The Incidence of Co-Morbidities Related To Obesity and Overweight - A Systematic Review and Meta-Analysis

BMC Public Health
Research article
BioMed Central
Open Access
The incidence of co-morbidities related to obesity and overweight: A systematic review and meta-analysis
Daphne P Guh1, Wei Zhang1, Nick Bansback1, Zubin Amarsi1, C Laird Birmingham1,2 and Aslam H Anis*1,3
Address: 1Centre for Health Evaluation and Outcome Sciences, St Paul's Hospital, Vancouver, BC, Canada, 2Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada and 3School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada Email: Daphne P Guh - daphne@sm.hivnet.ubc.ca; Wei Zhang - wzhang@cheos.ubc.ca; Nick Bansback - nbansback@cheos.ubc.ca; Zubin Amarsi - zamarsi@arthritisresearch.ca; C Laird Birmingham - clbirm@interchange.ubc.ca; Aslam H Anis* - aslam.anis@ubc.ca * Corresponding author
Published: 25 March 2009 BMC Public Health 2009, 9:88 doi:10.1186/1471-2458-9-88 This article is available from: http://www.biomedcentral.com/1471-2458/9/88
Received: 3 July 2008 Accepted: 25 March 2009
2009 Guh et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background: Overweight and obese persons are at risk of a number of medical conditions which can lead to further morbidity and mortality. The primary objective of this study is to provide an estimate of the incidence of each co-morbidity related to obesity and overweight using a metaanalysis. Methods: A literature search for the twenty co-morbidities identified in a preliminary search was conducted in Medline and Embase (Jan 2007). Studies meeting the inclusion criteria (prospective cohort studies of sufficient size reporting risk estimate based on the incidence of disease) were extracted. Study-specific unadjusted relative risks (RRs) on the log scale comparing overweight with normal and obese with normal were weighted by the inverse of their corresponding variances to obtain a pooled RR with 95% confidence intervals (CI). Results: A total of 89 relevant studies were identified. The review found evidence for 18 comorbidities which met the inclusion criteria. The meta-analysis determined statistically significant associations for overweight with the incidence of type II diabetes, all cancers except esophageal (female), pancreatic and prostate cancer, all cardiovascular diseases (except congestive heart failure), asthma, gallbladder disease, osteoarthritis and chronic back pain. We noted the strongest association between overweight defined by body mass index (BMI) and the incidence of type II diabetes in females (RR = 3.92 (95% CI: 3.104.97)). Statistically significant associations with obesity were found with the incidence of type II diabetes, all cancers except esophageal and prostate cancer, all cardiovascular diseases, asthma, gallbladder disease, osteoarthritis and chronic back pain. Obesity defined by BMI was also most strongly associated with the incidence of type II diabetes in females (12.41 (9.0317.06)). Conclusion: Both overweight and obesity are associated with the incidence of multiple comorbidities including type II diabetes, cancer and cardiovascular diseases. Maintenance of a healthy weight could be important in the prevention of the large disease burden in the future. Further studies are needed to explore the biological mechanisms that link overweight and obesity with these co-morbidities.
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(page number not for citation purposes)
BMC Public Health 2009, 9:88
http://www.biomedcentral.com/1471-2458/9/88
Background
A substantial literature has emerged which has found that overweight and obesity are major causes of co-morbidities which can lead to further morbidity and mortality [1-3]. The related health care costs are substantial [4-6]. As the number of associated co-morbidities continues to increase, systematic reviews and meta-analysis are important tools to summarize the findings and produce more precise estimates of risk associated with overweight and obesity. The primary objective of this study is to provide a comprehensive review of the incidence of co-morbidities related to obesity and overweight. We have identified a number of recent systematic reviews and meta-analyses on type II diabetes [7], cardiovascular diseases [8,9], cancer [10], breast cancer [11,12], esophageal or cardia adenocarcinoma [13], pancreatic cancer [14] and prostate cancer [15]. The rationale for re-conducting a review is threefold. Firstly, it has been reported that abdominal obesity, defined by waist circumference (WC) measurement in comparison to the more traditional obesity definition, based on Body Mass Index (BMI) measurement, is an even better predictor of many cardiovascular diseases and type II diabetes [16-24]. However, most recent reviews have only focused on obesity defined by BMI instead of WC. For example, a recent meta-analysis study has compared BMI and WC as risk factors for ischaemic heart disease and stroke but it only included studies with population from the Asia Pacific region [8]. Also, only meta-analysis studies on BMI and type II diabetes have been conducted [7]. Secondly, associating the incidence of co-morbidities with overweight and obesity can be done in many ways since there are many different definitions. For instance, many previous reviews have combined studies that have found the association with per unit change of BMI (kg/m2) and WC (cm) measurements [7-9,11,14,15]. We are interested in measuring the incidence by categorization of overweight and obesity defined by BMI and WC measurements, which has not been the focus of a majority of previous reviews. Thirdly, the previous meta-analysis studies primarily focused on individual co-morbidities and they were conducted by different authors and using different search strategies, inclusion criteria and analysis methods. Only one recent meta-analysis study conducted by Katzmarzyk and Janssen comprehensively estimated the incidence of eight different chronic diseases associated with obesity [5]. An objective of this review is to apply a consistent methodology across all relevant co-morbidities. This enables us to compare the number of studies and size of effect across all co-morbidities.
Methods
Exposure variables The definition for overweight is having a BMI greater than or equal to 25 kg/m2 and below 30 kg/m2. The definition for obesity is having a BMI greater than or equal to 30 kg/ m2 [25,26]. According to the World Health Organization (WHO), the definition for abdominally overweight or obesity is a WC of greater than or equal to 80 cm and 88 cm, respectively, for females, and 94 cm and 102 cm, respectively, for males [25,26]. Disease outcomes Possible co-morbidities of overweight and obesity were identified from a preliminary search reviewed by an eating disorder and obesity expert and a review of previous systematic reviews [1-3]. We also reviewed the leading causes of global burden of disease and included the diseases reported with burden attributable to overweight and obesity [27]. Twenty co-morbidities were initially included in this analysis: cancer (kidney, colorectal, prostate, ovarian, uterine/endometrial, esophageal, pancreatic, and postmenopausal breast), type II diabetes, cardiovascular disease risk (hypertension, coronary artery disease, congestive heart failure, pulmonary embolism, stroke, dislipidaemia), gallbladder disease, chronic back pain, osteoarthritis, asthma, and sleep apnea. Literature review A literature search was conducted using the search terms: 'Incidence, Prevalence, Risk, Risk Factors, Cohort Studies, Longitudinal Studies, Follow-up Studies, or Prospective Studies' in combination with 'Adipose Tissue, Obesity, Body Mass Index, or Body Composition' (all "exploded"). These same search terms were applied to each co-morbidity (also "exploded") for both Medline and Embase search engines to retrieve all potentially relevant English articles (until January, 2007). We also searched ISI Web of Science, Google Scholar, and the bibliographies of retrieved articles.
The articles obtained from the literature search were then evaluated according to criteria set out in Figure 1. Criteria for inclusion were: prospective cohort study of the general population of a Western country (countries in Europe or North America, Australia or New Zealand), relevant outcomes, a sample size of at least 200 subjects, and risk estimate based on the incidence of disease instead of the mortality rate of disease. For large cohorts with multiple articles meeting the defined criteria, the most recent article or the article with the most usable information was used. Studies were excluded if they did not provide enough data to allow calculation of unadjusted relative risks (RRs) with 95% confidence intervals (CI) for the overweight and obese groups compared to the normal group. Data extracted for study characteristics included study design,
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Potentially relevant articles identified through Medline and Embase searches: n = A Articles excluded based on title and abstract review: n = B - Not prospective cohort: n = B (i) - Non-generalizable population: n = B (ii) - Irrelevant subject matter: n = B (iii) - Drug or treatment: n = B (iv) - Food and nutrition: n = B (v) - Review article: n = B (vi) - Duplicate: n = B (vii) Articles ordered for more detailed review: n = C Articles excluded after detailed review: n = D - Population not generalizable: n = D (i) - Mortality rates used: n = D (ii) - Study too small: n = D (iii) Articles meeting inclusion criteria and information extracted for metaanalysis: n = E Articles not amenable to meta-analysis: n = F - Required information not provided: n = F (i) - Same cohort already used: n = F (ii) Articles included in final metaanalysis calculations: n = G
the RRs based on WC measurements for these co-morbidities were available, they were pooled separately from those based on BMI and used as the final RRs for these comorbidities. When both IRR and RR-P estimates were available, both estimates were presented. Final results of RRs were selected based on the number of pooled studies, the duration of study follow-up and the sample size of included studies
Results
A total of 89 relevant and unique studies were identified; several studies featured for more than one co-morbidities. Of the 20 co-morbidities, 18 were identified to have at least one study meeting the inclusion criteria. Some studies were applicable to more than one co-morbidity. No studies were found for dislipidaemia and sleep apnea. The total numbers of studies included for each co-morbidity varied from 1 to 14. Reasons for exclusion are given in Table 1. The majority of the studies were conducted in US (55%) and in European countries (40%). Study characteristics such as age criteria, study follow-up, ascertainment of exposure and outcome variables were reported by the majority of the studies. However, only a small number of studies reported sample ethnicity and of those, the majority was US studies. Among those US studies, one study (endometrial cancer) was about the black women [31] while for the remaining US studies, the proportion of whites ranged from 81% to 95%. The mean duration of study follow-up was 12.5 (SD = 7.2) years. Over half of the studies (53%) were longer than 10 years while less than 10% of the studies were shorter than 5 years. BMI and WC measurements were clinically measured on 43% of the studies and were self-reported on 56% of the studies while one study did not provide such information. Regarding the ascertainment of cases, 43 (48%) studies identified cases from registry, database centre or clinical evaluation; 34 (38%) studies were based on subject selfreported information with some kind of confirmation method such as medical records review; 6 studies were based on medical records review and 5 studies (4 for asthma and 1 for type-2 diabetes) were relying on selfreported information alone. Note that cancer cases were identified from cancer registry/database on 66% of the studies. Table 2 summarized our final results. Figures 2 to 18 presented the detailed results including study-specific and pooled estimates. Results from the meta-analysis were summarized in the following sections for each co-morbidity.
Figure 1 of article distribution for all diseases Flowchart Flowchart of article distribution for all diseases.
country, cohort name, duration of follow-up, number of patients in each study group, age range, gender and ethnicity. Ascertainment of exposure and outcome variables was also recorded. The literature search was conducted by ZA, the decisions on inclusion and exclusion were made by ZA, NB, DPG, CLB and the data were extracted by ZA and DPG.
Meta-analysis RRs were measured by incidence rate ratios (IRRs) when person-time data were available and by the ratios of proportions (RR-Ps) when person-time data were not available. Study-specific unadjusted RRs on the log scale comparing overweight with normal and obese with normal were weighted by the inverse of their corresponding variances to obtain a pooled RR with 95% CIs. We used the random-effects model to estimate the pooled RR using the maximum likelihood estimation method [28]. The Q statistic was also calculated to assess the homogeneity of RRs (log scale) [28]. Potential publication bias was visually inspected by funnel plots and tested by asymmetry tests [29,30]; however it was performed only on those meta-analyses which included sufficient number of studies (N>5). We also did various sensitivity analyses stratified on the length of follow-up, age criteria and country to examine the robustness of the results.
WC measurements were considered to be the better risk predictor for some co-morbidities such as diabetes, hypertension, coronary artery disease, congestive heart failure, stroke and gallbladder disease [16-24]. Therefore, when
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Table 1: Article distribution for all diseases (see Figure 1 for explanation)
Diseases
B (i) 6687 5 55 28 145 23 103 5 23 59 96 10 48 172 89 29 43 30
B (ii) 18 22 12 1 18 1 17 0 0 55 17 5 13 29 13 9 10 20
B (iii) 1216 261 2010 258 1793 143 729 81 103 2256 2202 418 321 1747 598 175 390 143
B (iv) 20 8 51 0 19 0 8 0 2 53 42 6 1 17 47 0 51 39
B (v) 28 42 50 37 110 10 30 14 13 78 66 1 0 24 47 7 38 11
B (vi) 18 57 127 52 195 13 105 7 34 81 82 41 24 234 84 32 123 24
B (vii) 88 18 301 86 402 38 200 24 47 191 461 105 90 532 481 53 169 39
D (i) 17 2 16 5 6 1 27 5 4 23 10 0 3 6 2 0 5 0
D (ii) 6 2 18 9 34 3 3 10 2 53 27 14 3 5 25 2 2 4
D (iii) 14 2 9 0 3 0 11 0 0 12 13 11 5 6 9 3 7 2
F (i) 19 14 7 6 13 0 5 2 1 17 11 9 18 4 9 5 12 11
F (ii) 2 0 0 1 3 0 1 1 0 0 3 1 0 0 0 0 0 0
Type II Diabetes Colorectal cancer Kidney cancer Prostate cancer Breast cancer Ovarian cancer Endometrial cancer Pancreatic cancer Esophageal cancer Hypertension CAD CHF PE Stroke Asthma GD OA CBP
8142 445 2661 491 2755 241 1249 155 230 2882 3041 625 527 2783 1408 319 853 324
8075 413 2606 462 2682 228 1192 131 222 2773 2966 586 497 2755 1359 305 824 306
67 32 55 29 73 13 57 24 8 109 75 39 30 28 49 14 29 18
37 6 43 14 43 4 41 15 6 88 50 25 11 17 36 5 14 6
30 26 12 15 30 9 16 9 2 21 25 14 19 11 13 9 15 12
21 14 7 7 16 0 6 3 1 17 14 10 18 4 9 5 12 11
9 12 5 8 14 9 10 6 1 4 11 4 1 7 4 4 3 1
CAD: Coronary Artery Disease; CHF: Congestive Heart Failure; PE: Pulmonary Embolism; GD: Gallbladder Disease; OA: Osteoarthritis; CBP: Chronic Back Pain
Breast cancer In total, 14 studies were identified for post menopausal breast cancer (Figure 2) [19,32-44]. The pooled IRRs [95% CI] across categories of WC were 1.13 [1.011.07] for overweight and 1.30 [1.171.44] for obesity while across categories of BMI the IRRs were 1.08 [1.031.14] for overweight and 1.13 [1.051.22] for obesity. Endometrial cancer In total, 10 studies were identified to meet the inclusion criteria for endometrial cancer (Figure 3) [19,31,35,36,42,45-49]. The study on the US black women was not included in the final result as it showed systematic difference from other studies mainly on Cauca-
sian population [31]. The pooled IRRs [95% CI] across categories of WC were 1.15 [1.021.30] for overweight and 1.42 [0.802.49] for obesity while across categories of BMI IRRs were 1.53 [1.451.61] for overweight and 3.22 [2.913.56] for obesity.
Ovarian cancer In total, 9 studies were identified for ovarian cancer (Figure 4) [19,35,36,42,45,50-53]. The single IRR [95% CI] across categories of WC were 0.61 [0.351.08] for overweight and 1.35 [0.951.93] for obesity while pooled IRRs estimates across categories of BMI were 1.18 [1.12 1.23] for overweight and 1.28 [1.201.36] for obesity.
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Overweight
0.5 1 2 4 16 0.5 1 2
Obese
4 16 32
Study Huang (1999) [44] Folsom (2000) [19] Sellers (2002) [32]
Obesity Sex WC WC WC F F F
Age 55+ 55-69 55-69
F-up 8 10.1 13
Country US US US
N 5865 31702 32573
Outcome IRR IRR RR-P
Risk Est (95% CI) 1.22 1.05 1.16 1.13 1.16 1.20 1.18 1.13 1.10 1.09 1.09 1.06 1.06 0.97 0.92 1.27 1.19 1.10 1.06 0.96 1.08 1.11 1.10 1.10 1.15 1.11 1.13 1.18 1.15 1.08 1.09 1.09 1.12 1.10 1.09 (1.04 (0.90 (1.02 (1.01 (1.02 (1.09 (1.03 (0.98 (1.00 (0.98 (0.93 (0.94 (0.92 (0.87 (0.74 (1.14 (0.96 (0.98 (0.99 (0.86 (1.03 (1.01 (1.04 (1.05 (1.05 (1.06 (1.07 (1.06 (1.08 (0.99 (1.02 (0.95 (1.01 (1.02 (1.02 - 1.42 ) - 1.23 ) - 1.32 ) - 1.27 ) - 1.32 ) - 1.33 ) - 1.35 ) - 1.30 ) - 1.40 ) - 1.22 ) - 1.28 ) - 1.19 ) - 1.20 ) - 1.09 ) - 1.13 ) - 1.41 ) - 1.47 ) - 1.24 ) - 1.13 ) - 1.07 ) - 1.14 ) - 1.22 ) - 1.15 ) - 1.16 ) - 1.25 ) - 1.17 ) - 1.21 ) - 1.32 ) - 1.23 ) - 1.18 ) - 1.15 ) - 1.24 ) - 1.24 ) - 1.19 ) - 1.15 )
Risk Est (95% CI) 1.26 1.31 1.34 1.30 1.34 1.30 1.07 1.21 1.20 1.04 0.99 1.15 1.38 1.02 1.06 1.38 1.40 1.17 1.09 0.98 1.13 1.17 1.15 1.15 1.23 1.17 1.17 1.28 1.20 1.10 1.30 1.14 1.23 1.14 1.30 (1.05 (1.16 (1.20 (1.17 (1.20 (1.17 (0.85 (1.04 (0.80 (0.88 (0.82 (0.96 (1.10 (0.91 (0.81 (1.22 (1.07 (0.99 (1.01 (0.88 (1.05 (1.04 (1.07 (1.07 (1.09 (1.09 (1.07 (1.12 (1.10 (0.98 (1.02 (0.97 (1.06 (1.03 (1.02 - 1.52 ) - 1.48 ) - 1.49 ) - 1.44 ) - 1.49 ) - 1.43 ) - 1.35 ) - 1.42 ) - 1.60 ) - 1.22 ) - 1.19 ) - 1.37 ) - 1.75 ) - 1.14 ) - 1.39 ) - 1.57 ) - 1.83 ) - 1.39 ) - 1.18 ) - 1.10 ) - 1.22 ) - 1.32 ) - 1.23 ) - 1.24 ) - 1.37 ) - 1.25 ) - 1.28 ) - 1.47 ) - 1.31 ) - 1.23 ) - 1.65 ) - 1.34 ) - 1.42 ) - 1.26 ) - 1.65 )
IRR: RR-P:
Sweeney (2004) [33] Dirx (2001) [34] Tornberg (1994) [35] Jonsson (2003) [36] Navarro Silvera (2006) [37] Chang (2006) [38] Suzuki (2006) [39] Tehard (2004) [40] McTiernan (2003) [41] Lukanova (2006) [42] Sellers (2002) [32] Lukanova (2006) [42] Suzuki (2006) [39] Barlow (2006) [43] McTiernan (2003) [41] BMI BMI BMI BMI BMI BMI BMI BMI BMI BMI BMI BMI BMI BMI BMI F F F F F F F F F F F F F F F 56-84 55-69 55-75 44-83 40-59 55-74 55-70 40-65 50-79 49+ 55-69 49+ 55-70 45-84 50-79
All studies (2) All studies (1)

