ) 1.12 ( ) 1.09 ( ) 1.09 ( ) 1.15 ( ) 1.12 ( ) 1.08 ( ) P value for trend < < P interaction with sex Per Std Dev 1.38 ( ) 1.29 ( ) 1.27 ( ) 1.36 ( ) 1.26 ( ) 1.28 ( ) 1.46 ( ) 1.38 ( ) 1.23 ( ) Waist to height ratio M <0.50, W < (ref) 1.00 (ref) 1.00 (ref) (ref) 1.00 (ref) 1.00 (ref) (ref) 1.00 (ref) 1.00 (ref) M 0.50 <0.55, W 0.45 < ( ) 1.20 ( ) 1.15 ( ) ( ) 1.09 ( ) 1.05 ( ) ( ) 1.63 ( ) 1.50 ( ) M 0.55 <0.60, W 0.50 < ( ) 1.62 ( ) 1.47 ( ) ( ) 1.45 ( ) 1.38 ( ) ( ) 2.25 ( ) 1.72 ( ) M 0.60þ, W 0.55þ ( ) 1.67 ( ) 1.42 ( ) ( ) 1.52 ( ) 1.38 ( ) ( ) 2.22 ( ) 1.51 ( ) Per ( ) 1.30 ( ) 1.24 ( ) 1.41 ( ) 1.27 ( ) 1.29 ( ) 1.46 ( ) 1.37 ( ) 1.06 ( ) P value for trend < < P interaction with sex Per Std Dev 1.30 ( ) 1.22 ( ) 1.18 ( ) 1.30 ( ) 1.20 ( ) 1.21 ( ) 1.33 ( ) 1.27 ( ) 1.05 ( ) Hip circumference (cm) M <95, W < (ref) 1.00 (ref) 1.00 (ref) (ref) 1.00 (ref) 1.00 (ref) (ref) 1.00 (ref) 1.00 (ref) M 95 <105, W 90 < ( ) 1.67 ( ) 1.66 ( ) ( ) 2.05 ( ) 2.11 ( ) ( ) 0.98 ( ) 0.78 ( ) M 105 <115, W 100 < ( ) 2.00 ( ) 1.92 ( ) ( ) 1.95 ( ) 2.01 ( ) ( ) 2.33 ( ) 1.54 ( ) M 115þ, W 110þ ( ) 2.93 ( ) 2.74 ( ) ( ) 3.04 ( ) 3.24 ( ) ( ) 3.01 ( ) 1.96 ( ) Per 5 cm 1.17 ( ) 1.13 ( ) 1.13 ( ) 1.16 ( ) 1.12 ( ) 1.14 ( ) 1.22 ( ) 1.19 ( ) 1.10 ( ) P value for trend < < < P interaction with sex Per Std Dev 1.37 ( ) 1.30 ( ) 1.28 ( ) 1.35 ( ) 1.27 ( ) 1.31 ( ) 1.50 ( ) 1.42 ( ) 1.21 ( ) Waist to hip ratio M <0.90, W < (ref) 1.00 (ref) 1.00 (ref) (ref) 1.00 (ref) 1.00 (ref) (ref) 1.00 (ref) 1.00 (ref) M 0.90 <0.95, W 0.75 < ( ) 1.42 ( ) 1.35 ( ) ( ) 1.47 ( ) 1.43 ( ) ( ) 1.31 ( ) 1.13 ( ) M 0.95 <1.00, W 0.80 < ( ) 1.23 ( ) 1.11 ( ) ( ) 1.26 ( ) 1.17 ( ) ( ) 1.14 ( ) 0.83 ( ) M 1.00þ, W 0.85þ ( ) 1.43 ( ) 1.19 ( ) ( ) 1.43 ( ) 1.27 ( ) ( ) 1.49 ( ) 0.96 ( ) Per ( ) 1.12 ( ) 1.03 ( ) 1.17 ( ) 1.09 ( ) 1.03 ( ) 1.26 ( ) 1.22 ( ) 1.04 ( ) P value for trend P interaction with sex Per Std Dev 1.18 ( ) 1.12 ( ) 1.03 ( ) 1.16 ( ) 1.09 ( ) 1.03 ( ) 1.25 ( ) 1.21 ( ) 1.04 ( ) Abbreviation: RR, relative risk. a Some counts do not add to totals because of missing data. b Adjusted for age, sex, and study. c Adjusted for age, sex, study, race, physical activity, education, smoking, alcohol, and gallstones. d Adjusted for age, sex, study, race, physical activity, education, smoking, alcohol, gallstones, and BMI. Cancer Epidemiol Biomarkers Prev;

8 Campbell et al Rate ra o Figure 2. Restricted cubic spline analysis of waist circumference and risk of gallbladder cancer in the Rare Cancer Collaboration. The solid line indicates the HR, whereas the dashed line indicates 95% CIs Waist circumference (cm) 381 with the more recent, larger studies lacked sufficient statistical 382 power to detect a meaningful association for men. 383 We are not aware of any epidemiologic studies on young adult 384 BMI as a risk factor for gallbladder cancer; therefore, our finding of 385 higher risk with obese levels of BMI during young adulthood is 386 novel but requires replication in other large, prospective studies. 387 This finding may highlight the importance of early life energy 388 excess with gallbladder cancer etiology. We identified a moderate 389 association between adult weight gain and gallbladder cancer risk: 390 only one previous cohort study assessed adult weight gain with 391 gallbladder cancer risk (11) and reported that average weight gain 392 (in kg) per year from age 20 years onward was not statistically 393 significantly associated with risk, although only 37 gallbladder 394 cancer cases were identified in the cohort, so statistical power to 395 detect an association was limited. 