Supplementary appendix

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1 Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Papadimitriou N, Tsilidis KK, Orfanos P, et al. Burden of hip fracture using disability-adjusted life-years: a pooled analysis of prospective cohorts in the CHANCES consortium. Lancet Public Health 2017; published online April 11.

2 SUPPLEMENTARY MATERIALS Study population Data for the current paper was provided from six cohorts (i.e., COSM, EPIC-Elderly, ESTHER, NHS, SMC and Tromsø Study). The cohort of Swedish men (COSM) was initiated in 1997, when all men born between 1918 and 1952 residing in two counties in central Sweden were invited to participate, and of them were included in this study. EPIC-Elderly is a subset of the European Prospective Investigation into Cancer and Nutrition (EPIC) and includes only participants who were at least 60 years old at recruitment and were based in the following countries (Denmark, Greece, Netherlands, Spain, Sweden) participants from two centers (Greece and Umea in Sweden) were used in the current analysis. ESTHER (Epidemiological Study on Chances of Prevention, Early Recognition and Optimised Treatment of Chronic Diseases in the Older Population) is a population-based study that recruited participants aged years from the federal state of Saarland in Germany in , and 9853 participants were included herein. The Nurses Health Study (NHS) was initiated in 1976 and consists of female nurses across the USA, of whom were included in this study. The Swedish Mammography Cohort (SMC) is a population-based cohort of women residing in central Sweden, and of them were included herein. The Tromsø study is a repeated population-based health survey consisting of six surveys that took part in the municipality of Tromsø in Norway from 1974 (Tromsø 1) to 2008 (Tromsø 6). Our analysis includes participants from Tromsø 2 (1979) to Tromsø 5 (2001). 1-6 Data harmonization Variables harmonized across the cohorts were created following predetermined standardized procedures. 1 Very briefly: a) a list of exposures/outcomes of interest was created by the consortium, b) for each of those exposures/outcomes, relevant variables were identified and compared among the cohorts, c) new common variables were created based on the available data in each cohort, and d) the quality of the new variables from each cohort was assessed and documented. Assessment of hip fractures Incident hip fractures were identified through telephone interviews or questionnaires eliciting selfreported information in EPIC-Elderly Greece, ESTHER and NHS or through linkage with inpatient or fracture registries in EPIC-Elderly Umea, Tromsø, COSM and SMC. Validation studies to ascertain the accuracy of self-reported hip fractures were conducted, and the percentage of confirmation to medical records was 52% in ESTHER, 86% in EPIC-Elderly Greece (only the validated confirmed self-reported cases were considered as outcomes in the current analysis) and 100% in NHS. 7,8 The accuracy of the inpatient or fracture registries used in Sweden and Norway was very high Mortality was assessed from death certificates, death registries or via public health departments in EPIC-Elderly Greece, EPIC- Elderly Umea and ESTHER, from family reports, state mortality files and the National Death Index in NHS or via linkage to Statistics Norway for Tromsø and to Statistics Sweden for SMC and COSM. The International Classification of Diseases (ICD) codes were used for the classification of hip fractures as ICD-8 code N820 and ICD-10 code S Assessment of risk factors Information on the risk factors was obtained through questionnaires or interviews at the time of recruitment in each of the participating cohorts. Measured body mass index was categorized in six groups (i.e., <18.5, , 25-30, 30-35, >35 vs kg/m 2 ). Current alcohol consumption was divided into six categories (i.e., 0, 2 5-5, 5-10, 10-15, 15 vs g/d). Smoking status (current, former vs. never) was modeled using a three-level categorical variable, whereas vigorous physical activity (yes vs. no), self-reported history of diabetes mellitus type two (yes vs. no), parity (never vs. ever), hormone replacement therapy (never vs. ever), and use of oral contraceptives (never vs. ever) were divided in two categories. Physical activity was considered vigorous if it caused sweating, and participants who exercised vigorously at least once per week were coded as yes in the binary variable. The NHS, SMC and COSM cohorts did not have information on vigorous physical activity but provided instead information on how many hours per week someone participated in sports. Similarly, we assigned those who participate in sports for an hour or more per week in the yes category. More information regarding the risk factor assessment by cohort can be found in previous publications. 1,6,12-16 The SMC and COSM cohorts did not provide information for body mass index and alcohol, and were therefore excluded from the relevant analyses. 1

