Supplementary Appendix

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1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Juonala M, Magnussen C, Berenson G, et al. Childhood adiposity, adult adiposity, and cardiovascular risk factors. N Engl J Med 2011;365:

2 1 Supplementary Appendix Childhood Adiposity, Adult Adiposity, and Cardiovascular Risk Factors Short title: Childhood Adiposity and Cardiovascular Risk Factors Markus Juonala, MD, PhD 1 ; Costan G. Magnussen, PhD 1,2,3 ; Gerald S. Berenson, MD 5 ; Alison Venn, PhD 2 ; Trudy L. Burns, MPH, PhD 6 ; Matthew A. Sabin, MD, PhD 3,4 ; Sathanur R. Srinivasan, PhD 5 ; Stephen R. Daniels MD, PhD 7, Patricia H. Davis, MD 6 ; Wei Chen, MD, PhD 5 ; Cong Sun, MD, PhD 3,4 ; Michael Cheung, MD, PhD 3,4 ; Jorma S.A. Viikari, MD, PhD 1 ; Terence Dwyer, MD, MPH 3 ; Olli T. Raitakari, MD, PhD 1 1 From the Research Centre of Applied and Preventive Cardiovascular Medicine (MJ, CGM, OTR) and the Departments of Clinical Physiology (OTR) and Medicine (JSAV, MJ), University of Turku and Turku University Hospital, Turku, Finland. 2 Menzies Research nstitute (CGM, AV), University of Tasmania, Hobart, Australia. 3 Murdoch Childrens Research nstitute (CGM, MAS, CS, MC, TD), Melbourne, Australia. 4 The University of Melbourne, Department of Paediatrics at the Royal Children's Hospital (MAS, CS, MC), Melbourne, Australia 5 Tulane Center for Cardiovascular Health(GSB, SRS, WC), Tulane University, New Orleans, LA, USA. 6 Department of Epidemiology, College of Public Health (TLB), and Department of Neurology, Carver College of Medicine (PHD), University of owa, owa City, A, USA. 7 Department of Pediatrics(SRD), University of Colorado Denver and Health Science Center, Aurora, CO, USA.

3 2 SUPPLEMENTARY APPENDX TABLE OF CONTENTS Supplementary Methods Page 3 Supplementary Results Page 6 Supplementary Table 1. Childhood BM Cutpoints Page 7 Supplementary Table 2. Baseline Characteristics by Adiposity Group Page 8 Supplementary Table 3. Childhood Adiposity and Outcomes from Random-Effects Meta-Analysis Page 9 Supplementary Table 4. Outcomes by Adiposity Group and Cohort Page 10 Supplementary Table 5. Outcomes by Degree of Childhood Adiposity () Page 11 Supplementary Table 6. Outcomes by Degree of Childhood Adiposity () Page 12 Supplementary Table 7. Outcomes by Baseline Age, Length of Follow-up, and Height Page 13 Supplementary Table 8. Outcomes Using Different Baseline Age Ranges Page 14 Supplementary Table 9. Outcomes Using Different Definitions for Diabetes and Hypertension Page 15 Supplementary Table 10. Outcomes Adjusted for Socioeconomic Status Page 16 Supplementary Table 11. Outcomes Adjusted for Pubertal Staging Page 17 Supplementary Table 12. Outcomes Using Skinfold Thickness to Define Adiposity Page 18 Supplementary Table 13. Outcomes Of Analyses Restricted to Whites Page 19 Supplementary Table 14. Association of Smoking Status with Outcomes Page 20 Supplementary Table 15. Outcomes Adjusted for Smoking Status Page 21 Supplementary Table 16. Multivariable Analyses of Adiposity and Outcomes () Page 22 Supplementary Table 17. Multivariable Analyses of Adiposity and Outcomes () Page 23 Supplementary Table 18. Age and Normalization of BM Page 24 Supplementary Table 19. Outcomes by Age at Normalization of BM Page 24 Supplementary Figure 1. Risk of Having One or More Outcomes by Adiposity Group Page 25 Supplementary Figure 2. Risk of ndividual Outcomes by Childhood Adiposity Status And Adult BM Page 26 References Page 28