396 Taller height was associated with higher risk of gallbladder 397 cancer in this study, whereas in one previous large prospective 398 cohort study (16), height was not associated with gallbladder 399 cancer risk. The Million Women Study collaboration reported an 400 association between height and cancer risk overall (30), consistent 401 with this study for gallbladder cancer, but that study did not report 402 results specifically for gallbladder cancer, and it is unlikely that the 403 overall result was materially affected from what would have been 404 very few gallbladder cancer cases. 405 Prospective studies on waist and hip circumference related 406 measures and gallbladder cancer risk are especially rare, with 407 only one published study to date (11) that reported each 5 cm 408 increase in waist and hip circumferences was associated with 17% 409 and 18% higher risks of gallbladder cancer risk, respectively, and 410 the results were statistically significant despite a relatively small 411 number of cases (n ¼ 76). Likewise, a 0.1 increase in the waist hip 412 ratio was associated with a nonstatistically significant 33% higher 413 risk of gallbladder cancer (11). With over 300 prospectively 414 identified gallbladder cancer cases with reported waist- and hip 415 circumference related measures, our study adds considerably to 416 the sparse literature on central adiposity and gallbladder cancer 417 risk, although further research from additional large, prospective 418 cohort studies is still warranted. From the statistical models that included mutual adjustment of BMI and waist circumference, some of the risk imparted by these variables is likely shared since both of the main effect associations were attenuated to the null and were no longer statistically significant, although the HR for BMI decreased appreciably more than did the HR for waist circumference. Obesity increases risk of cholesterol gallstones and other gallbladder diseases (31), and gallstones, in turn, are a major risk factor for gallbladder cancer (4). Thus, gallstones might lie on the causal pathway between obesity and gallbladder cancer risk for some men and women; but when history of gallstones at baseline was included in the statistical models, there was no appreciable change to the HRs for obesity. In addition, when persons with a history of gallstones at baseline were excluded, the results were not materially different (data not shown). More work is needed to define the mechanisms that connect general and central obesity to gallbladder cancer risk. Some plausible mechanisms to explain this link may include localized inflammation and the ensuing damage that occurs to gallbladder epithelial tissue over time which for some men and women may lead to gallbladder cancer. The current study's strengths include its large sample size, prospective study design, inclusion of cohort studies from several regions of the world, long follow-up, and inclusion of harmonized data on many confirmed and plausible gallbladder cancer risk factors. Several limitations of this study should be also considered, particularly regarding the reliance by most studies on self-reported height and weight. Cross-sectional studies suggest that self-reported BMI is slightly lower than directly measured BMI, especially at obese levels of BMI (32); under-reporting of BMI may inflate associations for overweight BMI and gallbladder cancer risk and simultaneously underestimate the association for obese BMI. Good-to-excellent agreement has been reported for self-reported and directly measured values of height and weight, however, in studies with participants who shared similar demographic characteristics to this study (33, 34), and it is reassuring that the main associations for adult BMI and gallbladder cancer risk were similar for studies with directly measured versus self-reported height and weight. Six studies in this study Cancer Epidemiol Biomarkers Prev; 2017 Cancer Epidemiology, Biomarkers & Prevention