16 7.3 20.3 26 16.4 9.3 8.3 9.7 4.7 8.3 13 8.3 8.3 6 4.7 US Netherlands Sweden Sweden Canada US Sweden France US Sweden US Sweden Sweden US US
1.6(0.21)*
36658 62537 47003 11598 40318 27541 51823 41427 74171 35362 32549 35362 51823 729129 74171
IRR IRR IRR IRR IRR IRR IRR IRR IRR IRR RR-P RR-P RR-P RR-P RR-P
IRR: RR-P: IRR & RR-P: IRR: RR-P: IRR & RR-P: IRR: RR-P: IRR & RR-P: IRR: IRR: RR-P: RR-P: IRR & RR-P: IRR & RR-P:
All studies (10) All studies (5) All studies (12) F-up>=5 yrs (9) F-up>=5 yrs (4) F-up>=5 yrs (11) min.age>=55 (5) min.age>=55 (2) min.age>=55 (6) US/Canada studies (4) Europe studies (6) US studies (3) Europe studies (2) US/Canada studies (6) Europe studies (6)
12(0.22)* 13.8(0.01)* 25.8(0.03)* 7.7(0.47)* 7.9(0.05)* 15.6(0.21)* 3.1(0.54)* 2.9(0.09)* 6.7(0.35)* 7.3(0.06)* 4.6(0.47)* 13(0)* 0.4(0.54)* 20.5(0)* 5.2(0.63)*
0.5
16
0.5
16
32
RR
RR
Figure 2 Meta-analysis of studies for post menopausal breast cancer Meta-analysis of studies for post menopausal breast cancer. *Q-statistic(p-value); F-up is follow-up in years; square shape: study- and gender- specific risk estimates; diamond shape: pooled risk estimates.
Overweight
0.5
Study Wise (2005) [31] Folsom (2000) [19] Obesity WC WC Sex F F Age 21-Pre-M** 55-69 F-up 4 7 Country US US N 17876 31702 Outcome IRR IRR
Obese
16 Risk Est (95% CI) 1.15 (1.01 - 1.31 ) 1.14 (0.79 - 1.65 ) 1.15 (1.02 - 1.30 ) 2.26 (1.58 - 3.22 ) 1.77 (1.40 - 2.25 ) 1.60 (1.19 - 2.14 ) 1.58 (1.50 - 1.65 ) 1.53 (1.22 - 1.92 ) 1.34 (0.87 - 2.07 ) 1.30 (0.90 - 1.90 ) 1.17 (1.05 - 1.29 ) 1.09 (0.84 - 1.41 ) 2.30 (1.61 - 3.28 ) 1.76 (1.15 - 2.71 ) 1.68 (1.33 - 2.14 ) 1.55 (1.42 - 1.69 ) 1.90 (1.53 - 2.36 ) 1.30 (1.00 - 1.69 ) 1.27 (1.13 - 1.42 ) 1.59 (1.52 - 1.66 ) 1.53 (1.45 - 1.61 ) 0.5 1 2 4 16 32
Risk Est (95% CI) 0.96 (0.85 - 1.08 ) 2.17 (1.67 - 2.82 ) 1.42 (0.80 - 2.49 ) 4.82 (3.35 - 6.95 ) 2.92 (2.28 - 3.74 ) 3.30 (2.32 - 4.69 ) 2.91 (2.76 - 3.06 ) 3.73 (2.94 - 4.72 ) 2.90 (1.85 - 4.54 ) 3.20 (2.00 - 5.20 ) 1.06 (0.96 - 1.18 ) 3.41 (2.69 - 4.31 ) 4.58 (3.18 - 6.60 ) 3.59 (2.29 - 5.62 ) 2.61 (2.04 - 3.34 ) 2.86 (2.17 - 3.78 ) 3.39 (2.51 - 4.58 ) 3.37 (2.77 - 4.10 ) 2.36 (1.22 - 4.54 ) 2.95 (2.80 - 3.10 ) 3.22 (2.91 - 3.56 )
IRR:
Rapp (2005) [45] Tornberg (1994) [35] Schouten (2004) [46] Bjorge (2006) [47] Silvera (2005) [48] Lukanova (2006) [42] Jonsson (2003) [36] Wise (2005) [31] Folsom (2003) [49] Rapp (2005) [45] Lukanova (2006) [42] Tornberg (1994) [35] BMI BMI BMI BMI BMI BMI BMI BMI BMI BMI BMI BMI F F F F F F F F F F F F 35-54 25-75 55-69 20-74 40-59 30-61 44-83 21-Pre-M** 55-69 35-54 30-61 25-75
All studies (2)

10.2 20.3 9.3 24.3 16.4 8.3 26 4 13.1 10.2 8.3 20.3 Austria Sweden Netherlands Norway Canada Sweden Sweden US US Austria Sweden Sweden
0(0.98)*
78484 47003 1739 1036877 34391 35362 11598 21506 23335 78484 35362 47003
IRR IRR IRR IRR IRR IRR IRR IRR IRR RR-P RR-P RR-P
IRR: IRR: IRR: IRR: IRR:
All studies (9) min.age>=55 (2) US/Canada studies (3) Europe studies (6) exclude black cohort (8)
41.5(0)* 2.1(0.35)* 3.7(0.05)* 5.2(0.07)* 6.3(0.28)* 14.4(0.05)*
RR-P: All studies (3)
0.5
16
0.5
16
32
RR
RR
Figure 3 Meta-analysis of studies for endometrial cancer Meta-analysis of studies for endometrial cancer. *Q-statistic(p-value); **pre-menopause, square shape: study- and gender- specific risk estimates; diamond shape: pooled risk estimates.
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Overweight
0.1
Study Folsom (2000) [19] Obesity Sex WC F Age 55-69 F-up 8.5 Country US N 31702 Outcome IRR
Obese
16 Risk Est (95% CI) 0.61 (0.35 - 1.08 ) 0.61 (0.35 - 1.08 ) 0.1 0.5 1 2 4 16 32
0.5
Risk Est (95% CI) 1.35 (0.95 - 1.93 ) 1.35 (0.95 - 1.93 ) 1.97 (1.20 - 3.24 ) 1.73 (0.97 - 3.07 ) 1.28 (1.20 - 1.37 ) 1.17 (0.83 - 1.65 ) 1.44 (0.89 - 2.32 ) 0.30 (0.10 - 1.10 ) 1.29 (0.98 - 1.70 ) 1.08 (0.80 - 1.45 ) 1.98 (1.12 - 3.51 ) 1.88 (1.14 - 3.08 ) 1.92 (1.43 - 2.57 ) 1.14 (1.07 - 1.22 ) 1.15 (0.87 - 1.52 ) 1.28 (1.20 - 1.36 ) 1.47 (1.13 - 1.91 ) 1.28 (1.20 - 1.36 ) 1.26 (0.95 - 1.66 ) 1.12 (0.89 - 1.40 ) 1.29 (1.21 - 1.38 )
IRR:
Rapp (2005) [45] Lukanova (2006) [42] Engeland (2003) [50] Anderson (2004) [51] Schouten (2003) [52] Jonsson (2003) [36] Tornberg (1994) [35] Fairfield (2002) [53] Lukanova (2006) [42] Rapp (2005) [45] Fairfield (2002) [53] Engeland (2003) [50] Tornberg (1994) [35] BMI BMI BMI BMI BMI BMI BMI BMI BMI BMI BMI BMI BMI F F F F F F F F F F F F F 35-54 30-60 20-74 55-69 55-69 44-83 25-75 30-55 30-60 35-54 30-55 20-74 25-75
All studies (1)