4 3 SUPPLEMENTARY METHODS Data from four prospective studies conducted in the United States (the Bogalusa Heart Study and the Muscatine Study), Australia (the Childhood Determinants of Adult Health Study) and Finland (the Cardiovascular Risk in Young Finns Study) (i.e. the nternational Childhood Cardiovascular Cohort [i3c] Consortium) were used. Detailed descriptions of these studies, including attrition analyses demonstrating the representativeness of the cohorts, have been previously published 1-8. Each study received ethical approval, and obtained written informed consent from the study subjects or their parents for each of the longitudinal examinations. n each study, body mass index (BM) was calculated as weight(kg)/[height(m) 2 ] and all blood biochemistry was measured from fasting samples. The Bogalusa Heart Study Data on 635 participants from the biracial community aged 4 to 19 years at baseline (between 1981 and 1988) who attended an adult follow-up (2001 to 2002 or 2003 to 2007, age 24 to 42 years) were included. Height was measured to the nearest 0.1 cm using a manual height board, and weight was recorded to the nearest 0.1 kg using a balance beam metric scale. Triceps skinfold thicknesses were measured with Lange skinfold calipers (Cambridge Scientific, Cambridge, MA, USA) 9. Serum lipid levels were measured according to the laboratory manual of the Lipid Research Clinics program 10. Plasma glucose was measured enzymatically. Blood pressures were recorded using a mercury sphygmomanometer. To measure carotid artery intima-media thickness (MT), B-mode ultrasound examinations with a Toshiba Sonolayer SSH160A (Toshiba Medical, Tokyo, Japan) using a 7.5-MHz linear array transducer were performed as previously described 8. Smoking in childhood was assessed with a questionnaire 11. Those reporting smoking at least one cigarette per week were defined as regular smokers. Daily smoking in adulthood was assessed with a question: do you smoke everyday 12.

5 4 The Muscatine Study Between 1996 and 1999, 722 individuals aged 33 to 46 years who were representative of the childhood participants (age 8 to 18 years, study years 1970 to 1981) participated again in adulthood 2. Height was recorded to the nearest 0.5 cm using the owa Stadiometer, and weight was recorded to the nearest 0.1 kg using a portable scale. At follow-up, total cholesterol, HDL cholesterol, triglycerides and glucose were measured 2,5. Blood pressure levels were measured using a random-zero sphygmomanometer in adulthood. Carotid ultrasound studies were performed by a single technician using the Biosound Phase 2 ultrasound machine and a 10-MHz transducer (Biosound Esaote nc., ndianapolis, N) 2. Daily smoking in adulthood was assessed by a questionnaire 13. Childhood smoking data were not available in the Muscatine Study. The Childhood Determinants of Adult Health (CDAH) Study Data for 2331 participants aged 7 to 15 years at baseline (1985) who attended follow-up when aged 26 to 36 years (2004 to 2006) were included. Height was measured to the nearest 0.1 cm using a portable stadiometer. Weight was measured using regularly calibrated bathroom scales that recorded to the nearest 0.5 kg at baseline, and with a digital scale to the nearest 0.1 kg at follow-up. n childhood, triceps skinfolds were measured using Holtain calibers. n adulthood, lipid concentrations were determined enzymatically 10,3. Fasting plasma glucose levels were measured in adulthood by the Olympus AU5400 automated analyser. n adulthood, blood pressure measurements were recorded using a digital automatic monitor (Omron HEM907, Omron Healthcare nc, Kyoto, Japan). Participants retrospectively reported the highest level of education completed by their mother/female guardian and their father/male guardian (low indicates school only; medium, trade/vocational certificate; high, university). The highest level of parental education achieved was used as an indicator of child socioeconomic status 14. B-mode ultrasound studies of the carotid artery were performed using a validated portable Acuson Cypress (Siemens Medical Solutions USA nc.,

6 5 Mountainview, CA) ultrasound machine with a 7.0-MHz linear-array transducer 15. Smoking was assessed with questionnaires. Regular smoking in childhood was assessed with a question: How long have you been smoking regularly? Daily smoking in adulthood was assessed by a question: How often do you now smoke cigarettes, cigars, pipes or any other tobacco products? The Cardiovascular Risk in Young Finns Study Data from 2640 participants aged 3 to 18 years in 1980 who participated in either the 2001 or 2007 follow-up studies when aged 24 to 45 years were included. Height was measured using a wall-mounted Seca stadiometer with 0.5 cm accuracy, and weight was measured with a digital Seca scale to the nearest 0.1 kg. Triceps skinfold thickness, expressed as mm, were measured in triplicate from the non-dominating arm using a Harpenden skinfolds caliper (Holtain and Bull, British ndicators Ltd., Luton, Beds., UK). Serum cholesterol and triglyceride concentrations were determined using enzymatic methods. HDL cholesterol was analyzed after precipitation of very lowdensity lipoprotein and LDL cholesterol with dextran sulfate Glucose concentrations were analyzed enzymatically. n adulthood, blood pressure was measured using a random zero sphygmomanometer. Carotid MT studies were performed using Sequoia 512 ultrasound mainframes (Acuson, CA, USA) with 13.0 MHz linear array transducers 4. Socioeconomic position in childhood or adolescence was assessed in 1980 from parental educational level categorized as low (number of school years less than 9), average (number of school years 9 to 12), and high (number of school years more than 12). Where education differed between parents, data on the parent with the higher educational level were used. At baseline, pubertal status was assessed by Tanner staging and categorized as not started, on-going or finished. Smoking was assessed using questionnaires. n childhood, those reporting smoking daily or weekly were defined as regular smokers. n adulthood those reporting smoking once a day or more often were defined as daily smokers.