9 Anthropometry and Gallbladder Cancer Risk 460 had interviewer-measured waist and hip circumference data, 461 whereas eight studies had these data from participant measure- 462 ments. The validity of self-measured versus interviewer-measured 463 waist and hip circumferences is generally quite high, with correla- 464 tions coefficients of 0.84 to 0.9 (35). Nonetheless, if circumfer- 465 ence-related measures are more measurement-error prone than 466 height and weight, then studies of body circumference measures 467 and disease outcomes would tend to underestimate the true 468 associations compared with studies that rely on height and 469 weight. Further, waist hip ratio tends to show weaker correlations 470 between self-measured and interviewer-measured indices, sug- 471 gesting that it is more prone to measurement error than other 472 body size variables (35, 36). This potential measurement error 473 may explain, at least in part, our null result for waist hip ratio and 474 gallbladder cancer risk. We did not have access to updated risk 475 factor information in this pooling project study even though some 476 individual cohort studies collected updated risk factor informa- 477 tion during follow-up. For factors that change over time, including 478 body weight and circumference-related measures, this limitation 479 likely causes underestimation of the true associations. Another 480 limitation in this study is the lack of data on cholecystectomy (i.e., 481 gallbladder removal); although it is unclear what effect, if any, this 482 omission would have on the HRs in this study. Five cohort studies 483 did not collect circumference-related measures, and other studies 484 only collected this information after their initial baseline enroll- 485 ment; thus, we had fewer case numbers for these measures than for 486 the height- and weight-related analyses. 487 In conclusion, this pooled cohort analysis of individual-level 488 data from 19 prospective cohort studies identified higher risks of 489 gallbladder cancer with indicators of general and central obesity 490 and height. Because gallbladder cancer has such a poor prognosis 491 with so few established risk factors, additional studies are required 492 to identify further primary prevention opportunities for this 493 disease. 494 Disclosure of Potential Conflicts of Interest 495Q8 No potential conflicts of interest were disclosed. 496 Authors' Contributions 497 Conception and design: P.T. Campbell, C.C. Newton, C.M. Kitahara, P. Hartge, 498 M. Jenab, R.L. Milne, E. Weiderpass, A. Wolk, S.M. Gapstur 499 Development of methodology: P.T. Campbell, E. Weiderpass 500 Acquisition of data (provided animals, acquired and managed patients, 501 provided facilities, etc.): P.T. Campbell, A.V. Patel, A. Berrington, L.E. Beane 502 Freeman, L. Bernstein, J.E. Buring, N.D. Freedman, Y.-T. Gao, G.G. Giles, 503 M.J. Gunter, M. Jenab, R.L. Milne, K. Robien, D.P. Sandler, C. Schairer, 504 X.-O. Shu, E. Weiderpass, A. Wolk, Y.-B. Xiang, A. Zeleniuch-Jacquotte, 505 W. Zheng, S.M. Gapstur 506 Analysis and interpretation of data (e.g., statistical analysis, biostatistics, 507 computational analysis): P.T. Campbell, C.C. Newton, H.-O. Adami, 508 H.D. Sesso, E. Weiderpass, A. Wolk, Y.-B. Xiang, A. Zeleniuch-Jacquotte, 509 S.M. Gapstur 510 Writing, review, and/or revision of the manuscript: P.T. Campbell, 511 C.C. Newton, C.M. Kitahara, A.V. Patel, P. Hartge, J. Koshiol, K. McGlynn, 512 H.-O. Adami, A. Berrington, L.E. Beane Freeman, L. Bernstein, J.E. Buring, 513 N.D. Freedman, Y.-T. Gao, G.G. Giles, M.J. Gunter, M. Jenab, L.M. Liao, 514 R.L. Milne, K. Robien, D.P. Sandler, C. Schairer, H.D. Sesso, X.-O. Shu, 515 E. Weiderpass, A. Wolk, Y.