3 References 1. Boffetta P, Bobak M, Borsch-Supan A, et al. The Consortium on Health and Ageing: Network of Cohorts in Europe and the United States (CHANCES) project-- design, population and data harmonization of a large-scale, international study. Eur J Epidemiol 2014; 29(12): Trichopoulou A, Orfanos P, Norat T, et al. Modified Mediterranean diet and survival: EPIC-elderly prospective cohort study. BMJ 2005; 330(7498): Harris H, Håkansson N, Olofsson C, et al. The Swedish mammography cohort and the cohort of Swedish men: study design and characteristics of two populationbased longitudinal cohorts. OA Epidemiology 2013; 1(2): Colditz GA, Hankinson SE. The Nurses' Health Study: lifestyle and health among women. Nat Rev Cancer 2005; 5(5): Jacobsen BK, Eggen AE, Mathiesen EB, Wilsgaard T, Njolstad I. Cohort profile: the Tromso Study. Int J Epidemiol 2012; 41(4): Schottker B, Haug U, Schomburg L, et al. Strong associations of 25- hydroxyvitamin D concentrations with all-cause, cardiovascular, cancer, and respiratory disease mortality in a large cohort study. Am J Clin Nutr 2013; 97(4): Benetou V, Orfanos P, Feskanich D, et al. Education, marital status, and risk of hip fractures in older men and women: the CHANCES project. Osteoporos Int 2015; 26(6): Colditz GA, Martin P, Stampfer MJ, et al. Validation of questionnaire information on risk factors and disease outcomes in a prospective cohort study of women. Am J Epidemiol 1986; 123(5): Ahmed LA, Schirmer H, Bjornerem A, et al. The gender- and age-specific 10- year and lifetime absolute fracture risk in Tromso, Norway. Eur J Epidemiol 2009; 24(8): Gedeborg R, Engquist H, Berglund L, Michaelsson K. Identification of incident injuries in hospital discharge registers. Epidemiology 2008; 19(6): Ludvigsson JF, Andersson E, Ekbom A, et al. External review and validation of the Swedish national inpatient register. BMC Public Health 2011; 11: Bamia C, Trichopoulos D, Ferrari P, et al. Dietary patterns and survival of older Europeans: the EPIC-Elderly Study (European Prospective Investigation into Cancer and Nutrition). Public Health Nutr 2007; 10(6): Jorde R, Schirmer H, Njolstad I, et al. Serum calcium and the calcium-sensing receptor polymorphism rs in relation to coronary heart disease, type 2 diabetes, cancer and mortality: the Tromso Study. Eur J Epidemiol 2013; 28(7): Shivappa N, Harris H, Wolk A, Hebert JR. Association between inflammatory potential of diet and mortality among women in the Swedish Mammography Cohort. Eur J Nutr Dorans KS, Mostofsky E, Levitan EB, Hakansson N, Wolk A, Mittleman MA. Alcohol and incident heart failure among middle-aged and elderly men: cohort of Swedish men. Circ Heart Fail 2015; 8(3): Virtanen JK, Mozaffarian D, Willett WC, Feskanich D. Dietary intake of polyunsaturated fatty acids and risk of hip fracture in men and women. Osteoporos Int 2012; 23(11):

4 Supplementary Table 1. Disability-adjusted life years for hip fracture in the CHANCES consortium under the base scenario* with varying assumptions of age weighting, discounting and excess mortality Age weighting/discount Excess YLD YLL DALYs YLD/YLL YLD/DALYs mortality (%) Abbreviations: CHANCES, Consortium on Health and Ageing Network of Cohorts in Europe and the United States; YLD, years of life lost due to disability; YLL, years of life lost due to premature mortality; DALY, disability-adjusted life years * Disability weights d1=0 468 for the 1 st year, d2=0 17 for the 2 nd year, and then 10% annual discount as proposed by National Osteoporosis Foundation (NOF). We also assumed that 25% of the deaths due to any cause within a year after the hip fracture are causally related to it. 3

5 Supplementary Table 2. Disability-adjusted life years for hip fracture in the CHANCES consortium using different disability weights by age group NOF 1 WHO 2 WHO 3 NBD 4 Age groups YLL YLD DALYs YLD DALYs YLD DALYs YLD DALYs , , , Total Abbreviations: CHANCES, Consortium on Health and Ageing Network of Cohorts in Europe and the United States; YLD, years of life lost due to disability; YLL, years of life lost due to premature mortality; DALY, disabilityadjusted life years; NOF, National Osteoporosis Foundation; WHO, World Health Organization; NBD, Netherlands Burden of Disease study. 1 Disability weights d1=0 468 for the 1 st year, d2=0 17 for the 2 nd year, and then 10% annual discount. 2 Disability weights d1=0 372 for first 51 days, and d2=0 272 for the remaining time for 5% of the patients. 3 Disability weights d1=0 372 for the first 6 months, and d2=0 272 for the remaining time for 29% of the patients. 4 Disability weights are d1=0 19 for the 1 st year, d2=0 13 for the 2 nd year, and then 10% annual discount. 4