10.2 8.3 23 15 7.3 26 20.3 15.6 8.3 10.2 15.6 23 20.3 Austria Sweden Norway US Netherlands Sweden Sweden US Sweden Austria US Norway Sweden 78484 35362 1024468 31381 1636 11598 47003 1636 35362 78484 1636 1024468 47003 IRR IRR IRR IRR IRR IRR IRR IRR RR-P RR-P RR-P RR-P RR-P
1.54 (1.03 - 2.30 ) 1.46 (0.92 - 2.31 ) 1.20 (1.14 - 1.26 ) 1.13 (0.83 - 1.53 ) 1.09 (0.79 - 1.51 ) 1.00 (0.70 - 1.50 ) 0.96 (0.75 - 1.23 ) 0.94 (0.74 - 1.19 ) 1.76 (1.11 - 2.78 ) 1.57 (1.05 - 2.35 ) 1.37 (1.08 - 1.73 ) 1.14 (1.09 - 1.20 ) 0.91 (0.71 - 1.16 ) 1.18 (1.12 - 1.23 ) 1.29 (1.12 - 1.50 ) 1.18 (1.13 - 1.24 ) 1.11 (0.89 - 1.39 ) 1.01 (0.84 - 1.21 ) 1.19 (1.13 - 1.25 )
IRR: RR-P: IRR: IRR: IRR: IRR:
All studies (8) All studies (5) min.age<55 (6) min.age>=55 (2) US studies (2) Europe studies (6)
10.2(0.18)* 11.3(0.02)* 9.9(0.08)* 0(0.89)* 0.9(0.34)* 6.3(0.27)*
0.1
0.5
16
0.1
0.5
16
32
RR
RR
Figure 4 Meta-analysis of studies for ovarian cancer Meta-analysis of studies for ovarian cancer. *Q-statistic(p-value); F-up is follow-up in years; square shape: study- and gender- specific risk estimates; diamond shape: pooled risk estimates.
Overweight
0.5 1 2 4 16 0.5 1 2
Obese
4 16 32
Study Moore (2004) [56] Folsom (2000) [19] Pischon (2006) [57] Moore (2004) [56]
Obesity Sex WC WC WC WC F F F F
Age 30-79 55-69 25-70 30-79
F-up 30.4 10.2 6.3 30.4
Country US US European US
N 4221 31702 238546 4221
Outcome IRR IRR RR-P RR-P
Risk Est (95% CI) 1.30 1.24 1.45 1.37 1.25 1.45 1.95 1.78 1.60 1.54 1.32 1.32 1.28 1.22 1.99 1.64 1.50 1.32 1.29 1.45 1.55 1.49 1.44 1.58 1.50 1.55 1.42 1.92 1.33 1.55 1.39 1.31 1.55 1.40 1.66 1.31 1.49 (0.72 (0.95 (1.23 (0.76 (0.98 (1.23 (1.58 (1.16 (1.15 (1.50 (1.04 (0.96 (0.83 (1.05 (1.61 (1.06 (1.09 (0.97 (1.09 (1.30 (1.30 (1.22 (1.27 (1.27 (1.09 (1.22 (1.27 (1.58 (1.16 (1.22 (1.27 (1.18 (1.50 (1.12 (1.29 (1.18 (1.32 - 2.36 ) - 1.61 ) - 1.72 ) - 2.47 ) - 1.59 ) - 1.70 ) - 2.42 ) - 2.74 ) - 2.23 ) - 1.58 ) - 1.68 ) - 1.80 ) - 1.97 ) - 1.41 ) - 2.46 ) - 2.53 ) - 2.08 ) - 1.80 ) - 1.52 ) - 1.62 ) - 1.86 ) - 1.83 ) - 1.63 ) - 1.95 ) - 2.08 ) - 1.96 ) - 1.58 ) - 2.32 ) - 1.52 ) - 1.96 ) - 1.52 ) - 1.46 ) - 1.59 ) - 1.76 ) - 2.13 ) - 1.46 ) - 1.68 )
Risk Est (95% CI) 1.82 1.52 1.54 1.74 1.55 1.55 1.81 1.66 1.56 1.74 1.52 1.34 1.93 1.44 1.72 2.60 1.29 1.33 1.21 1.66 1.49 1.60 1.64 1.53 1.29 1.68 1.61 1.92 1.24 1.68 1.50 1.47 1.74 1.32 1.61 1.47 1.64 (1.02 (1.23 (1.31 (0.98 (1.27 (1.33 (1.35 (1.06 (1.00 (1.68 (1.16 (0.93 (1.19 (1.22 (1.29 (1.60 (0.83 (0.93 (1.02 (1.52 (1.21 (1.34 (1.47 (1.20 (0.83 (1.38 (1.45 (1.50 (1.07 (1.38 (1.32 (1.30 (1.68 (0.99 (1.20 (1.30 (1.34 - 3.25 ) - 1.87 ) - 1.81 ) - 3.08 ) - 1.88 ) - 1.82 ) - 2.42 ) - 2.61 ) - 2.45 ) - 1.81 ) - 1.97 ) - 1.93 ) - 3.14 ) - 1.70 ) - 2.30 ) - 4.23 ) - 2.01 ) - 1.92 ) - 1.43 ) - 1.81 ) - 1.82 ) - 1.91 ) - 1.83 ) - 1.94 ) - 2.01 ) - 2.03 ) - 1.78 ) - 2.46 ) - 1.43 ) - 2.03 ) - 1.70 ) - 1.66 ) - 1.81 ) - 1.75 ) - 2.16 ) - 1.66 ) - 2.00 )
IRR: RR-P:
Rapp (2005) [45] Ford (1999) [58] Moore (2004) [56] Engeland (2005) [59] Martinez (1997) [60] Lin (2004) [61] Lukanova (2005) [42] McCarl (2006) [62] Rapp (2005) [45] Lukanova (2005) [42] Moore (2004) [56] Lin (2004) [61] Pischon (2006) [57] BMI BMI BMI BMI BMI BMI BMI BMI BMI BMI BMI BMI BMI F F F F F F F F F F F F F 35-54 25-74 30-79 20-74 30-55 45+ 30-61 55-69 35-54 30-61 30-79 45+ 25-70

10.2 16.6 30.4 23.7 5.7 7.4 8.3 15 10.2 8.3 30.4 7.4 6.3 Austria US US Norway US US Sweden US Austria Sweden US US European
0(0.89)* 0(0.85)*
78484 7914 4221 1037077 89488 37671 35362 35197 78484 35362 4221 37671 238546
IRR IRR IRR IRR IRR IRR IRR IRR RR-P RR-P RR-P RR-P RR-P
IRR: RR-P: IRR: IRR: RR-P: RR-P: IRR: IRR: RR-P: RR-P: IRR & RR-P: IRR & RR-P: IRR: IRR: RR-P: RR-P: IRR & RR-P: IRR & RR-P:
All studies (8) All studies (5) F-up<10 yrs (4) F-up>=10 yrs (4) F-up<10 yrs (4) F-up>=10 yrs (1) max.age<65 (3) max.age>=65 (5) max.age<65 (2) max.age>=65 (3) max.age<65 (3) max.age>=65 (6) US studies (5) Europe studies (3) US studies (2) Europe studies (3) US studies (5) Europe studies (4)
18.3(0.01)* 10.9(0.03)* 8.1(0.05)* 10.3(0.02)* 10.9(0.01)* 6.9(0.03)* 11.1(0.03)* 0.6(0.43)* 0.7(0.71)* 9.6(0.05)* 15.9(0.03)* 4.4(0.36)* 5.5(0.06)* 0.3(0.57)* 10.2(0.01)* 5(0.55)* 15.7(0.01)*
0.5
16
0.5
16
32
RR
RR
Figure 5 Meta-analysis of studies for colorectal cancer-females Meta-analysis of studies for colorectal cancer-females. *Q-statistic(p-value); F-up is follow-up in years; square shape: study- and gender- specific risk estimates; diamond shape: pooled risk estimates.
Page 6 of 20
Overweight
0.5 1 2 4 16 0.5 1 2
Obese
4 16 32
Study MacInnis (2004) [54] Giovannucci (1995) [55] Moore (2004) [56] Moore (2004) [56] Pischon (2006) [57]
Obesity Sex WC WC WC WC WC M M M M M
Age 40-69 40-75 30-79 30-79 25-70
F-up 8.8 5.5 30.4 30.4 6.3
Country Australia US US US European
N 16556 31055 3345 3345 129731
Outcome IRR IRR IRR RR-P RR-P
Risk Est (95% CI) 2.17 1.81 1.71 1.58 1.37 1.88 2.02 1.73 1.74 1.74 1.37 1.89 1.61 1.60 1.48 1.43 1.40 1.16 1.90 1.59 1.51 1.43 1.14 1.51 1.48 1.54 1.41 1.48 1.51 1.52 1.41 1.76 1.36 1.52 1.40 1.57 1.53 1.56 1.45 1.57 1.44 (1.43 (1.07 (1.17 (1.09 (1.14 (1.47 (1.46 (1.33 (1.28 (1.28 (1.14 (1.52 (1.09 (1.18 (0.98 (0.92 (1.37 (0.80 (1.52 (1.18 (1.03 (0.99 (0.97 (1.37 (1.23 (1.25 (1.37 (1.19 (1.03 (1.06 (1.37 (1.46 (1.10 (1.06 (1.36 (1.27 (1.29 (1.23 (1.11 (1.27 (1.20 - 3.30 ) - 3.06 ) - 2.50 ) - 2.28 ) - 1.65 ) - 2.41 ) - 2.80 ) - 2.26 ) - 2.37 ) - 2.37 ) - 1.65 ) - 2.36 ) - 2.38 ) - 2.16 ) - 2.24 ) - 2.23 ) - 1.44 ) - 1.69 ) - 2.36 ) - 2.16 ) - 2.22 ) - 2.09 ) - 1.35 ) - 1.67 ) - 1.79 ) - 1.89 ) - 1.44 ) - 1.83 ) - 2.22 ) - 2.18 ) - 1.44 ) - 2.13 ) - 1.67 ) - 2.18 ) - 1.44 ) - 1.93 ) - 1.81 ) - 1.98 ) - 1.90 ) - 1.93 ) - 1.74 )
Risk Est (95% CI) 3.03 3.38 2.45 2.11 1.72 2.93 3.18 2.49 2.87 2.87 1.72 3.08 2.38 1.88 1.28 1.90 1.67 1.65 2.84 1.87 2.04 1.91 1.38 1.95 1.95 2.13 1.68 1.93 2.04 2.34 1.68 2.58 1.65 2.34 1.66 1.86 2.00 1.94 1.94 1.86 1.77 (2.05 (2.20 (1.59 (1.39 (1.45 (2.31 (2.38 (1.74 (2.12 (2.12 (1.45 (2.31 (1.44 (1.24 (0.71 (1.18 (1.59 (0.99 (2.13 (1.24 (1.25 (1.15 (1.14 (1.59 (1.51 (1.59 (1.59 (1.44 (1.25 (1.47 (1.60 (2.01 (1.30 (1.47 (1.58 (1.40 (1.40 (1.41 (1.33 (1.40 (1.30 - 4.48 ) - 5.19 ) - 3.76 ) - 3.20 ) - 2.05 ) - 3.73 ) - 4.25 ) - 3.57 ) - 3.89 ) - 3.89 ) - 2.05 ) - 4.12 ) - 3.93 ) - 2.84 ) - 2.33 ) - 3.04 ) - 1.76 ) - 2.75 ) - 3.80 ) - 2.82 ) - 3.33 ) - 3.18 ) - 1.67 ) - 2.39 ) - 2.51 ) - 2.86 ) - 1.77 ) - 2.60 ) - 3.33 ) - 3.72 ) - 1.77 ) - 3.32 ) - 2.09 ) - 3.72 ) - 1.74 ) - 2.46 ) - 2.87 ) - 2.65 ) - 2.83 ) - 2.46 ) - 2.40 )
IRR: IRR: IRR & RR-P: IRR: IRR & RR-P: IRR & RR-P:
Rapp (2005) [45] Moore (2004) [56] Giovannucci (1995) [55] Ford (1999) [58] MacInnis (2004) [54] Engeland (2005) [59] Lukanova (2005) [42] Rapp (2005) [45] Giovannucci (1995) [55] Moore (2004) [56] Lukanova (2005) [42] Pischon (2006) [57] BMI BMI BMI BMI BMI BMI BMI BMI BMI BMI BMI BMI M M M M M M M M M M M M 35-54 30-79 40-75 25-74 40-69 20-74 30-61 35-54 40-75 30-79 30-61 25-70
All studies (3) F-up<10 yrs (2) F-up<10 yrs (3) US studies (2) US studies (2) Europe studies (1)
9.6 30.4 5.5 16.6 8.8 23.7 8.2 9.6 5.5 30.4 8.2 6.3 Austria US US US Australia Norway Sweden Austria US US Sweden European
0.7(0.7)* 0.3(0.59)* 4.4(0.11)* 0(0.86)* 0.2(0.9)*
IRR: RR-P: IRR: IRR: RR-P: RR-P: IRR: IRR: RR-P: RR-P: IRR & RR-P: IRR & RR-P: IRR: IRR: RR-P: RR-P: IRR & RR-P: IRR & RR-P:
All studies (7) All studies (5) F-up<10 yrs (4) F-up>=10 yrs (3) F-up<10 yrs (4) F-up>=10 yrs (1) max.age<65 (2) max.age>=65 (5) max.age<65 (2) max.age>=65 (3) max.age<65 (2) max.age>=65 (6) US studies (3) Europe studies (3) US studies (2) Europe studies (3) US studies (3) Europe studies (4)
67447 3345 47723 5506 16556 962901 33424 67447 47723 3345 33424 129731
IRR IRR IRR IRR IRR IRR IRR RR-P RR-P RR-P RR-P RR-P
9.1(0.17)* 13.7(0.01)* 5.2(0.16)* 0.5(0.77)* 13.6(0)* 4.8(0.03)* 1.2(0.88)* 1.6(0.21)* 4.5(0.11)* 6.6(0.09)* 7.8(0.35)* 0.1(0.95)* 7.9(0.02)* 0(0.84)* 12.9(0)* 0.2(1)* 20.9(0)*
0.5
16
0.5
16
32
RR
RR
Figure Meta-analysis 6 of studies for colorectal cancer-males Meta-analysis of studies for colorectal cancer-males. *Q-statistic(p-value); F-up is follow-up in years; square shape: study- and gender- specific risk estimates; diamond shape: pooled risk estimates.
Overweight
0.1
Study Rapp (2005) [45] Flaherty (2005) [64] Bjorge (2004) [65] Lukanova (2006) [42] Rapp (2005) [45] Lukanova (2006) [42] Pischon (2006) [57] Obesity Sex BMI BMI BMI BMI BMI BMI BMI M M M M M M M 20-74 30-60 35-54 30-60 25-70 Age 35-54 F-up 9.6 NA 23 8.2 9.6 8.2 6 Country Austria US Norway Sweden Austria Sweden European N 67447 48953 963442 33424 67447 33424 129745
11(0)* 3(0.23)* 14.7(0.01)*
Obese
16 Risk Est (95% CI) 1.92 (1.32 - 2.78 ) 1.41 (0.94 - 2.10 ) 1.39 (1.30 - 1.48 ) 1.14 (0.44 - 2.95 ) 1.92 (1.32 - 2.78 ) 1.47 (0.57 - 3.79 ) 0.80 (0.55 - 1.15 ) 1.40 (1.31 - 1.49 ) 1.34 (0.80 - 2.25 ) 1.40 (1.31 - 1.49 ) 1.35 (0.97 - 1.87 ) 3.31 (2.10 - 5.23 ) 1.80 (1.65 - 1.96 ) 1.70 (1.17 - 2.47 ) 0.83 (0.30 - 2.34 ) 3.38 (2.14 - 5.32 ) 1.91 (1.27 - 2.89 ) 1.20 (0.43 - 3.38 ) 1.82 (1.68 - 1.98 ) 2.29 (1.55 - 3.37 ) 1.83 (1.68 - 1.99 ) 1.83 (1.69 - 1.99 ) 0.1 0.5 1 2 4 16 32 Risk Est (95% CI) 2.64 (1.57 - 4.42 ) 1.44 (0.72 - 2.87 ) 1.77 (1.56 - 2.02 ) 3.29 (1.15 - 9.37 ) 2.43 (1.45 - 4.07 ) 3.91 (1.37 - 11.14) 1.25 (0.84 - 1.86 ) 1.82 (1.61 - 2.05 ) 1.97 (1.20 - 3.22 ) 1.83 (1.62 - 2.07 ) 1.76 (1.32 - 2.35 ) 2.15 (1.11 - 4.17 ) 2.65 (2.40 - 2.94 ) 2.70 (1.74 - 4.18 ) 1.83 (0.61 - 5.47 ) 2.04 (1.05 - 3.96 ) 1.91 (1.27 - 2.89 ) 2.39 (0.80 - 7.14 ) 2.64 (2.39 - 2.90 ) 1.99 (1.42 - 2.78 ) 2.63 (2.38 - 2.91 ) 2.59 (2.35 - 2.85 )
0.5
Outcome IRR IRR IRR IRR RR-P RR-P RR-P
IRR: RR-P: IRR: IRR & RR-P:

Rapp (2005) [45] Bjorge (2004) [65] Flaherty (2005) [64] Lukanova (2006) [42] Rapp (2005) [45] Pischon (2006) [57] Lukanova (2006) [42] BMI BMI BMI BMI BMI BMI BMI F F F F F F F 30-60 35-54 25-70 30-60 35-54 20-74
All studies (4) All studies (3) Europe studies (3) Europe studies (4)
10.2 23 NA 8.3 10.2 6 8.3 Austria Norway US Sweden Austria European Sweden
3(0.39)*
78484 1037788 118191 35362 78484 218805 35362
IRR IRR IRR IRR RR-P RR-P RR-P
IRR: RR-P:
9.1(0.03)* 5(0.08)* 8.9(0.01)* 16.4(0.01)*
Europe studies (3) IRR: IRR & RR-P: Europe studies (4)
0.1
0.5
16
0.1
0.5
16
32
RR
RR
Figure 7 Meta-analysis of studies for kidney cancer Meta-analysis of studies for kidney cancer. *Q-statistic(p-value); F-up is follow-up in years; square shape: study- and gender- specific risk estimates; diamond shape: pooled risk estimates.
Page 7 of 20
Overweight
0.5
Study Rapp (2005) [45] Michaud (2001)[66] Larsson (2005)[67] Patel (2005) [68] Rapp (2005) [45] Patel (2005) [68] Obesity Sex BMI BMI BMI BMI BMI BMI M M M M M M Age 35-54 40-75 45-83 50-74 35-54 50-74 F-up 9.6 12 6.8 7 9.6 7 Country Austria US Sweden US Austria US N 67447 46648 45906 69589 67447 69589 Outcome IRR IRR IRR IRR RR-P RR-P
Obese
16 Risk Est (95% CI) 2.05 1.46 1.02 0.92 2.06 0.93 1.28 1.33 1.21 1.46 1.18 1.43 1.75 1.46 1.44 1.23 1.07 0.91 1.78 1.71 1.07 0.92 1.24 1.24 1.31 1.15 1.48 1.03 1.75 0.97 1.13 1.47 0.97 1.75 (1.16 (1.02 (0.60 (0.62 (1.16 (0.63 (0.94 (0.75 (0.79 (1.02 (0.85 (0.83 (1.00 (1.06 (0.82 (0.63 (0.69 (0.66 (1.01 (0.88 (0.69 (0.67 (0.98 (0.90 (1.00 (0.79 (1.14 (0.81 (1.14 (0.75 (0.85 (1.03 (0.75 (1.14 - 3.64 ) - 2.09 ) - 1.73 ) - 1.36 ) - 3.64 ) - 1.38 ) - 1.75 ) - 2.37 ) - 1.85 ) - 2.09 ) - 1.62 ) - 2.48 ) - 3.06 ) - 2.01 ) - 2.54 ) - 2.39 ) - 1.66 ) - 1.24 ) - 3.12 ) - 3.31 ) - 1.65 ) - 1.26 ) - 1.56 ) - 1.69 ) - 1.72 ) - 1.67 ) - 1.91 ) - 1.30 ) - 2.68 ) - 1.25 ) - 1.50 ) - 2.11 ) - 1.25 ) - 2.68 ) 0.5 1 2 4 16 32 Risk Est (95% CI) 4.25 1.78 1.99 2.04 3.92 2.06 2.29 2.74 2.55 1.78 1.94 2.91 2.97 2.10 1.32 1.00 1.50 1.07 2.82 1.44 1.49 1.06 1.60 1.57 1.68 1.48 2.11 1.20 2.28 1.18 1.48 1.73 1.18 2.28 (2.13 (1.01 (1.00 (1.32 (1.97 (1.33 (1.65 (1.60 (1.62 (1.01 (1.37 (1.53 (1.59 (1.42 (0.56 (0.40 (0.91 (0.76 (1.51 (0.57 (0.90 (0.75 (1.17 (1.06 (1.16 (0.90 (1.54 (0.92 (1.36 (0.89 (1.03 (0.97 (0.89 (1.36 - 8.48 ) - 3.11 ) - 3.98 ) - 3.18 ) - 7.82 ) - 3.20 ) - 3.19 ) - 4.67 ) - 3.99 ) - 3.11 ) - 2.74 ) - 5.54 ) - 5.53 ) - 3.11 ) - 3.08 ) - 2.52 ) - 2.47 ) - 1.50 ) - 5.25 ) - 3.62 ) - 2.46 ) - 1.50 ) - 2.20 ) - 2.33 ) - 2.44 ) - 2.44 ) - 2.88 ) - 1.57 ) - 3.82 ) - 1.57 ) - 2.13 ) - 3.09 ) - 1.57 ) - 3.82 )