-B. Xiang, A. Zeleniuch-Jacquotte, W. Zheng, 516 S.M. Gapstur 517 Administrative, technical, or material support (i.e., reporting or organizing 518 data, constructing databases): P.T. Campbell, C.M. Kitahara, L. Bernstein, N.D. 519 Freedman, Y.-T. Gao, G.G. Giles, K. Robien, E. Weiderpass 520Q9 Study supervision: P.T. Campbell, L. Bernstein, X.-O. Shu, E. Weiderpass Grant Support The AHS was funded by the Intramural Program of the NIH, National Cancer Institute (Z01 P010119) and the National Institute of Environmental Health Sciences (Z01 ES ). The BCDDP Follow-up Study has been supported by the Intramural Research Program of the NCI, NIH. The American Cancer Society funds the creation, maintenance, and updating of the CPS-II cohort. The CTS was supported by NCI grants R01 #CA and K05 CA (awarded to Leslie Bernstein). The coordination of the EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society, Denmark; Ligue Contre le Cancer, France; Institut Gustave Roussy, France; Mutuelle Generale de l'education Nationale, France; Institut National de la Sante et de la Recherche Medicale, France; Deutsche Krebshilfe, Germany; Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research, Germany; Hellenic Health Foundation, Greece; Italian Association for Research on Cancer; National Research Council, Italy; Dutch Ministry of Public Health, Welfare and Sports, the Netherlands; Netherlands Cancer Registry, the Netherlands; LK Research Funds, the Netherlands; Dutch Prevention Funds, the Netherlands; Dutch ZON (Zorg Onderzoek Nederland), the Netherlands; World Cancer Research Fund, London, UK; Statistics Netherlands, the Netherlands; European Research Council, Norway; Health Research Fund, Regional Governments of Andalucía, Asturias, Basque Country, Murcia (project no. 6236) and Navarra, ISCIII RETIC (RD06/0020/0091), Spain; Swedish Cancer Society, Sweden; Swedish Scientific Council, Sweden; Regional Government of Ska ne and V asterbotten, Sweden; Cancer Research United Kingdom; Medical Research Council, United Kingdom; Stroke Association, United Kingdom, British Heart Foundation, United Kingdom; Department of Health, Food Standards Agency, United Kingdom; and Wellcome Trust, United Kingdom. The IWHS is supported by a grant from the NCI (R01 CA39742). The MCCS receives core funding from the Cancer Council Victoria and is additionally supported by grants from the Australian NHMRC (209057, , , and ). The NYUWHS is supported by grant R01 CA and Center grant CA from the NCI and by Center grant ES The NIH-AARP Diet and Health Study (NIH-AARP) was supported by the Intramural Research Program of the NCI, NIH. The PHS was supported by grants CA 97193, CA 34944, CA 40360, HL 26490, and HL from the NIH. The PLCO Cancer Screening Trial is supported by contracts from the NCI. SISTER was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES044005). The SMC was supported by the Swedish Research Council, Swedish Council for Working Life and Social Research, and the Swedish Cancer Foundation. The SMHS was supported by grants (R01 CA and UM1 CA173640) from the NIH. The SWHS was supported by grants R37 CA and UM1 CA from the NCI and in part by the NCI intramural program (N02 CP ). VITAL study: Dr. White was supported by the NIH grant K05-CA (National Cancer Institute and Office of Dietary Supplements). The WHS was supported by CA047988, HL043851, HL080467, and HL The WLH project was supported by the Swedish Research Council (grant number ) and a Distinguished Professor Award at Karolinska Institutet to Hans-Olov Adami, grant number: 2368/ The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received October 7, 2016; revised November 18, 2016; accepted November 23, 2016; published OnlineFirst xx xx, xxxx. Q Cancer Epidemiol Biomarkers Prev;