6 Supplemental Table 3. Disability-adjusted life years for hip fracture by sex, age group and cohort in the CHANCES consortium under different sensitivity analysis scenarios. 1st case: Non uniform age weights and 3% discount factor applied 1st scenario: Disability weights d1=0 372 for first 51 days and d2=0 272 for the remaining time for 5% of the patients. excess mortality: 25% of excess mortality: 50% of excess mortality: 100% of No excess mortality. COSM Females SMC Females NHS Females EPIC Females

7 Supplemental Table 3 (continue) excess mortality: 25% of excess mortality: 50% of excess mortality: 100% of No excess mortality. ESTHER Females TROMSO Females nd scenario: Disability weights d1=0 372 for first 6 months and d2=0 272 for the remaining time for 29% of the patients. COSM Females SMC Females

8 Supplemental Table 3 (continue) excess mortality: 25% of excess mortality: 50% of excess mortality: 100% of No excess mortality. NHS Females EPIC Females ESTHER Females TROMSO Females

9 Supplemental Table 3 (continue) 3rd scenario: Disability weights d1=0 468 for the 1st year, d2=0 17 for the 2nd and then 10% annual discount. excess mortality: 25% of excess mortality: 50% of excess mortality: 100% No excess mortality. of COSM Females SMC Females NHS Females EPIC Females

10 Supplemental Table 3 (continue) excess mortality: 25% of excess mortality: 50% of excess mortality: 100% of No excess mortality. ESTHER Females TROMSO Females th scenario: Disability weights d1=0 19 for the 1st year, d2=0 13 for the 2nd and then 10% annual discount. COSM Females SMC Females

11 Supplemental Table 3 (continue) excess mortality: 25% of excess mortality: 50% of excess mortality: 100% of No excess mortality. NHS Females EPIC Females ESTHER Females TROMSO Females

12 Supplemental Table 3 (continue) 2nd case: Uniform age weights and no discount factor 1st scenario: Disability weights d1=0 372 for first 51 days and d2=0 272 for the remaining time for 5% of the patients. excess mortality: 25% of excess mortality: 50% of excess mortality: 100% of No excess mortality. COSM Females SMC Females NHS Females EPIC Females

13 Supplemental Table 3 (continue) excess mortality: 25% of excess mortality: 50% of deaths occurred in the first year after the hip fracture are due to the excess mortality: 100% of deaths occurred in the first year after the hip fracture are due to the No excess mortality. ESTHER Females TROMSO Females nd scenario: Disability weights d1=0 372 for first 6 months and d2=0 272 for the remaining time for 29% of the patients. COSM Females SMC Females

14 Supplemental Table 3 (continue) excess mortality: 25% of excess mortality: 50% of deaths occurred in the first year after the hip fracture are due to the excess mortality: 100% of deaths occurred in the first year after the hip fracture are due to the No excess mortality. NHS Females EPIC Females ESTHER Females TROMSO Females

15 Supplemental Table 3 (continue) 3rd scenario: Disability weights d1=0 468 for the 1st year, d2=0 17 for the 2nd and then 10% annual discount. excess mortality: 25% of excess mortality: 50% of excess mortality: 100% No excess mortality. of deaths occurred in the first year after the hip fracture are due to the COSM Females SMC Females NHS Females EPIC Females

16 Supplemental Table 3 (continue) excess mortality: 25% of excess mortality: 50% of deaths occurred in the first year after the hip fracture are due to the excess mortality: 100% of deaths occurred in the first year after the hip fracture are due to the No excess mortality. ESTHER Females TROMSO Females th scenario: Disability weights d1=0 19 for the 1st year, d2=0 13 for the 2nd and then 10% annual discount. COSM Gender Females SMC Females

17 Supplemental Table 3 (continue) excess mortality: 25% of excess mortality: 50% of excess mortality: 100% of No excess mortality. NHS Females EPIC Females ESTHER Females TROMSO Females Abbreviations: YLD, years of life lost due to disability; YLL, years of life lost due to premature mortality; DALYs, disability-adjusted life years; COSM, Cohort of the Swedish Men; SMC, Swedish Mammography Cohort; NHS, Nurses 16

18 Health Study; EPIC, European Prospective Investigation into Cancer Nutrition-Elderly; ESTHER, Epidemiological Study on Chances of Prevention, Early Recognition and Optimised Treatment of Chronic Diseases in the Older Population 17