7 6 SUPPLEMENTARY RESULTS The observation that initially overweight or obese children who became non-obese adults had similar risks of outcomes as children with persistently favorable BM was consistently seen regardless of the degree of childhood overweight or obesity (Supplementary Appendix Tables 5 and 6 and Figure 1), and regardless of baseline age, length of follow-up or baseline height (Supplementary Appendix Table 7). Similar results were additionally seen in subsets of participants sampled using different baseline age ranges (Supplementary Appendix Table 8), by using alternative definitions for type 2 diabetes and hypertension (Supplementary Appendix Table 9), in analyses adjusted for childhood socioeconomic position (Supplementary Appendix Table 10) and pubertal staging (Supplementary Appendix Table 11), in analyses defining childhood adiposity by using skinfold thickness (Supplementary Appendix Table 12), and in analyses restricted to whites (Supplementary Appendix Table 13). Smoking in adulthood was associated with increased risk of low HDL cholesterol and high triglycerides (Supplementary Appendix Table 14), but the main findings remained unchanged after adjustment for smoking (Supplementary Appendix Table 15).

8 7 Supplementary Appendix Table 1. BM (kg/m 2 ) cutpoints used to define childhood overweight and obesity. Males Females Age Overweight BM Obese BM Overweight BM Obese BM

9 Supplementary Appendix Table 2. Baseline characteristics of study subjects according to adiposity status 8 Normal weight child- nonobese adult () Overweight or obese child non-obese adult () Overweight or obese child obese adult () Normal weight child- obese adult (V) N Male sex, N (%) 2202 (46.4) 119 (43.4) 254 (50.8) 386 (47.5) Childhood characteristics Age, y 11.2± ± ± ±4.0 Height, cm 146.7± ± ± ±7.8 BM, kg/m ± ± ± ±1.8 Systolic blood pressure, mm/hg 110.9± ± ± ±11.0 Diastolic blood pressure, mm/hg 66.0± ± ± ±11.1 Total cholesterol, mmol/l 4.99± ± ± ±0.90 Triglycerides, mmol/l 0.62± ± ± ±0.41* LDL cholesterol, mmol/l 3.16± ±0.84* 3.14± ±0.84 HDL cholesterol, mmol/l 1.56± ± ± ±0.35* Statistics are means±sd for continuous variables or N and percent for dichotomous variables. *P<0.05 and P<0.01 for continuous variables is from linear regression analyses that adjusted for age, sex, and cohort, with group as the referent category; and for the categorical variable of sex, is from logistic analysiss. P<0.01 between groups and (initially overweight or obese children). Triglyceride levels were log-transformed prior to analyses. LDL cholesterol and HDL cholesterol only measured in Young Finns, Bogalusa, and CDAH cohorts.

10 9 Supplementary Appendix Table 3. Relative risks (RR) and 95% confidence intervals (95%C) for childhood overweight or obesity in predicting adult outcomes. Results from random effects meta-analysis. Meta-analysis result Type 2 diabetes RR (95% C) 2.5 ( ) P-value <0.001 Hypertension RR (95% C) 2.1 ( ) P-value <0.001 High-risk LDL-C RR (95% C) 1.6 ( ) P-value <0.001 High-risk HDL-C RR (95% C) 1.7 ( ) P-value <0.001 High-risk triglycerides RR (95% C) 1.8 ( ) P-value <0.001 High-risk carotid MT ( 90 th percentile) RR (95% C) 1.7 ( ) P-value <0.001 Childhood overweight or obesity was defined according to the international cut-points 16