Rapp (2005) [45] Michaud (2001)[66] Larsson (2005)[67] Lukanova (2006) [42] Patel (2005) [68] Sinner (2005) [69] Rapp (2005) [45] Lukanova (2006) [42] Patel (2005) [68] Sinner (2005) [69] BMI BMI BMI BMI BMI BMI BMI BMI BMI BMI F F F F F F F F F F 35-54 30-55 45-83 30-60 50-74 55-69 35-54 30-60 50-74 55-69
All studies (4) All studies (2) F-up<10 yrs (3) F-up>=10 yrs (1) US studies (2) Europe studies (2)
10.2 19.4 6.8 8.3 7 12 10.2 8.3 7 12 Austria US Sweden Sweden US US Austria Sweden US US
6.6(0.09)* 5(0.03)* 5.4(0.07)* 2.9(0.09)* 3.1(0.08)*
78484 117041 37147 35362 76038 38002 78484 35362 76038 38002
IRR IRR IRR IRR IRR IRR RR-P RR-P RR-P RR-P
IRR: RR-P: IRR: IRR: IRR: IRR: RR-P: RR-P: IRR: IRR: RR-P: RR-P:
All studies (6) All studies (4) F-up<10 yrs (4) F-up>=10 yrs (2) min.age<45 (3) min.age>=45 (3) min.age<45 (2) min.age>=45 (2) US studies (3) Europe studies (3) US studies (2) Europe studies (2)
6.9(0.23)* 5.7(0.13)* 2(0.58)* 4.4(0.04)* 0.6(0.73)* 2(0.37)* 0(0.93)* 0.3(0.59)* 4.4(0.11)* 0.6(0.73)* 0.3(0.59)* 0(0.93)*
0.5
16
0.5
16
32
RR
RR
Figure 8 Meta-analysis of studies for pancreatic cancer Meta-analysis of studies for pancreatic cancer. *Q-statistic(p-value); F-up is follow-up in years; square shape: study- and gender- specific risk estimates; diamond shape: pooled risk estimates.
Overweight
0.5
Study Obesity Sex Age F-up Country N Outcome
Obese
16 Risk Est (95% CI) 0.5 1 2 4 16 32 Risk Est (95% CI)
Rapp (2005) [45] Engeland (2003) [70] Lund Nilsen (1999) [71] Zeegers (2005) [72] Jonsson (2003) [36] Lukanova (2006) [42] Giovannucci (1997) [73] Rapp (2005) [45] Habel (2000) [74] Lukanova (2006) [42] Lund Nilsen (1999) [71]
BMI BMI BMI BMI BMI BMI BMI BMI BMI BMI BMI
M M M M M M M M M M M
35-54 20-74 40+ 55-69 44-83 30-60 40-75 35-54 18-84 30-60 40+
9.6 21 10.4 9.3 22 8.2 7.2 9.6 19.5 8.2 10.4
Austria Norway Norway Netherlands Sweden Sweden US Austria US Sweden Norway
67447 951459 2411 2335 8998 33424 46694 67447 70712 33424 2411
IRR IRR IRR IRR IRR IRR IRR RR-P RR-P RR-P RR-P
1.65 (1.45 - 1.86 ) 1.40 (1.37 - 1.43 ) 1.08 (0.91 - 1.29 ) 1.05 (0.94 - 1.17 ) 1.00 (0.80 - 1.20 ) 0.97 (0.80 - 1.17 ) 0.95 (0.85 - 1.06 ) 1.65 (1.46 - 1.86 ) 1.30 (1.17 - 1.45 ) 1.24 (1.03 - 1.51 ) 1.10 (0.92 - 1.31 ) 1.14 (1.00 - 1.31 ) 1.32 (1.14 - 1.53 ) 1.12 (0.90 - 1.41 ) 1.18 (0.99 - 1.40 ) 1.45 (1.19 - 1.78 ) 1.24 (1.12 - 1.37 ) 1.28 (1.01 - 1.61 ) 1.02 (0.94 - 1.11 ) 1.17 (1.01 - 1.36 ) 1.32 (1.08 - 1.62 )
1.41 (1.14 - 1.74 ) 1.46 (1.40 - 1.54 ) 1.22 (0.99 - 1.50 ) 0.82 (0.60 - 1.13 ) 1.00 (0.60 - 1.50 ) 0.77 (0.56 - 1.07 ) 0.76 (0.62 - 0.91 ) 1.30 (1.06 - 1.60 ) 1.15 (1.02 - 1.31 ) 0.96 (0.69 - 1.33 ) 1.20 (0.98 - 1.48 ) 1.05 (0.85 - 1.30 ) 1.17 (1.06 - 1.30 ) 0.91 (0.69 - 1.20 ) 1.27 (1.10 - 1.47 ) 1.14 (0.88 - 1.47 ) 1.17 (1.05 - 1.30 ) 1.27 (0.92 - 1.75 ) 0.93 (0.75 - 1.16 ) 1.14 (0.93 - 1.39 ) 1.19 (1.03 - 1.38 )
IRR: RR-P: IRR: IRR: RR-P: RR-P: IRR: IRR: IRR: RR-P:
All studies (7) All studies (4) F-up<10 yrs (4) F-up>=10 yrs (3) F-up<10 yrs (2) F-up>=10 yrs (2) min.age<40 (3) min.age>=40 (4) Europe studies (6) Europe studies (3)
102.4(0)* 16.6(0)* 49.1(0)* 16.9(0)* 5.9(0.02)* 2.6(0.11)* 20.7(0)* 2.2(0.52)* 61.7(0)* 15.7(0)*
0.5
16
0.5
16
32
RR
RR
Figure 9 Meta-analysis of studies for prostate cancer Meta-analysis of studies for prostate cancer. *Q-statistic(p-value); F-up is follow-up in years; square shape: study- and gender- specific risk estimates; diamond shape: pooled risk estimates.
Page 8 of 20
Overweight
0.5 1 2 4 16 0.5 1 2
Obese
4 16 32
Study Wang (2005) [82] Meisinger (2006) [77] Wang (2005) [82] Meisinger (2006) [77]
Obesity Sex WC WC WC WC M M M M
Age 40-75 35-74 40-75 35-74
F-up 13 9.5 13 9.5
Country US Germany US Germany
N 27270 3055 27270 3055
Outcome IRR IRR RR-P RR-P
Risk Est (95% CI) 2.77 1.87 2.72 1.81 2.36 2.27 2.69 2.63 2.20 2.19 2.63 2.16 2.11 2.40 2.29 2.51 2.28 2.34 4.85 2.99 2.63 2.80 3.40 2.80 5.47 4.01 3.27 3.26 3.97 3.12 3.92 3.64 4.01 3.88 4.17 (2.27 (1.29 (2.24 (1.26 (1.76 (1.67 (2.12 (1.99 (1.37 (1.95 (2.09 (1.36 (1.88 (2.12 (1.98 (1.98 (2.06 (2.03 (3.89 (1.76 (2.12 (1.67 (2.42 (1.67 (4.82 (3.37 (2.77 (1.97 (3.34 (1.90 (3.10 (2.93 (3.37 (2.84 (3.24 - 3.37 ) - 2.71 ) - 3.31 ) - 2.60 ) - 3.15 ) - 3.10 ) - 3.40 ) - 3.46 ) - 3.53 ) - 2.47 ) - 3.32 ) - 3.43 ) - 2.36 ) - 2.72 ) - 2.64 ) - 3.19 ) - 2.54 ) - 2.71 ) - 6.06 ) - 5.05 ) - 3.26 ) - 4.70 ) - 4.78 ) - 4.70 ) - 6.22 ) - 4.78 ) - 3.85 ) - 5.39 ) - 4.72 ) - 5.11 ) - 4.97 ) - 4.52 ) - 4.78 ) - 5.28 ) - 5.37 )
Risk Est (95% CI) 6.47 4.67 6.16 4.07 5.67 5.13 7.12 8.79 6.10 5.60 6.46 5.53 4.56 6.74 5.36 7.78 6.14 6.84 (5.51 (3.43 (5.26 (3.02 (4.46 (3.81 (5.40 (6.34 (3.84 (4.51 (4.97 (3.52 (3.74 (5.55 (4.32 (5.96 (5.17 (4.96 - 7.60 ) - 6.38 ) - 7.21 ) - 5.48 ) - 7.20 ) - 6.90 ) - 9.40 ) - 12.19) - 9.69 ) - 6.97 ) - 8.40 ) - 8.68 ) - 5.56 ) - 8.19 ) - 6.65 ) - 10.16) - 7.29 ) - 9.43 )
IRR: RR-P:
Wannamethee (2005) [79] Koh-Banerjee (2004) [80] Meisinger (2006) [77] Oguma (2005) [81] Wannamethee (2005) [79] Meisinger (2006) [77] Oguma (2005) [81] BMI BMI BMI BMI BMI BMI BMI M M M M M M M 40-59 40-75 35-74 40-59 35-74

17.6 3.7 9.5 23.8 17.6 9.5 23.8 UK US Germany US UK Germany US
3.3(0.07)* 3.8(0.05)*
7176 22172 3055 20187 7176 3055 20187
IRR IRR IRR IRR RR-P RR-P RR-P
IRR: RR-P: IRR: IRR: IRR:

Carey (1997) [78] Meisinger (2006) [77] Folsom (2000) [19] Meisinger (2006) [77] WC WC WC WC F F F F 30-55 35-74 55-69 35-74
All studies (4) All studies (3) F-up<10 yrs (2) F-up>=10 yrs (2) US studies (2)
7.6 9.5 9.4 9.5 US Germany US Germany
3.2(0.37)* 2.9(0.23)* 0.4(0.53)* 2.3(0.13)* 1.4(0.24)*
42492 2957 31702 2957
IRR IRR IRR RR-P
IRR: RR-P:
Hu (2001) [75] Weinstein (2004) [76] Folsom (2000) [19] Meisinger (2006) [77] Weinstein (2004) [76] Meisinger (2006) [77] BMI BMI BMI BMI BMI BMI F F F F F F 30-55 45+ 55-69 35-74 45+ 35-74