19 Supplemental Table 4 Hazard ratios (HR) and 95% confidence intervals (95% CI) for the association of five generic and four reproductive factors with risk of hip fracture incidence and mortality by cohort and sex in the CHANCES consortium. Men and Women EPIC ESTHER TROMSO NHS SMC COSM Overall Meta-analysis Hip fracture incidence cases HR (95% CI) cases HR (95% CI) cases HR (95% CI) cases HR (95% CI) cases HR (95% CI) cases HR (95% CI) cases HR (95% CI) HR (95% CI) I 2 Smoking (current vs. never smoker) ( ) ( ) ( ) ( ) ( ) ( ) ( ) 1 45 ( ) 0 Smoking (former vs. never smoker) ( ) ( ) ( ) ( ) ( ) ( ) ( ) 1 06 ( ) 0 Consumption (0 vs gr/day) 318 Current AIcohol Consumption (2 5-5 vs gr/day) 318 Consumption (5-10 vs gr/day) 318 Consumption (10-15 vs gr/day) 318 Consumption ( 15 vs gr/day) 318 BMI (<18 5 vs kg/m 2 ) 316 BMI ( 18 5 & <21 5 vs ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) NA NA ( ) NA NA ( ) ( ) NA NA ( ) ( ) NA NA ( ) 1 16 ( ) ( ) 0 93 ( ( ) 0 98 ( ) ( ) 1 03 ( ) ( ( ( (0 94- ) ( ) ) ) NA NA ) 1 03 ( ) ( ( ( ( ) ( ) ) ) NA NA ) 2 1 ( ) ( ( ( kg/m 2 ) ( ) ( ) ) ) NA NA ( ) 1 47) 24 BMI (25-30 vs ( ( ( (0 77- kg/m 2 ) ) ( ) ) ( ) NA NA ) 0 92) 0 BMI (30-35 vs ( (0 59- kg/m 2 ) ( ) ( ) ( ) ) NA NA ( ) 0 86) 0 BMI ( 35 vs ( ( ( (0 54- kg/m 2 ) ( ) ( ) ) ) NA NA ) 0 79) 0 Vigorous Ph. Activity (no 1 14 ( ( ( ( (1 05- vs. yes) ( ) ( ) ) ) ) ) ) 1 39 ( ) ( ( ( ( ( (1 53- Diabetes (yes vs. no) ) ( ) ) ( ) ) ) ) 1 97) 48 18

20 Supplemental Table 4 (continue) Men and Women EPIC ESTHER TROMSO NHS SMC COSM Overall Meta-analysis Hip fracture mortality cases HR (95% CI) cases HR (95% CI) cases HR (95% CI) cases HR (95% CI) cases HR (95% CI) cases HR (95% CI) cases HR (95% CI) HR (95% CI) I 2 Smoking (current vs ( ( ( (1 33- never smoker) ) 1 NA 0 NA ) ) ( ) ) 2 26 ( ) 0 Smoking (former vs (0 66- never smoker) 5 NA 1 NA 0 NA ( ) ( ) ( ) ) 1 6 ( ) 70 Consumption (0 vs gr/day) 5 NA 1 NA 0 NA 78 Current AIcohol Consumption (2 5-5 vs gr/day) 5 NA 1 NA 0 NA 78 Consumption (5-10 vs ( ) NA NA ( ) NA NA ( ) NA NA ( ) NA 1 05 ( ) NA 0 79 ( ) NA gr/day) 5 NA 1 NA 0 NA 78 Consumption (10-15 vs gr/day) 5 NA 1 NA 0 NA ( ) NA NA ( ) NA Consumption ( 15 vs gr/day) 5 NA 1 NA 0 NA ( ) NA NA ( ) NA BMI (<18 5 vs (0 49- kg/m 2 ) 5 NA 1 NA 0 NA ) NA NA 92 BMI ( 18 5 & <21 5 vs ( ( kg/m 2 ) ) 1 NA 0 NA ) NA NA 92 BMI (25-30 vs ( (0 46- kg/m 2 ) ) 1 NA 0 NA ) NA NA 92 BMI (30-35 vs (0 05- kg/m 2 ) ) 1 NA 0 NA ( ) NA NA 92 BMI ( 35 vs (0 69- kg/m 2 ) 5 NA 1 NA 0 NA ) NA NA 92 Vigorous Ph. Activity (no 0 51 ( ( (0 54- vs. yes) ) 1 NA 0 NA ) ) ( ) ( ( (0 51- Diabetes (yes vs. no) ) 1 NA 0 NA ) ) ( ) ( ) NA 1 32 ( ( ) 48 15) ( ( ) 1 28) ( ) 0 8 ( ) ( ) NA 3 09 ( ( ) 2 33) ( ( ) 4 45) 68 19