11 Supplementary Appendix Table 4. Relative risks (RR) and 95% confidence intervals (95%C) for adult outcomes according to adiposity status* in childhood and adulthood. The cohort-specific risk ratios and results of meta-analyses are based on models adjusted for age, sex, length of follow-up, and height. Bogalusa Muscatine CDAH YFS Meta-analysis Adiposity status RR (95% C) RR (95% C) RR (95% C) RR (95% C) RR (95% C) P-value Type 2 diabetes 2.2( ) n/a 1.4( ) n/a 1.6( ) ( ) 13.8( ) n/a 9.3( ) 5.2( ) <0.001 V 1.6( ) 8.7( ) 3.5( ) 10.6( ) 4.7( ) <0.001 Hypertension 0.9( ) 0.5( ) 0.7( ) 1.2( ) 0.9( ) ( ) 3.7( ) 2.4( ) 2.5( ) 2.8( ) <0.001 V 2.5( ) 2.4( ) 1.8( ) 2.0( ) 2.1( ) <0.001 High-risk LDL-C 0.8( ) 1.0( ) 1.3( ) 0.9( ) 1.0( ) ( ) 1.3( ) 2.2( ) 1.4( ) 1.8( ) 0.02 V 1.6( ) 0.8( ) 2.0( ) 1.4( ) 1.5( ) 0.09 High-risk HDL-c 0.8( ) 1.1( ) 0.9( ) 1.0( ) 1.0( ) ( ) 1.8( ) 2.3( ) 2.4( ) 2.1( ) <0.001 V 1.6( ) 2.1( ) 2.8( ) 2.3( ) 2.2( ) <0.001 High-risk TG n/a 0.4( ) 1.0( ) 0.8( ) 1.3( ) ( ) 3.9( ) 3.6( ) 2.4( ) 3.5( ) <0.001 V 2.5( ) 4.2( ) 3.9( ) 2.9( ) 3.6( ) <0.001 High-risk MT 1.6( ) 0.3( ) 0.9( ) 1.1( ) 0.9( ) ( ) 2.0( ) 1.2( ) 2.3( ) 1.9( ) V 1.3( ) 1.3( ) 1.2( ) 2.2( ) 1.5( ) *Group ) Normal BM in childhood, non-obese in adulthood, N=4,742; group ) overweight or obese in childhood, non-obese in adulthood, N=274; group ) overweight or obese in childhood, obese in adulthood, N=500; group V) normal BM in childhood, obese in adulthood, N=812 No evidence for heterogeneity in any of the comparisons between cohorts; P always >0.4. Comparison to group (reference). n/a=not applicable, no cases with the outcome.

12 11 Supplementary Appendix Table 5. nfluence of initial BM status on relative risks (RR) between patients with various degrees of adiposity in childhood* but non-obese adult BM, as compared with the reference group (BM<75 th percentile in childhood and BM<30 kg/m2 in adulthood). Childhood BM between th* Childhood BM between th* and adult BM<30 kg/m2 Childhood BM over 95 th * and adult BM<30 kg/m2 and adult BM<30 kg/m2 N=435 N=330 N=96 RR (95% C) RR (95% C) RR (95% C) Type 2 diabetes 1.2( ) 0.3( ) 2.2( ) Hypertension 0.9( ) 1.0( ) 0.8( ) High-risk LDL-c 1.0( ) 1.1( ) 0.7( ) High-risk HDL-c 0.9( ) 0.8( ( ) High-risk TG 0.8( ) 0.5( ) 0.8( ) High-risk MT 1.1( ) 1.2( ) 0.9( ) *According to the US Preventive Services Task Force recommendation 17 (mildly overweight BM th percentile, overweight BM th percentile, obese BM >95 th percentile.

13 12 Supplementary Appendix Table 6. nfluence of initial BM status on relative risks between patients with various degrees of adiposity in childhood* but non-obese adult BM, as compared with the reference group (normal BM in childhood according to the nternational definition and BM<30 kg/m2 in adulthood). Childhood BM Childhood BM obese* overweight* and adult BM<30 kg/m2 and adult BM<30 kg/m2 N=248 N=26 RR (95% C) RR (95% C) Type 2 diabetes 0.9( ) 4.4( ) Hypertension 1.0( ) 0.5( ) High-risk LDL-c 1.1( ) 0.5( ) High-risk HDL-c 0.9( ) 0.8( ) High-risk TG 0.8( ) n/a High-risk MT 0.8( ) 1.5( ) *According to the nternational definition 16

