AIC, as a decision criterion, is used for informal comparisons of models with differing numbers of parameters. In this study, AIC was used to judge the model fitness, the lower the AIC value the better the model fitness, with reduction of AIC evaluated by the LRT or a deviance difference test (192,193) (Studies II-IV). AIC difference ≥4 was considered to be considerably less supported relative to the lowest AIC value between non-nested models (194) (Study III). The shape of relationship between anthropometric measures of obesity and health outcomes was explored using both parametric models (conventional linear or polynomial models) and nonparametric models (the linear or restricted cubic spline regression model) (Studies II and III). Several important approaches were applied in our data analysis, including competing risk analysis and particularly paired homogeneity test, as one formal test of comparing strengths of different measures, which have not been used widely in this research field.
Age was used as the time-scale in Studies II-V, instead of follow-up time used in Study I, as many statisticians have recommended the use of age as the time-scale for the analysis of epidemiologic cohort studies with covariates of interest which were either time-dependent or strongly associated with age (287,288). Fat tissue mass increases through middle age and declines in old age (155,156).
Fat is redistributed among different fat depots over time, especially during and after middle age, when fat redistributes from subcutaneous to intra-abdominal visceral depots (156-161). VAT accumulation increases more rapidly in women with aging, especially after menopause (141,162), despite the higher VAT accumulation in men than in women throughout the life span (162,163,249).
This study showed the interaction between BMI and smoking on cancer mortality and incidence of all cancers combined in women (Study I/II). Smoking is associated with both a lower body weight and an increased risk of mortality, and is interrelated with obesity in relation to mortality (16,176-178). Several recent studies have suggested that cigarette smoking aggravates abdominal obesity (164-168), perhaps through simultaneously inhibiting lipoprotein lipase activity and increasing cortisol levels (167,168). This study found a reduced visceral fat accumulation in Turkish female smokers (169). Several studies have identified cigarette smoking as a risk factor for sarcopenia (289-291), which is characterized by a muscle atrophy, along with a reduction in muscle tissue quality, a replacement of muscle fibres with fat, an increase in fibrosis, changes in muscle metabolism, oxidative stress, and degeneration of the neuromuscular junction and leading to progressive loss of muscle function and frailty (292), although the cellular and molecular mechanisms leading to smoking-induced muscle breakdown still remains elusive.
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Limited evidence indicates that leisure-time physical inactivity might play an intermediate role in the relationship of anthropometric measures of abdominal obesity with mortality (186), and weaken, but not eliminate, the risk associated with excess weight (176). No significant interaction was detected between anthropometric measure of obesity and leisure-time physical activity (Studies II-V). In addition, no substantial influence was observed when further adjusting for education levels in Study II.
This study was based on several European population- or occupation-based prospective studies, with large sample size, long follow-up, reliable assessment of end-points, and detailed assessment of lifestyle variables, thus having sufficient power to investigate the association between anthropometric measurements and the risk of mortality (Studies I and III-V). Information on incidence of cancers was obtained from the FCR (Study II). The data coverage in the FCR is virtually complete, 99% for solid tumours, and the data accuracy is high as previously validated by different researchers (190).
This study does not have data on changes in anthropometric measurements before the baseline and during the follow-up, which makes it impossible to exclude the possibility of ‘reverse causation’
(106,187). In particular, this study showed that men who died within the first five years of follow-up had slightly lower age-adjusted mean values of baseline BMI than other men (Study III).
Potential benefits of a lower BMI might be offset by the negative effect associated with weight loss.
The potential influence of reverse causality was checked by excluding the deaths within the first five years of follow-up, or excluding the first five years of follow-up, and the results were not substantially altered (Studies I and III-V). Similarly, the results were not substantially altered much after excluding the first five years of follow-up in Study II.