21 Supplemental Table 4 (continue) Men only EPIC ESTHER TROMSO NHS SMC COSM Overall Meta-analysis Hip fracture incidence cases HR (95% CI) cases HR (95% CI) cases HR (95% CI) cases HR (95% CI) cases HR (95% CI) cases HR (95% CI) cases HR (95% CI) HR (95% CI) I 2 Smoking (current vs. never smoker) ( ) ( ) ( ) NA NA ( ) ( ) 1 29 ( ) 59 Smoking (former vs. never smoker) ( ) ( ) ( ) NA NA ( ) ( ) 1 0 ( ) 1 Consumption (0 vs gr/day) ( ) ( ) 184 Current AIcohol Consumption (2 5-5 vs gr/day) ( ) ( ) 184 Consumption (5-10 vs ( gr/day) ( ) ) 184 Consumption (10-15 vs gr/day) ( ) ( ) 184 Consumption ( 15 vs gr/day) ( ) ( ) 184 BMI (<18 5 vs (4 27- kg/m 2 ) ( ) ) 183 BMI ( 18 5 & <21 5 vs ( kg/m 2 ) ( ) ) 183 BMI (25-30 vs (0 36- kg/m 2 ) ( ) ) 183 BMI (30-35 vs (0 29- kg/m 2 ) ( ) ) 183 BMI ( 35 vs kg/m 2 ) 78 NA 37 NA 183 Vigorous Ph. Activity (no 3 82 ( (1 14- vs. yes) ) ) (1 67- Diabetes (yes vs. no) ) ( ) ( ) NA NA NA ( ) NA NA NA ( ) NA NA NA ( ) NA NA NA ( ) NA NA NA ( ) NA NA NA ( ) NA NA NA ( ) NA NA NA ( ) NA NA NA ( ) NA NA NA ( ( ) NA NA ) ( ( ) NA NA ) ( ) 1 12 ( ) ( ) 1 06 ( ) 0 99 ( ) ( ) ( ) 1 24 ( ) ( ) 1 22 ( ) ( ( ) 24 4) ( ) 1 22 ( ) ( ( ) 1 27) ( ( ) 1 21) ( ) NA 1 58 ( ( ) 2 41) ( ( ) 2 43) 44 20

22 Supplemental Table 4 (continue) Men only EPIC ESTHER TROMSO NHS SMC COSM Overall Meta-analysis Hip fracture mortality cases HR (95% CI) cases HR (95% CI) cases HR (95% CI) cases HR (95% CI) cases HR (95% CI) cases HR (95% CI) cases HR (95% CI) HR (95% CI) I 2 Smoking (current vs. never smoker) 3 NA 0 NA 0 NA NA NA ( ) 3 NA NA Smoking (former vs. never smoker) 3 NA 0 NA 0 NA NA NA ( ) 3 NA NA Consumption (0 vs gr/day) 3 NA 0 NA 0 NA NA NA NA 3 NA NA Current AIcohol Consumption (2 5-5 vs gr/day) 3 NA 0 NA 0 NA NA NA NA 3 NA NA Consumption (5-10 vs gr/day) 3 NA 0 NA 0 NA NA NA NA 3 NA NA Consumption (10-15 vs gr/day) 3 NA 0 NA 0 NA NA NA NA 3 NA NA Consumption ( 15 vs gr/day) 3 NA 0 NA 0 NA NA NA NA 3 NA NA BMI (<18 5 vs kg/m 2 ) 3 NA 0 NA 0 NA NA NA NA 3 NA NA BMI ( 18 5 & <21 5 vs kg/m 2 ) 3 NA 0 NA 0 NA NA NA NA 3 NA NA BMI (25-30 vs kg/m 2 ) 3 NA 0 NA 0 NA NA NA NA 3 NA NA BMI (30-35 vs kg/m 2 ) 3 NA 0 NA 0 NA NA NA NA 3 NA NA BMI ( 35 vs kg/m 2 ) 3 NA 0 NA 0 NA NA NA NA 3 NA NA Vigorous Ph. Activity (no vs. yes) 3 NA 0 NA 0 NA NA NA ( ) 3 NA NA Diabetes (yes vs. no) 3 NA 0 NA 0 NA NA NA ( ) 3 NA NA 21