14 13 Supplementary Appendix Table 7. Analyses assessing the influence of baseline age, length of follow-up and baseline height on relative risks between group (overweight or obese in childhood*, non-obese in adulthood) and group (normal BM in childhood, non-obese in adulthood). Models adjusted for age and sex. Age group 3-9 yrs Age group yrs Age group yrs N=1824 N=1506 N=1686 RR(95%C) RR(95%C) RR(95%C) Type 2 diabetes n/a 2.6( ) 1.0( ) Hypertension 0.9( ) 0.6( ) 1.0( ) High-risk LDL-c 1.1( ) 1.4( ) 0.5( ) High-risk HDL-c 0.6( ) 1.2( ) 1.3( ) High-risk TG 0.3( ) 0.8( ) 1.0( ) High-risk MT 0.8( ) 1.0( ) 1.0( ) Length follow-up Length follow-up Length follow-up less than 20 yrs, N= yrs, N=1431 >26 yrs, N=1865 RR(95%C) RR(95%C) RR(95%C) Type 2 diabetes 2.6( ) 0.6( ) n/a Hypertension 0.8( ) 0.5( ) 1.1( ) High-risk LDL-c 1.4( ) 0.9( ) 0.7( ) High-risk HDL-c 1.0( ) 1.0( ) 1.0( ) High-risk TG 1.1( ) 0.3( ) 0.8( ) High-risk MT 0.9( ) 0.7( ) 1.2( ) Height at follow up Height at follow up Height at follow up 121±13 cm, N= ±7 cm, N= ±7 cm, N=1672 RR(95%C) RR(95%C) RR(95%C) Type 2 diabetes n/a 0.9( ) 2.0( ) Hypertension 0.7( ) 0.7( ) 1.0( ) High-risk LDL-c 0.8( ) 1.7( ) 0.4( ) High-risk HDL-c 0.8( ) 1.1( ) 1.0( ) High-risk TG n/a 1.0( ) 1.0( ) High-risk MT 0.5( ) 1.2( ) 1.1( ) * According to the nternational definition 16 n/a=not applicable, no cases with the outcome.

15 14 Supplementary Appendix Table 8. Analyses in subsets of participants sampled using different overlapping baseline age ranges. Risk ratios are adjusted by age, sex, height, cohort and length of follow-up. Baseline age 6-12 yrs Baseline age 8-14 yrs Baseline age yrs Baseline age yrs RR (95%C) P RR (95%C) P RR (95%C) P RR (95%C) P Type 2 diabetes 0.9( ) ( ) ( ) ( ) ( ) ( ) < ( ) < ( ) <0.001 V 3.7( ) ( ) < ( ) < ( ) <0.001 Hypertension 0.8( ) ( ) ( ) ( ) ( ) < ( ) < ( ) < ( ) <0.001 V 2.1( ) < ( ) < ( ) < ( ) <0.001 High-risk LDL-c 1.3( ) ( ) ( ) ( ) ( ) < ( ) < ( ) < ( ) <0.001 V 1.5( ) ( ) ( ) < ( ) <0.001 High-risk HDL-c 0.9( ) ( ) ( ) ( ) ( ) < ( ) < ( ) < ( ) <0.001 V 2.3( ) < ( ) < ( ) < ( ) <0.001 High-risk TG 0.5( ) ( ) ( ) ( ) ( ) < ( ) < ( ) < ( ) <0.001 V 2.9( ) < ( ) < ( ) < ( ) <0.001 High-risk MT 1.0( ) ( ) ( ) ( ) ( ) ( ) < ( ) < ( ) <0.001 V 1.8( ) < ( ) < ( ) ( ) Group ) normal BM in childhood, non-obese in adulthood; group ) overweight or obese in childhood, non-obese in adulthood; group ) overweight or obese in childhood, obese in adulthood; group V) normal BM in childhood, obese in adulthood. Baseline age range 6-12 (=2492, =173, =233, V=374); Baseline age 8-14 yrs (=2555, =173, =294, V=427); Baseline age yrs (=2604, =142, =313, V=483); Baseline age yrs (=2524, =124, =313, V=511)

16 15 Supplementary Appendix Table 9. Analyses using alternative definitions for type 2 diabetes and hypertension. Risk ratios are adjusted for age, sex, length-of-follow up and cohort. Type 2 diabetes* RR (95%C) P-value 1.5( ) ( ) <0.001 V 8.6( ) <0.001 Hypertension 0.9( ) ( ) <0.001 V 2.0( ) <0.001 * Type 2 diabetes was defined by using fasting glucose values available in Young Finns and CDAH, total N=4,824, diabetes cases N=50. Hypertension was defined by a systolic blood pressure 140 mmhg or a diastolic blood pressure 90 mmhg. Group ) normal BM in childhood, non-obese in adulthood; group ) overweight or obese in childhood, non-obese in adulthood; group ) overweight or obese in childhood, obese in adulthood; group V) normal BM in childhood, obese in adult.