16 6.9 9.4 9.5 6.9 9.5 US US US Germany US Germany
15.4(0)*
15.26 (12.43 - 18.72) 9.81 (6.23 - 15.43) 8.88 (7.49 - 10.52) 8.39 (5.38 - 13.09) 11.10 (8.23 - 14.96) 8.39 (5.38 - 13.09) 19.58 (17.37 - 22.06) 13.47 (11.45 - 15.86) 9.49 (8.09 - 11.14) 8.34 (5.37 - 12.97) 12.83 (10.93 - 15.07) 7.41 (4.81 - 11.42) 12.41 (9.03 - 17.06) 10.47 (7.31 - 15.00) 13.47 (11.45 - 15.86) 11.96 (7.79 - 18.37) 13.60 (9.70 - 19.07)
84941 37878 31702 2957 37878 2957
IRR IRR IRR IRR RR-P RR-P
IRR: RR-P: IRR: IRR: IRR:
All studies (4) All studies (2) F-up<8 yrs (1) F-up>=8 yrs (3) US studies (3)
26.2(0)* 0.8(0.37)* 25.1(0)* 24.9(0)*
0.5
16
0.5
16
32
RR
RR
Figure 10 of studies for type II diabetes Meta-analysis Meta-analysis of studies for type II diabetes. *Q-statistic(p-value); F-up is follow-up in years; square shape: study- and gender- specific risk estimates; diamond shape: pooled risk estimates.
Overweight
0.5 Study Hu (2004) [83] Radi (2004) [84] Obesity Sex BMI BMI M M Age 25-64 15-69 F-up Country 11 1 Finland France N 8302 9691 Outcome IRR RR-P 1 2 4 16 Risk Est (95% CI) 1.28 (1.09 - 1.50 ) 2.34 (1.85 - 2.98 ) 1.28 (1.10 - 1.50 ) 2.34 (1.85 - 2.98 ) 31702 IRR 1.38 (1.27 - 1.51 ) 1.38 (1.27 - 1.51 ) 82473 31702 9139 7774 IRR IRR IRR RR-P
175.6(0)*
Obese
0.5 1 2 4 16 32 Risk Est (95% CI) 1.84 (1.51 - 2.24 ) 5.93 (4.39 - 8.00 ) 1.84 (1.51 - 2.24 ) 5.93 (4.39 - 8.00 ) 1.90 (1.77 - 2.03 ) 1.90 (1.77 - 2.03 ) 4.01 (3.83 - 4.19 ) 2.06 (1.89 - 2.24 ) 1.59 (1.32 - 1.93 ) 3.48 (2.12 - 5.71 ) 2.42 (1.59 - 3.67 ) 3.48 (2.12 - 5.71 ) 2.54 (1.34 - 4.82 ) 2.54 (1.34 - 4.82 ) 2.06 (1.89 - 2.24 ) 2.76 (1.72 - 4.45 ) 2.88 (1.81 - 4.57 ) 2.23 (1.30 - 3.83 )
IRR: RR-P: Folsom (2000) [19] WC F 55-69
All studies (1) All studies (1) 5.9 US
IRR: Huang (1998) [85] Folsom (2000) [19] Hu (2004) [83] Radi (2004) [84] BMI BMI BMI BMI F F F F 30-55 55-69 25-64 15-69
All studies (1) 16 5.9 11 1 US US Finland France
2.32 (2.25 - 2.40 ) 1.44 (1.34 - 1.54 ) 1.40 (1.20 - 1.63 ) 2.04 (1.33 - 3.12 ) 1.65 (1.24 - 2.19 ) 2.04 (1.33 - 3.12 ) 1.81 (1.27 - 2.57 ) 1.81 (1.27 - 2.57 ) 1.44 (1.34 - 1.54 ) 1.89 (1.45 - 2.46 ) 1.83 (1.31 - 2.55 ) 1.64 (1.24 - 2.18 )
All studies (3) All studies (1) F-up>=10 yrs (2) min.age<55 (2) min.age>=55 (1)
40.1(0)* 40.1(0)*
IRR & RR-P: min.age<55 (3) US studies (2) IRR & RR-P: Europe studies (2)
40.3(0)* 148.3(0)* 2.6(0.11)*
0.5
16
0.5
16
32
RR
RR
Figure 11 of studies for hypertension Meta-analysis Meta-analysis of studies for hypertension. *Q-statistic(p-value); F-up is follow-up in years; square shape: study- and gender- specific risk estimates; diamond shape: pooled risk estimates.
Page 9 of 20
Overweight
0.5 Study Obesity Sex Age F-up Country N Outcome 1 2 4 16 Risk Est (95% CI) 0.5 1 2
Obese
4 16 32 Risk Est (95% CI)
Kurth (2002) [86] Kurth (2002) [86] Jood (2004) [87] Shaper (1997) [88] Murphy (2006) [89]
BMI BMI BMI BMI BMI
M M M M M
40-84 40-84 47-55 40-59 45-64 IRR: RR-P: RR-P:
12.5 US 12.5 US 22.8 Sweden 14.8 UK 20 UK All studies (1) All studies (4)
21414 21414 7402 7735 7048
IRR RR-P RR-P RR-P RR-P
1.34 (1.16 - 1.56 ) 1.34 (1.16 - 1.55 ) 1.19 (1.04 - 1.36 ) 1.19 (0.93 - 1.52 ) 1.07 (0.89 - 1.29 ) 1.34 (1.16 - 1.56 )
1.68 (1.27 - 2.21 ) 1.66 (1.27 - 2.18 ) 1.57 (1.28 - 1.92 ) 1.37 (0.94 - 2.01 ) 1.35 (1.03 - 1.78 ) 1.68 (1.27 - 2.21 ) 1.51 (1.33 - 1.72 ) 1.47 (1.26 - 1.71 )
3.5(0.32)* 0.9(0.64)*
1.23 (1.13 - 1.34 ) 1.16 (1.05 - 1.28 )
Europe studies (3)
Rexrode (1997) [90] Wessel (2004) [91] Kurth (2005) [92] Murphy (2006) [89]
BMI BMI BMI BMI
F F F F
30-55
14.7 US 3.9 US US UK All studies (1) All studies (3)
87437 906 39876 8354
IRR RR-P RR-P RR-P
1.29 (1.03 - 1.62 ) 2.69 (0.91 - 7.94 ) 1.20 (0.97 - 1.48 ) 1.09 (0.91 - 1.31 ) 1.29 (1.03 - 1.62 )
1.50 (1.27 - 1.77 ) 2.05 (0.68 - 6.16 ) 1.32 (1.03 - 1.69 ) 1.60 (1.30 - 1.98 ) 1.50 (1.27 - 1.77 ) 1.49 (1.27 - 1.74 ) 1.49 (1.33 - 1.67 ) 1.48 (1.26 - 1.73 ) 1.35 (1.06 - 1.71 ) 1.45 (1.27 - 1.66 )
45+ 45-64 IRR: RR-P:
9.8 20
2.9(0.24)* 1.3(0.52)* 0.4(0.51)* 2.1(0.15)* 2.1(0.34)*
1.15 (1.00 - 1.32 ) 1.18 (1.04 - 1.32 ) 1.13 (0.99 - 1.31 ) 1.24 (1.00 - 1.52 ) 1.26 (1.08 - 1.47 )
IRR & RR-P: F-up>=10 yrs (3) RR-P: RR-P: F-up>=9 yrs (2) US studies (2)
IRR & RR-P: US studies (3)
0.5
16
0.5
16
32
RR
RR
Figure 12 of studies for stroke Meta-analysis Meta-analysis of studies for stroke. *Q-statistic(p-value); F-up is follow-up in years; square shape: study- and gender- specific risk estimates; diamond shape: pooled risk estimates.
Colorectal cancer A total of 12 studies were identified for colorectal cancer (Figures 5 and 6) [19,42,45,54-62]. For men, the pooled IRRs [95% CI] across categories of WC were 1.88 [1.47 2.41] for overweight and 2.93 [2.313.73] for obesity and across categories of BMI were 1.51 [1.371.67] for overweight and 1.95 [1.592.39] for obesity. For women, the pooled IRRs across categories of WC were 1.25 [0.98 1.59] for overweight and 1.55 [1.271.88] for obesity and those across categories of BMI were 1.45 [1.301.62] for overweight and 1.66 [1.521.81] for obesity. Esophageal cancer Only 1 study was identified for esophageal cancer [63]. The study found the risk of cancer based on overweight to be 1.15 [0.971.36] and 1.13 [1.021.26] for females and males, respectively. The corresponding risks for obesity were 1.20 [0.951.53] and 1.21 [0.971.52]. Kidney cancer We identified 5 studies meeting the inclusion criteria relating overweight and obesity to kidney cancer (Figure 7) [42,45,57,64,65]. The pooled IRRs [95% CI] across categories of BMI for men were 1.40 [1.311.49] for overweight and 1.82 [1.612.05] for obesity. For women the corresponding risks were 1.82 [1.681.98] and 2.64 [2.392.90].
Pancreatic cancer The search identified 6 studies giving information on the risk of pancreatic cancer attributable to overweight and obesity (Figure 8) [42,45,66-69]. The pooled IRRs [95% CI] across categories of BMI for men were 1.28 [0.94 1.75] for overweight and 2.29 [1.653.19] for obesity. For women the corresponding risks were 1.24 [0.981.56] and 1.60 [1.172.20]. Prostate cancer The search identified 8 studies giving information on the risk of prostate cancer attributable to overweight and obesity (Figure 9) [36,42,45,70-74]. The pooled IRRs [95% CI] across categories of BMI were 1.14 [1.001.31] for overweight and 1.05 [0.851.30] for obesity. Type II diabetes Nine studies met the inclusion criteria and were included in the meta-analysis (Figure 10) [19,75-82]. In general, elevated BMI and WC were significantly associated with type II diabetes in men and women. The pooled IRRs [95% CI] across categories of BMI were 2.40 [2.122.72] and 6.74 [5.558.19] in men while the corresponding IRRs in women were 3.92 [3.104.97] and 12.41 [9.03 17.06]. The association between increased WC and type II diabetes was similar but weaker in comparison with BMI. Only two studies were included in men. The pooled IRRs
Page 10 of 20
Overweight
0.5
Obese
16
Risk Est (95% CI)
0.5
16
32
Risk Est (95% CI)
Rexrode (1998) [20] Rexrode (1998) [20]
WC WC
F F
40-65 40-65
8 8
US US
44702 44702
IRR RR-P
1.82 (1.41 - 2.36 ) 1.82 (1.40 - 2.36 ) 1.82 (1.41 - 2.36 ) 1.82 (1.40 - 2.36 )
2.69 (2.05 - 3.53 ) 2.66 (2.03 - 3.49 ) 2.69 (2.05 - 3.53 ) 2.66 (2.03 - 3.49 )
IRR: RR-P:
Li (2006) [99] Wilson (2002) [94] Kannel (2002) [97] Tuomilehto (1987) [98] Seeman (1993) [96] Wessel (2004) [91]
BMI BMI BMI BMI BMI BMI
F F F F F F
34-59 35-75 30-74 30-59 65-98
20 44 16 9 6 3.9
US US US Finland US US
88393 433 2798 4037 1262 906
IRR IRR RR-P RR-P RR-P RR-P
1.81 (1.65 - 1.99 ) 1.54 (0.97 - 2.46 ) 1.33 (0.93 - 1.91 ) 1.32 (0.69 - 2.51 ) 0.82 (0.44 - 1.53 ) 0.79 (0.27 - 2.30 ) 1.80 (1.64 - 1.98 ) 1.14 (0.88 - 1.48 ) 0.99 (0.66 - 1.50 ) 1.33 (0.93 - 1.91 )
3.15 (2.84 - 3.48 ) 2.13 (1.25 - 3.65 ) 2.33 (1.60 - 3.39 ) 1.98 (0.99 - 3.94 ) 1.32 (0.76 - 2.30 ) 1.47 (0.58 - 3.72 ) 3.10 (2.81 - 3.43 ) 1.91 (1.45 - 2.50 ) 1.53 (1.04 - 2.27 ) 2.33 (1.60 - 3.39 ) 2.46 (1.96 - 3.09 ) 1.85 (1.33 - 2.58 ) 2.15 (1.59 - 2.91 )
IRR: RR-P: RR-P: RR-P:
All studies (2) All studies (4) F-up<10 yrs (3) F-up>=10 yrs (1)
0.4(0.51)* 2.4(0.49)* 1.3(0.53)*
IRR & RR-P: min.age<=40 (5) RR-P: US studies (3)
5.8(0.21)* 2.2(0.33)* 10.7(0.03)*
1.50 (1.25 - 1.80 ) 1.14 (0.85 - 1.54 ) 1.32 (1.02 - 1.71 )
IRR & RR-P: US studies (5)
0.5
16
0.5
16
32
RR
RR
Figure 13 of studies for coronary artery disease-females Meta-analysis Meta-analysis of studies for coronary artery disease-females. *Q-statistic(p-value); F-up is follow-up in years; square shape: study- and gender- specific risk estimates; diamond shape: pooled risk estimates.
[95% CI] across categories of WC were 2.36 [1.763.15] and 5.67 [4.467.20] in men and the pooled RR-Ps [95% CI] based on the same two studies were 2.27 [1.673.10] and 5.13 [3.816.90], respectively. The pooled RR-Ps were more conservative RR estimates and presented in the summary table (Table 2). The pooled IRRs [95% CI] across categories of WC were 3.40 [2.424.78] and 11.10 [8.23 14.96] in women.
Hypertension Four studies met the inclusion criteria and were included in the meta-analysis (Figure 11) [19,83-85]. The pooled IRR [95% CI] estimates for hypertension across categories BMI for men were 1.28 [1.101.50] for overweight and 1.84 [1.512.24] for obesity. The corresponding figures for females were 1.65 [1.242.19] and 2.42 [1.593.67]. The single IRR estimate based on WC for women was 1.38 [1.271.51] for overweight and 1.90 [1.772.03] for obesity. Stroke Seven studies met the inclusion criteria and were included in the meta-analysis (Figure 12) [86-92]. The pooled RRP [95% CI] estimates for stroke across categories BMI for men were 1.23 [1.131.34] for overweight and 1.51
[1.331.72] for obesity. The corresponding results for females were 1.15 [1.001.32] and 1.49 [1.271.74].
Coronary Artery Disease Eleven studies were identified with evidence for coronary artery disease related to obesity (Figures 13 and 14) [20,21,79,91,93-99]. The pooled RR-P estimates for coronary artery disease across categories of WC were more conservative RR estimates for men than the corresponding IRR estimates and thus were presented in the summary table (Table 2). The RR-P [95% CI] estimates for WC were 1.41 [1.161.72] for overweight and 1.81 [1.452.25] for obesity. The corresponding results for BMI were 1.29 [1.181.41] and 1.72 [1.511.96]. While the pooled RR-P estimates based on BMI measurements for women were generated from 4 studies, the IRR estimates were generated from 2 different studies with longer follow-up. Thus, the IRR estimates were the RR estimates for women presented in the summary table (Table 2). The estimates were 1.80 [1.641.98] for overweight and 3.10 [2.813.43] for obesity based on BMI measurements and 1.82 [1.41 2.36] and 2.69 [2.053.53] for WC. Congestive Heart Failure Four studies were identified with evidence for congestive heart failure related to obesity (Figure 15) [91,100-102].
Page 11 of 20
Overweight
0.5
Study Rexrode (2001) [21] Rexrode (2001) [21] Obesity Sex WC WC M M Age 40-84 40-84 F-up 3.9 3.9 Country US US N 16164 16164 Outcome IRR RR-P
Obese
16
Risk Est (95% CI) 1.43 1.41 1.43 1.41 1.42 1.42 1.31 1.01 2.20 1.41 1.26 1.12 0.98 1.28 1.29 1.33 1.29 2.20 1.31 1.24 1.11 1.36 1.21 1.31 1.16 1.34 (1.17 (1.16 (1.17 (1.16 (1.29 (0.95 (1.19 (0.79 (1.15 (1.28 (1.16 (0.89 (0.69 (1.14 (1.18 (0.78 (1.18 (1.15 (1.19 (1.08 (0.90 (1.27 (0.97 (1.19 (1.00 (1.26 - 1.75 ) - 1.72 ) - 1.75 ) - 1.72 ) - 1.57 ) - 2.11 ) - 1.44 ) - 1.30 ) - 4.22 ) - 1.56 ) - 1.37 ) - 1.41 ) - 1.39 ) - 1.45 ) - 1.41 ) - 2.24 ) - 1.42 ) - 4.22 ) - 1.43 ) - 1.42 ) - 1.38 ) - 1.46 ) - 1.50 ) - 1.43 ) - 1.35 ) - 1.44 )
0.5
16
32
Risk Est (95% CI) 1.86 1.81 1.86 1.81 2.08 1.73 1.79 1.26 1.98 1.99 1.62 1.50 1.74 1.75 1.72 1.83 1.71 1.98 1.76 1.72 1.40 1.92 1.55 1.76 1.48 1.90 (1.49 (1.45 (1.49 (1.45 (1.77 (1.04 (1.54 (0.88 (0.96 (1.71 (1.44 (1.13 (1.21 (1.44 (1.51 (1.31 (1.47 (0.96 (1.53 (1.43 (1.04 (1.72 (1.20 (1.53 (1.22 (1.71 - 2.32 ) - 2.25 ) - 2.32 ) - 2.25 ) - 2.45 ) - 2.91 ) - 2.08 ) - 1.80 ) - 4.08 ) - 2.32 ) - 1.83 ) - 1.98 ) - 2.50 ) - 2.12 ) - 1.96 ) - 2.54 ) - 1.98 ) - 4.08 ) - 2.02 ) - 2.06 ) - 1.88 ) - 2.14 ) - 2.01 ) - 2.02 ) - 1.80 ) - 2.12 )
IRR: RR-P:
Jonsson (2002) [93] Wilson (2002) [94] Wannamethee (2005) [79] St-Pierre (2005) [95] Seeman (1993) [96] Jonsson (2002) [93] Wannamethee (2005) [79] Kannel (2002) [97] Tuomilehto (1987) [98] BMI BMI BMI BMI BMI BMI BMI BMI BMI M M M M M M M M M 27-61 35-75 40-59 34-64 65-98 27-61 40-59 30-74 30-59