This study does not have precise information on menopausal status and hormone therapies that would have been potentially affected the development of female breast cancer (63,66,67,69,70), or sex differences in obesity with CVD mortality. In addition, this study does not have information on several lifestyles or behaviour factors, for instance, dietary factors or alcohol consumption, which might contribute to obesity, and is an independent etiologic factor for several cancers, especially for stomach cancer and liver cancer (73,293). There are relatively few cases among never smokers and hence cannot rule out the possibility of interactions between smoking and BMI in relation to incidence of lung cancer. Our data are based on Caucasian-originated European surveys, and further investigations are needed due to differences in constitutions of the causes of death across countries, or different percentage of body fat across ethnic groups (294).
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7 CONCLUSIONS AND FUTURE DIRECTIONS
This study confirmed the deleterious effect of obesity on mortality from various causes and incidence of cancers of certain sites. Anthropometric measures of abdominal obesity (WC, WHR, WHtR and WHHR) predicted CVD mortality better than BMI, which may imply a more important role of fat distribution than fat accumulation and also an effective obesity prevention strategy. Men had higher CVD mortality than women across all categories of anthropometric measures of obesity, which further supports the view of higher intra-abdominal fat accumulation in men than in women, even in non-obese individuals. The sex difference in CVD mortality was slightly attenuated in obese individuals, irrespective of diabetes status. This may indicate that women would gradually lose their cardiovascular advantage when they are obese, probably due to a more pronounced clustering of CVD risk factors among obese women.
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8 ACKNOWLEDGEMENTS
This work was carried out at the Department of Public Health, Faculty of Medicine, University of Helsinki and Diabetes Prevention Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland during the years 2009-2014. I hereby wish to thank the both institutes for providing me with excellent research facilities and creating the friendliest and most encouraging of working environment. I wish to express my gratitude to former director of Hjelt Institute, Professor Jaakko Kaprio, Adjunct Professor Ritva Halila and Professor Ossi Rahkonen for their quick and positive assistance.
I would like to express my sincere respect and deepest gratitude to my principal supervisor, Docent Qing Qiao. I have always benefited from her expert supervision, brilliant ideas, continuous enthusiasm, rigorous attitude to science, valuable advice and extensive knowledge. I would like also to thank her for providing me with research grants and the great opportunity to have received field research training by coordinating the Qingdao Diabetes Prevention Project in Qingdao, China during this time.
I am also most grateful to another supervisor, Professor Jaakko Tuomilehto, for his constructive guidance, generous support and inspired suggestions on my work during the years. He has always had shrewd insight and given valuable detailed comments and suggestions which have greatly helped to improve the work and create a better version of the manuscript and thesis. I always feel so lucky to have worked with the two excellent supervisors over these years.
I would like to thank the official reviewers of the dissertation, adjunct Professor Tea Lallukka and adjunct Professor Kai Savonen, for their careful work and valuable comments and suggestions, and Professor Per Wändell for accepting the role of Opponent in my thesis defence.
I owe my deep gratitude to all the researchers of the DECODE and FINRISK Studies and all the coauthors of my manuscript for their genuine interests, prompt response and skillful comments that greatly contributed to my manuscript. A special thank goes to Docent Janne Pitkäniemi, Professor Eero Pukkala, Professor Timo Hakulinen, Dr. Tadeusz Dyba and Dr. Vladislav Moltchanov who have actively participated in this work and kindly provided me with great helps.
I greatly appreciate Professor Zengchang Pang for his recommendation and introducing me to Qing and Jaakko. I wish to express my warm thanks to my colleagues and friends, Dr. Weiguo Gao, Dr. Lei Zhang, Dr. Regzedmaa Nyamdorj, M.Sci. Feng Ning, M.Sci. Yanlei Zhang, Dr. Xianghai Zhou, Dr. Haining Wang, M.Sci. Liang He who have always given me generous help and supports in my work and life in Finland. Meanwhile, I give my special thank to Mrs. Pirjo Saastamoinen for
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her kind help in preparing for the abstract of this work in Finnish, and Mrs. Pirkko Särkijärvi and Mrs. Sirkka Koskinen for their help with other other practical matters related to the work.
My deepest debt of gratitude is to my parents, my wife, my sister and brother-in-law for their unlimited love and support throughout these years here.
Helsinki, March 2015 Xin Song
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