17 16 Supplementary Appendix Table 10. Analysis in Young Finns and CDAH (N=4,764) adjusted for an indicator of childhood socioeconomic position (parent schooling) in addition to age, sex, height, cohort, and length of follow-up. Adiposity status RR (95%C) P-value Type 2 diabetes 1.1( ) ( ) <0.001 V 7.3( ) <0.001 Hypertension 1.1( ) ( ) <0.001 V 2.0( ) <0.001 High-risk LDL-C 1.0( ) ( ) V 1.6( ) <0.001 High-risk HDL-c 0.9( ) ( ) <0.001 V 2.5( ) <0.001 High-risk TG 0.9( ) ( ) <0.001 V 3.1( ) <0.001 High-risk MT 0.9( ) ( ) V 1.7( ) <0.001 Group ) normal BM in childhood, non-obese in adulthood, N=3,803; group ) overweight or obese in childhood, nonobese in adulthood, N=201; group ) overweight or obese in childhood, obese in adulthood, N=248; group V) normal BM in childhood, obese in adulthood, N=521.

18 17 Supplementary Appendix Table 11. Analysis in YFS (N=2640) adjusted for pubertal staging in addition to age, sex, height, and length of follow-up. Adiposity status RR (95%C) P-value Type 2 diabetes n/a 9.7( ) <0.001 V 11.0( ) <0.001 Hypertension High-risk LDL-C High-risk HDL-C High-risk TG High-risk MT 1.2( ) ( ) <0.001 V 2.0( ) < ( ) ( ) 0.14 V 1.4( ) ( ) ( ) <0.001 V 2.3( ) < ( ) ( ) <0.001 V 2.9( ) < ( ) ( ) <0.001 V 2.2( ) <0.001 Group ) normal BM in childhood, non-obese in adulthood, N=2,107; group ) overweight or obese child, non-obese in adulthood, N=93; group ) overweight or obese in childhood, obese in adulthood, N=125; group V) normal BM in childhood, obese in adulthood, N=315. n/a=not applicable, no cases with the outcome.

19 18 Supplementary Appendix Table 12a. Relative risks (RR) and 95% confidence intervals (95% C) for childhood overweight or obesity defined as high (>85 th percentile) triceps skinfold thickness, available in N=4,762. Adjusted for age, sex, length follow-up, height and cohort. RR (95%C) P Type 2 diabetes 2.1( ) <0.001 Hypertension 1.6( ) <0.001 High-risk LDL-c 1.1( ) 0.50 High-risk HDL-c 1.2( ) High-risk TG 1.3( ) 0.03 High-risk MT 1.3( ) 0.04 Supplementary Appendix Table 12b. Relative risks (RR) and 95% confidence intervals from cohort-pooled data for adult outcomes according to adiposity status in childhood and adulthood. Childhood overweight or obesity defined as triceps skinfold at or over age, sex and cohort specific 85th percentile (available in the Bogalusa, CDAH and Young Finns cohorts). Models adjusted for age, sex, length of follow-up, cohort and height. Adiposity status* % RR (95% C) P Type 2 diabetes ( ) ( ) <0.001 V ( ) <0.001 Hypertension ( ) ( ) <0.001 V ( ) <0.001 High-risk-LDL-C ( ) ( ) V ( ) <0.001 High-risk-HDL-C ( ) ( ) <0.001 V ( ) <0.001 High-risk-triglycerides ( ) ( ) <0.001 V ( ) <0.001 High-risk MT ( 90th percentile) ( ) ( ) <0.001 V ( ) <0.001 Group : normal skinfold thickness (<85 th percentile) in childhood, non-obese in adulthood, N=3,323; group : overweight or obese in childhood (skinfold thickness >85th percentile), non-obese in adulthood, N=362; group : overweight or obese in childhood (skinfold thickness >85th percentile), obese in adulthood, N=352; group V: normal skinfold thickness (<85th percentile) in childhood, obese in adulthood, N=724.

20 19 Supplementary Appendix Table 13. Relative risks (RR) and 95% confidence intervals from cohort-pooled data for adult outcomes in white participants (N=6,101) according to adiposity status* in childhood and adulthood. Adjustments for age, sex, height, length of follow-up and cohort. Adiposity status* RR (95%C) P Type 2 diabetes - 1.1( ) ( ) <0.001 V 6.1( ) <0.001 Hypertension - 0.9( ) ( ) <0.001 V 2.1( ) <0.001 High-risk LDL-C - 1.1( ) ( ) <0.001 V 1.5( ) <0.001 High-risk HDL-C - 0.9( ) ( ) <0.001 V 2.3( ) <0.001 High-risk triglycerides - 0.7( ) ( ) <0.001 V 3.3( ) <0.001 High -risk MT ( 90th percentile) - 0.9( ) ( ) V 1.5( ) *Group ) normal BM in childhood, non-obese in adulthood, N=4,632; Group ) overweight or obese in childhood, nonobese in adulthood, N=269; Group ) overweight or obese in childhood, obese in adulthood, N=456; Group V) normal BM in childhood, obese in adulthood, N=744.