23 44 21.3 13 6 23 21.3 16 9 Sweden US UK Canada US Sweden UK US Finland 22025 433 7175 1824 916 22025 7175 2453 3785 IRR IRR IRR IRR RR-P RR-P RR-P RR-P RR-P
IRR: RR-P: RR-P: RR-P: RR-P: RR-P: IRR & RR-P: IRR: IRR: RR-P: RR-P: IRR & RR-P: IRR & RR-P:
All studies (4) All studies (5) F-up<10 yrs (2) F-up>=10 yrs (3) min.age>=65 (1) max.age=<65 (3) max.age=<65 (4) US/Canada studies (2) Europe studies (2) US studies (2) Europe studies (3) US/Canada studies (4) Europe studies (3)
6.5(0.09)* 10.1(0.04)* 4.6(0.03)* 5.1(0.08)*
6(0.05)* 12.5(0.03)* 2(0.16)* 1.4(0.24)* 3.7(0.06)* 6(0.05)* 5.9(0.11)* 8(0.09)*
0.5
16
0.5
16
32
RR
RR
Figure 14 of studies for coronary artery disease-males Meta-analysis Meta-analysis of studies for coronary artery disease-males. *Q-statistic(p-value); F-up is follow-up in years; square shape: study- and gender- specific risk estimates; diamond shape: pooled risk estimates.
The pooled IRR [95% CI] estimates for congestive heart failure across categories of BMI for men were 1.31 [0.96 1.79] for overweight and 1.79 [1.242.59] for obesity. The pooled RR-P estimates for females based on 3 studies were 1.27 [0.682.37] and 1.78 [1.072.95], which were chosen as the RR estimates over the IRR estimates based on 2 studies.
Asthma Four studies were identified with evidence for asthma related to obesity (Figure 16) [103-106]. The pooled RR-P [95% CI] estimates for asthma across categories of BMI for men were 1.20 [1.081.33] for overweight and 1.43 [1.141.79] for obese. The corresponding numbers for females were 1.25 [1.051.49] and 1.78 [1.362.32]. Chronic back pain Only 1 study was identified to meet the inclusion criteria for chronic back pain [107]. The study identified the association for the overweight and obesity with early retirement due to chronic back pain. The study found RR-P [95% CI] estimates across categories of BMI of chronic back pain based on overweight to be 1.59 [1.341.89] and for obesity 2.81 [2.273.48].
Osteoarthritis We identified three studies meeting the inclusion criteria relating overweight and obesity to osteoarthritis (Figure 17) [108-110]. The studies identified the risk of joint replacement attributable to being overweight and obese. The pooled IRRs [95% CI] across categories of BMI for men were 2.76 [2.053.70] for overweight and 4.20 [2.766.41] for obesity. For women, the RR-P estimates were more conservative RR estimate and they were 1.80 [1.751.85] and 1.96 [1.882.04]. Pulmonary embolism Only 1 study was identified to meet the inclusion criteria for pulmonary embolism [111]. The study found IRR [95% CI] across categories of BMI of Pulmonary embolism based on overweight to be 1.91 [1.392.64] and for obesity 3.51 [2.614.73]. Gallbladder disease We identified four studies meeting the inclusion criteria relating overweight and obesity gallbladder disease (Figure 18) [59,112-114]. The pooled IRRs [95% CI] across categories of WC for men were 1.63 [1.421.88] for overweight and 2.51 [2.162.91] for obesity. The correspond-
Page 12 of 20
ing pooled RR-Ps were 1.61 [1.401.85] and 2.38 [2.06 2.75]. Thus, the pooled RR-Ps were more conservative RR estimates and presented in Table 2. Across categories of BMI, the pooled IRR and RR-P estimates were presented as the RR estimates in Table 2 and they were 1.09 [0.87 1.37] for overweight and 1.43 [1.041.96] for obesity. For women only estimates for BMI were identified giving pooled IRR and RR-P estimates of 1.44 [1.051.98] for overweight and 2.32 [1.174.57] for obesity. Potential publication bias was assessed for post-menopausal breast cancer, endometrial cancer, ovarian cancer, colorectal cancer, pancreatic cancer for females and prostate cancer. We found some evidence of funnel-plot asymmetry for obesity in prostate cancer where bigger studies tended to show stronger positive association than smaller studies. No evidence of publication bias was found in the other meta-analyses. Our sensitivity analyses showed that our results were in general robust with the following exceptions. For ovarian cancer, associations for both overweight and obesity were slightly weaker in US studies compared to European studies. Similar country differences were found in pancreatic cancers; in addition, weaker associations were observed in older population. Studies with shorter follow-up time and of older population showed slightly weaker association of obesity with prostate cancer. In coronary artery disease for females, studies with shorter follow-up showed weaker associations of both overweight and obese. In coronary artery disease for males, weaker associations were observed in US and Canadian studies. Studies of post-
menopausal and senior women on congestive heart failure showed weaker associations for both overweight and obesity.
Discussion
We have comprehensively reviewed 20 co-morbidities for high quality cohort studies which determine risk factors associated with overweight or obesity. 18 co-morbidities were identified and meta-analysis was performed where at least 1 study was found. A summary of the results can be found in Table 2. There are a number of alternative meta-analyses with which we can compare our results. For example, recent meta-analyses have been reported in diabetes [115,116], cardiovascular diseases [117], coronary heart disease [118], hypertension [116], cancer [119], colorectal cancer [120-122], gallbladder cancer [123], pancreatic cancer [124], ovarian cancer [125] and asthma [126]. However, each study uses different definitions of overweight and obesity, includes varying quality of study designs, uses different methods for meta-analysis and ultimately only focuses on individual co-morbidities. Hence, the objective of our study is not only to provide up to date estimates of the risk of all possible co-morbidities attributable to overweight and obesity, but also to do it using consistent definitions and methodology. In assessing whether obesity is related to a given co-morbidity, the occurrence timing of co-morbidities with respect to exposure of obesity is important in determining the causal pathway. Therefore, we included only the proOverweight Obese
16 Risk Est (95% CI) 0.1 0.5 1 2 4 16 32
0.1
0.5
Risk Est (95% CI)
Kenchaiah (2002) [101] Kenchaiah (2002) [101]
BMI BMI
M M
30+ 30+
14 14
US US
2704 2704
IRR RR-P
1.31 (0.96 - 1.79 ) 1.36 (1.01 - 1.83 ) 1.31 (0.96 - 1.79 ) 1.36 (1.01 - 1.83 )
1.79 (1.24 - 2.59 ) 1.80 (1.27 - 2.56 ) 1.79 (1.24 - 2.59 ) 1.80 (1.27 - 2.56 )
IRR: RR-P:
Kenchaiah (2002) [101] Rea (2003) [100] Kenchaiah (2002) [101] Bibbins-Domingo (2004) [102] Wessel (2004) [91]
BMI BMI BMI BMI BMI
F F F F F
30+ 65+ 30+ Post-M**
14 7.3 14 6.3 3.9
US US US US US
3177 3223 3177 2391 906
IRR IRR RR-P RR-P RR-P

18.2(0)* 16.8(0)* 0.6(0.45)*
2.41 (1.81 - 3.21 ) 1.03 (0.79 - 1.34 ) 2.38 (1.81 - 3.14 ) 1.21 (0.87 - 1.70 ) 0.63 (0.30 - 1.30 ) 1.57 (0.86 - 2.87 ) 1.27 (0.68 - 2.37 ) 1.10 (0.89 - 1.35 )
3.08 (2.23 - 4.25 ) 1.39 (1.04 - 1.84 ) 2.91 (2.14 - 3.95 ) 1.77 (1.28 - 2.43 ) 0.96 (0.51 - 1.83 ) 2.06 (1.16 - 3.66 ) 1.78 (1.07 - 2.95 ) 1.54 (1.25 - 1.90 )
IRR: RR-P:
IRR & RR: post-menopause and 65+ (2)
0.1
0.5
16
0.1
0.5
16
32
RR
RR
Figure 15 of studies for congestive heart failure Meta-analysis Meta-analysis of studies for congestive heart failure. *Q-statistic(p-value); **post-menopause; square shape: study- and gender- specific risk estimates; diamond shape: pooled risk estimates.
Page 13 of 20
Overweight
0.1
Study Nystad (2004) [104] Chen (2002) [103] Nystad (2004) [104] Ford (2004) [105] Obesity Sex BMI BMI BMI BMI M M M M Age 14-59 20-64 14-59 25-74 F-up 21 2 21 10 Country Norway Canada Norway US N 66723 4241 66723 3621 Outcome IRR RR-P RR-P RR-P
Obese
16 Risk Est (95% CI) 1.53 1.29 1.22 0.97 1.53 1.20 1.29 1.20 1.06 1.25 1.56 1.22 1.14 1.07 1.25 1.25 1.53 1.08 1.34 (1.37 (0.69 (1.09 (0.63 (1.37 (1.08 (0.69 (1.08 (0.75 (1.13 (1.38 (0.81 (0.84 (0.97 (1.13 (1.05 (1.36 (0.98 (1.11 - 1.71 ) - 2.41 ) - 1.36 ) - 1.48 ) - 1.71 ) - 1.33 ) - 2.41 ) - 1.33 ) - 1.51 ) - 1.38 ) - 1.76 ) - 1.85 ) - 1.56 ) - 1.18 ) - 1.38 ) - 1.49 ) - 1.72 ) - 1.19 ) - 1.63 ) 0.1 0.5 1 2 4 16 32
0.5
Risk Est (95% CI) 2.19 0.76 1.53 1.50 2.19 1.43 0.76 1.52 1.20 1.87 2.51 2.05 1.39 1.40 1.87 1.78 2.47 1.40 1.96 (1.68 (0.35 (1.17 (0.88 (1.68 (1.14 (0.35 (1.20 (0.78 (1.58 (2.23 (1.33 (1.00 (1.19 (1.58 (1.36 (2.21 (1.21 (1.46 - 2.87 ) - 1.63 ) - 1.99 ) - 2.56 ) - 2.87 ) - 1.79 ) - 1.63 ) - 1.93 ) - 1.86 ) - 2.21 ) - 2.82 ) - 3.17 ) - 1.93 ) - 1.65 ) - 2.21 ) - 2.32 ) - 2.77 ) - 1.62 ) - 2.63 )
IRR: RR-P: RR-P: RR-P: RR-P:

Nystad (2004) [104] Camargo (1999) [106] Chen (2002) [103] Ford (2004) [105] Nystad (2004) [104] BMI BMI BMI BMI BMI F F F F F 14-59 26-46 20-64 25-74 14-59
All studies (1) All studies (3) F-up<10 yrs (1) F-up>=10 yrs (2) US/Canada studies (2)
21 4 2 10 21 Norway US Canada US Norway
1.1(0.58)* 1(0.31)* 0.6(0.46)*
68682 85911 4679 5835 68682
IRR RR-P RR-P RR-P RR-P
IRR: RR-P: RR-P: RR-P: RR-P:
All studies (1) All studies (4) F-up<10 yrs (2) F-up>=10 yrs (2) US/Canada studies (3)
22.6(0)* 1.2(0.27)* 0.2(0.7)* 4.2(0.12)*
0.1
0.5
16
0.1
0.5
16
32
RR
RR
Figure 16 of studies for asthma Meta-analysis Meta-analysis of studies for asthma. *Q-statistic(p-value); F-up is follow-up in years; square shape: study- and gender- specific risk estimates; diamond shape: pooled risk estimates.
Overweight
0.5
Obese
16 Risk Est (95% CI) 0.5 1 2 4 16 32 Risk Est (95% CI)
Jarvholm (2005) [108] Flugsrud (2006) [109] Flugsrud (2006) [109]
BMI BMI BMI
M M M
15-67 18-67 18-67
10.7 13.8 13.8
Sweden Norway Norway
320192 526972 526972
IRR IRR RR-P
3.42 (3.11 - 3.76 ) 2.24 (2.14 - 2.34 ) 2.01 (1.92 - 2.09 ) 2.76 (2.05 - 3.70 ) 2.01 (1.92 - 2.09 )
5.70 (4.90 - 6.62 ) 3.12 (2.86 - 3.40 ) 2.47 (2.27 - 2.70 ) 4.20 (2.76 - 6.41 ) 2.47 (2.27 - 2.70 )
IRR: RR-P:
63.5(0)*
Flugsrud (2006) [109] Karlson (2003) [110] Flugsrud (2006) [109] Karlson (2003) [110]
BMI BMI BMI BMI
F F F F
18-67 30-55 18-67 30-55
13.8 7.3 13.8 7.3
Norway US Norway US
625034 93442 625034 93442
IRR IRR RR-P RR-P
2.07 (2.01 - 2.14 ) 1.42 (1.17 - 1.73 ) 1.80 (1.75 - 1.86 ) 1.63 (1.34 - 1.97 ) 1.75 (1.35 - 2.26 ) 1.80 (1.75 - 1.85 )
2.52 (2.42 - 2.63 ) 1.87 (1.52 - 2.30 ) 1.95 (1.87 - 2.03 ) 2.33 (1.89 - 2.86 ) 2.19 (1.77 - 2.71 ) 1.96 (1.88 - 2.04 )
IRR: RR-P:
13.9(0)* 1(0.31)*
0.5
16
0.5
16
32
RR
RR
Figure 17 of studies for osteoarthritis Meta-analysis Meta-analysis of studies for osteoarthritis. *Q-statistic(p-value); F-up is follow-up in years; square shape: study- and gender- specific risk estimates; diamond shape: pooled risk estimates.
Page 14 of 20
Overweight
0.5
Study Tsai (2004) [112] Tsai (2004) [112] Obesity Sex WC WC M M Age 40-75 40-75 F-up 8.9 8.9 Country US US N 29847 29847 Outcome IRR RR-P
Obese
16 Risk Est (95% CI) 1.63 1.61 1.63 1.61 1.37 1.00 0.91 1.18 0.91 1.09 1.15 2.15 1.27 1.20 1.64 1.20 1.44 (1.42 (1.40 (1.42 (1.40 (1.20 (0.84 (0.62 (0.94 (0.62 (0.87 (0.86 (1.57 (1.10 (0.90 (1.11 (0.90 (1.05 - 1.88 ) - 1.85 ) - 1.88 ) - 1.85 ) - 1.56 ) - 1.17 ) - 1.34 ) - 1.48 ) - 1.34 ) - 1.37 ) - 1.54 ) - 2.94 ) - 1.47 ) - 1.61 ) - 2.40 ) - 1.61 ) - 1.98 ) 0.5 1 2 4 16 32 Risk Est (95% CI) 2.51 2.38 2.51 2.38 1.94 1.38 0.95 1.67 0.95 1.43 1.42 5.36 1.88 1.24 3.08 1.24 2.32 (2.16 (2.06 (2.16 (2.06 (1.64 (1.01 (0.60 (1.29 (0.60 (1.04 (0.87 (3.43 (1.60 (0.92 (1.49 (0.92 (1.17 - 2.91 ) - 2.75 ) - 2.91 ) - 2.75 ) - 2.28 ) - 1.89 ) - 1.50 ) - 2.16 ) - 1.50 ) - 1.96 ) - 2.33 ) - 8.38 ) - 2.21 ) - 1.68 ) - 6.36 ) - 1.68 ) - 4.57 )
IRR: RR-P:
Tsai (2004) [112] Engeland (2005) [59] Boland (2002) [113] BMI BMI BMI M M M 40-75 20-74 45-64