21 20 Supplementary Appendix Table 14. Relative risks (RR, 95% C) for outcomes in adulthood in the Young Finns, CDAH and Bogalusa cohorts (N=5,466) according to smoking status in adulthood and childhood. Models adjusted for age, sex, cohort, height and length of follow-up. Smoking in Smoking in P-value 1 P-value 2 Adulthood Childhood RR (95%C) RR (95%C) Type 2 diabetes Model 1 1.1( ) 0.55 Model 2 0.6( ) 0.13 Model 3 1.2( ) 0.6( ) Hypertension Model 1 0.9( ) 0.07 Model 2 0.8( ) 0.08 Model 3 0.9( ) 0.8( ) High-risk LDL-c Model 1 1.1( ) 0.35 Model 2 1.0( ) 0.72 Model 3 1.1( ) 0.9( ) High-risk HDL-c Model 1 1.2( ) Model 2 1.0( ) 0.87 Model 3 1.2( ) 1.0( ) High-risk TG Model 1 1.3( ) Model 2 1.3( ) 0.04 Model 3 1.3( ) 1.3( ) High-risk MT Model 1 1.1( ) 0.15 Model 2 1.0( ) 0.84 Model 3 1.2( ) 0.9( ) P-value for the effect of smoking in adulthood (defined as daily smoking) 2 P-value for the effect of smoking in childhood (defined as regular smoking) Model 1; smoking in adulthood Model 2; smoking in childhood Model 3; smoking in childhood adjusted for smoking in adulthood

22 21 Supplementary Appendix Table 15. Analysis in the YFS, CDAH and Bogalusa cohorts (N=5466) adjusted for smoking in childhood and adulthood in addition to age, sex, height, and length of follow-up. Adiposity status RR (95%C) P-value Type 2 diabetes 1.5( ) ( ) <0.001 V 4.1( ) <0.001 Hypertension 1.0( ) ( ) <0.001 V 2.1( ) <0.001 High-risk LDL-C 1.0( ) ( ) <0.001 V 1.6( ) <0.001 High-risk HDL-c 0.9( ) ( ) <0.001 V 2.3( ) <0.001 High-risk TG 0.7( ) ( ) <0.001 V 3.0( ) <0.001 High-risk MT 0.9( ) ( ) <0.001 V 1.6( ) <0.001 Group ) normal BM in childhood, non-obese in adulthood, N=4,194; group ) overweight or obese in childhood, nonobese in adulthood, N=288; group ) overweight or obese in childhood, obese in adulthood, N=380; group V) normal BM in childhood, obese in adulthood, N=664.

23 22 Supplementary Appendix Table 16. The risks (RR, 95% C) of obesity in adulthood and childhood in predicting outcomes in adulthood. Models adjusted for age, sex, cohort, height and length of follow-up. Obesity in Adulthood Obesity in Childhood P-value 1 P-value 2 RR (95%C) RR (95%C) Type 2 diabetes Model 1 5.3( ) <0.001 Model 2 3.1( ) <0.001 Model 3 5.1( ) 1.4( ) < Hypertension Model 1 2.4( ) <0.001 Model 2 2.4( ) <0.001 Model 3 2.3( ) 1.5( ) < High-risk LDL-c Model 1 1.7( ) <0.001 Model 2 1.4( ) 0.11 Model 3 1.7( ) 1.1( ) < High-risk HDL-c Model 1 2.2( ) <0.001 Model 2 1.9( ) <0.001 Model 3 2.1( ) 1.2( ) < High-risk TG Model 1 3.2( ) <0.001 Model 2 1.8( ) Model 3 3.2( ) 1.0( ) < High-risk MT Model 1 1.6( ) <0.001 Model 2 1.7( ) Model 3 1.6( ) 1.3( ) < P-value for the effect of obesity in adulthood (defined as BM >30 kg/m 2 ) 2 P-value for the effect of obesity in childhood (defined using nternational cut-points) Model 1; obesity in adulthood Model 2; obesity in childhood Model 3; obesity in childhood adjusted for obesity in adulthood

24 23 Supplementary Appendix Table 17. The risks (RR, 95% C) of obesity in adulthood and overweight or obesity in childhood in predicting outcomes in adulthood. Models adjusted for age, sex, cohort, height and length of follow-up Obesity in Adulthood Overweight or Obesity in Childhood P-value 1 P-value 2 RR (95% C) RR (95% C) Type 2 diabetes Model 1 5.3( ) <0.001 Model 2 2.6( ) <0.001 Model 3 5.0( ) 1.2( ) < Hypertension Model 1 2.4( ) <0.001 Model 2 1.8( ) <0.001 Model 3 2.2( ) 1.2( ) < High-risk LDL-c Model 1 1.7( ) <0.001 Model 2 1.5( ) <0.001 Model 3 1.6( ) 1.1( ) < High-risk HDL-c Model 1 2.2( ) <0.001 Model 2 1.4( ) <0.001 Model 3 2.2( ) 0.9( ) < High-risk TG Model 1 3.2( ) <0.001 Model 2 1.6( ) <0.001 Model 3 3.3( ) 0.9( ) < High-risk MT Model 1 1.6( ) <0.001 Model 2 1.3( ) Model 3 1.6( ) 1.1( ) < P-value for the effect of obesity in adulthood 2 P-value for the effect of overweight or obesity in childhood Model 1; obesity in adulthood Model 2; overweight or obesity in childhood Model 3; overweight or obesity in childhood adjusted for obesity in adulthood

25 24 Supplementary Appendix Table 18. Number of initially overweight or obese children stratified by age cohorts in the Young Finns Study and the proportions of those who had normal BM at the 3-year follow-up. Combined data from time points collected in studies conducted 1980, 1983, and Number of initially overweight or obese children. Age range Proportion of individuals who had normal BM at follow-up % % % % % Supplementary Appendix Table 19. Risk of having one or more outcomes in the 93 initially obese or overweight participants who became non-obese adults in the Young Finns Study stratified according to the average age when their BM was first noted to be normal. Average age when BM was No. RR (95% C) P-value first noted to be normal* 13± ( ) ± ( ) ± ( ) 0.46 *Based on follow-up data collected 3 (in 1983), 6 (in 1986) and 21 years (in 2001) after the baseline study. Relative to group 1 (normal BM in childhood, non-obese in adulthood).

26 Supplementary Appendix Figure RSK OF ONE OR MORE OUTCOMES V V V Risk of having 1 or more high-risk outcomes in groups defined by childhood overweight and obesity definitions (combined 2-level outcome variable: 0=no high-risk outcomes, 1=1-6 high-risk outcomes). Group : Normal BM in childhood, non-obese in adulthood (reference), N=4742 Group : Overweight in childhood, non-obese in adulthood, N=248 (P=0.21 compared to group ) Group : Obese in childhood, non-obese in adulthood, N=26 (P=0.94 compared to group ; P=0.63 compared to group ) Group V: Normal BM in childhood, obese in adulthood, N=812 (P<0.001 compared to group ) Group V: Overweight in childhood, obese in adulthood, N=379 (P<0.001 compared to group ) Group V: Obese in childhood, obese in adulthood, N=121 (P<0.001 compared to group ; P=0.14 compared to group V) The figure shows that relative to those who were never obese, the risk of having 1 high-risk outcomes* is similar in groups that were either overweight or obese as children but non-obese as adults, and that the risk is similarly increased in individuals who were obese as adults, regardless of childhood BM. *Type 2 diabetes, hypertension, high-risk LDL cholesterol, high-risk HDL cholesterol, high-risk triglycerides, high-risk carotid artery intima-media thickness

27 Supplementary Appendix Figure 2 26

28 Risk ratios and 95% confidence intervals for adult outcomes: a) type 2 diabetes mellitus, b) hypertension, c) high-risk LDL cholesterol, d) high-risk HDL cholesterol, e) high-risk triglycerides, f) high-risk carotid artery intima-media thickness according to childhood and adult adiposity status ( =initially normal; =initially overweight or obese). Number of individuals in each group were: normal weight (child)/ BM<25 kg/m 2 (adult) (reference group) N=2,778; overweight or obese (child)/ BM<25 kg/m 2 (adult) N=78; normal (child)/ BM kg/m 2 (adult) N=1,964; overweight/obese (child)/ BM kg/m 2 (adult) N=196; normal (child)/ BM>30 kg/m 2 (adult) N=812; overweight/obese (child)/ BM>30 kg/m 2 (adult) N=500. All analyses were adjusted for baseline age, sex, cohort, height and length of follow up. The P-values are from comparisons between initially normal weight children vs. initially overweight or obese children within each adult BM category (Note that the relative risks in the category adult BM >30 kg/m 2 differ from those presented in Table 3 due to a differently defined reference group). 27

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