8.9 23.7 8.2 US Norway US 29847 962901 5839 IRR IRR RR-P
8(0.01)*
IRR: RR-P: IRR & RR-P: IRR & RR-P:

Layde (1982) [114] Engeland (2005) [59] Boland (2002) [113] BMI BMI BMI F F F 25-39 20-74 45-64
All studies (2) All studies (1) All studies (3) US studies (2)
9.1 23.7 8.2 UK Norway US
10.1(0.01)* 3.9(0.05)*
17032 1037077 6934

9(0)*
IRR IRR RR-P
IRR: RR-P: IRR & RR-P:
All studies (2) All studies (1) All studies (3)
9.8(0.01)*
0.5
16
0.5
16
32
RR
RR
Figure 18 of studies for gallbladder disease Meta-analysis Meta-analysis of studies for gallbladder disease. *Q-statistic(p-value); F-up is follow-up in years; square shape: study- and gender- specific risk estimates; diamond shape: pooled risk estimates.
spective cohort studies and excluded the cross-sectional studies and case control studies to minimize the associated potential biases. In addition, WC measurements were considered to be the better risk predictor for type II diabetes, hypertension, coronary artery disease, congestive heart failure, stroke and gallbladder disease [16-24]. In our studies, the risk for type II diabetes, female hypertension, coronary artery disease, and male gallbladder disease were estimated based on WC measurements. Some limitations are worthy of further consideration. Firstly, other variables not included in our analysis might potentially confound our results. Most important is the exclusion of the level of physical inactivity which is a known risk factor for some co-morbidities and related to overweight and obesity [127]. Physical inactivity is often poorly reported and requiring its inclusion would have reduced the number of included studies. Secondly, for certain co-morbidities, we only identified 1 or 2 prospective cohort studies that adopted the WC measurements as the risk predictor. Further studies are required to determine the association between WC and some co-morbidities before an estimate of the risk can be calculated through a meta-analysis. Thirdly, given the sizable literature and that we were searching for non RCT studies for which search filters are more complex, we determined to use Medline and Embase as the electronic databases, and complement the search with checking reference lists and thorough searching the internet. We did not search other databases such as CINHAL, HealthSTAR, AMED, and BIO-
SIS. Therefore, bias might have occurred due to our search strategy. However, given the nature of the studies we are looking for, i.e., prospective cohort studies with high quality, we consider our search within Medline and Embase sufficient. Lastly, due to the small number of studies for most co-morbidities, assessment of potential publication bias was infeasible. However, we did not find evidence of publication bias in those meta-analyses where the number of studies was relatively large except for prostate cancer.
Conclusion
In conclusion, this study provides a comprehensive estimate of the incidence of 18 co-morbidities attributable to overweight and obesity using standardized and consistent definitions and methodologies. Our findings confirm that overweight and obesity carry a profound health burden and will have a significant impact on health expenditures.
Abbreviations
WC: Waist Circumference; BMI: Body Mass Index; RR: Relative Risk; IRR: Incidence Rate Ratio; RR-P: Relative Risk calculated from the ratio of Proportions; CI: Confidence Interval; WHO: World Health Organization.
Competing interests
This manuscript is part of larger project funded by sanofiaventis Canada Inc.
Page 15 of 20
Table 2: Relative co-morbidity risks related to being overweight or obese
Co-morbidity
Measure Male
Overweight Female 3.92 (3.104.97) 3.40 (2.424.78) Male 6.74 (5.558.19)
Obesity Female 12.41 (9.0317.06) 11.10 (8.2314.96)
Type II Diabetes*
BMI WC
2.40 (2.122.72) 2.27 (1.673.10)
5.13 (3.816.90)
Cancer Breast, Postmenopausal Colorectal Endometrial Esophageal Kidney Ovarian Pancreatic Prostate Cardiovascular Diseases Hypertension* BMI WC Coronary Artery Disease* BMI WC Congestive Heart Failure* Pulmonary Embolism Stroke* Other Asthma Gallbladder Disease* BMI BMI WC Osteoarthritis Chronic Back Pain BMI BMI 1.20 (1.081.33) 1.09 (0.871.37) 1.61 (1.401.85) 2.76 (2.053.70) 1.59 (1.341.89) 1.25 (1.051.49) 1.44 (1.051.98) NA 1.80 (1.751.85) 1.59 (1.341.89) 1.43 (1.141.79) 1.43 (1.041.96) 2.38 (2.062.75) 4.20 (2.766.41) 2.81 (2.273.48) 1.78 (1.362.32) 2.32 (1.174.57) NA 1.96 (1.882.04) 2.81 (2.273.48) BMI BMI BMI 1.28 (1.101.50) NA 1.29 (1.181.41) 1.41 (1.161.72) 1.31 (0.961.79) 1.91 (1.392.64) 1.23 (1.131.34) 1.65 (1.242.19) 1.38 (1.271.51) 1.80 (1.641.98) 1.82 (1.412.36) 1.27 (0.682.37) 1.91 (1.392.64) 1.15 (1.001.32) 1.84 (1.512.24) NA 1.72 (1.511.96) 1.81 (1.452.25) 1.79 (1.242.59) 3.51 (2.614.73) 1.51 (1.331.72) 2.42 (1.593.67) 1.90 (1.772.03) 3.10 (2.813.43) 2.69 (2.053.53) 1.78 (1.072.95) 3.51 (2.614.73) 1.49 (1.271.74) BMI BMI BMI BMI BMI BMI BMI BMI 1.51 (1.371.67) 1.13 (1.021.26) 1.40 (1.311.49) 1.28 (0.941.75) 1.14 (1.001.31) 1.08 (1.031.14) 1.45 (1.301.62) 1.53 (1.451.61) 1.15 (0.971.36) 1.82 (1.681.98) 1.18 (1.121.23) 1.24 (0.981.56) 1.95 (1.592.39) 1.21 (0.971.52) 1.82 (1.612.05) 2.29 (1.653.19) 1.05 (0.851.30) 1.13 (1.051.22) 1.66 (1.521.81) 3.22 (2.913.56) 1.20 (0.951.53) 2.64 (2.392.90) 1.28 (1.201.36) 1.60 (1.172.20) -
Page 16 of 20
Table 2: Relative co-morbidity risks related to being overweight or obese (Continued)
BMI: body mass index; WC: waist circumference If indicated, the relative risks calculated from the ratios of proportions (RR-Ps) were used; otherwise, the incidence rate ratios (IRRs) were used; Both RR-Ps and IRRs were used *WC measures were considered to be the better risk predictor than BMI measures Cancer: cases, not mortality and indicated by physician diagnosis of cancer; Coronary Artery Disease: indicated by Myocardial Infarction or Angina; Osteoarthritis: indicated by joint replacement; Chronic Back Pain: indicated by early retirement due to back pain NA: Not available; "-" Not applicable
Authors' contributions
ZA conducted literature search. ZA, NB, DPG, CLB evaluated the study articles and made decisions on inclusion and exclusion of the articles. DPG, WZ, AHA performed statistical analyses. All authors (DPG, WZ, NB, ZA, CLB, AHA) were involved in the manuscript development and its revision. All authors read and approved the final manuscript.
14. 15. 16. 17. 18.
Acknowledgements
This manuscript is part of larger project funded by Sanofi-aventis Canada Inc.
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Page 20 of 20

The Incidence of Co-Morbidities Related To Obesity and Overweight - A Systematic Review and Meta-Analysis

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The Incidence of Co-Morbidities Related To Obesity and Overweight - A Systematic Review and Meta-Analysis

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BMC Public Health

Received: 3 July 2008 Accepted: 25 March 2009

BMC Public Health 2009, 9:88

BMC Public Health 2009, 9:88

BMC Public Health 2009, 9:88

B (i) 6687 5 55 28 145 23 103 5 23 59 96 10 48 172 89 29 43 30

B (vi) 18 57 127 52 195 13 105 7 34 81 82 41 24 234 84 32 123 24

BMC Public Health 2009, 9:88

Age 55+ 55-69 55-69

N 5865 31702 32573

Outcome IRR IRR RR-P

All studies (2) All studies (1)

All studies (2)

IRR: IRR: IRR: IRR: IRR:

41.5(0)* 2.1(0.35)* 3.7(0.05)* 5.2(0.07)* 6.3(0.28)* 14.4(0.05)*

RR-P: All studies (3)

BMC Public Health 2009, 9:88

All studies (1)

IRR: RR-P: IRR: IRR: IRR: IRR:

10.2(0.18)* 11.3(0.02)* 9.9(0.08)* 0(0.89)* 0.9(0.34)* 6.3(0.27)*

Age 30-79 55-69 25-70 30-79

F-up 30.4 10.2 6.3 30.4

N 4221 31702 238546 4221

Outcome IRR IRR RR-P RR-P

All studies (2) All studies (2)

BMC Public Health 2009, 9:88

Age 40-69 40-75 30-79 30-79 25-70

F-up 8.8 5.5 30.4 30.4 6.3

Country Australia US US US European

N 16556 31055 3345 3345 129731

Outcome IRR IRR IRR RR-P RR-P

0.7(0.7)* 0.3(0.59)* 4.4(0.11)* 0(0.86)* 0.2(0.9)*

Outcome IRR IRR IRR IRR RR-P RR-P RR-P

IRR: RR-P: IRR: IRR & RR-P:

78484 1037788 118191 35362 78484 218805 35362

IRR IRR IRR IRR RR-P RR-P RR-P

All studies (4) All studies (3)

9.1(0.03)* 5(0.08)* 8.9(0.01)* 16.4(0.01)*

BMC Public Health 2009, 9:88

IRR: RR-P: IRR: IRR: IRR: IRR:

6.6(0.09)* 5(0.03)* 5.4(0.07)* 2.9(0.09)* 3.1(0.08)*

9.6 21 10.4 9.3 22 8.2 7.2 9.6 19.5 8.2 10.4

Austria Norway Norway Netherlands Sweden Sweden US Austria US Sweden Norway

BMC Public Health 2009, 9:88

Age 40-75 35-74 40-75 35-74

F-up 13 9.5 13 9.5

Country US Germany US Germany

N 27270 3055 27270 3055

Outcome IRR IRR RR-P RR-P

All studies (2) All studies (2)

7176 22172 3055 20187 7176 3055 20187

IRR IRR IRR IRR RR-P RR-P RR-P

IRR: RR-P: IRR: IRR: IRR:

3.2(0.37)* 2.9(0.23)* 0.4(0.53)* 2.3(0.13)* 1.4(0.24)*

42492 2957 31702 2957

IRR IRR IRR RR-P

All studies (3) All studies (1)

84941 37878 31702 2957 37878 2957

IRR IRR IRR IRR RR-P RR-P

IRR: RR-P: IRR: IRR: IRR:

26.2(0)* 0.8(0.37)* 25.1(0)* 24.9(0)*

IRR: RR-P: Folsom (2000) [19] WC F 55-69

All studies (1) All studies (1) 5.9 US