title: BMI and all cause mortality: systematic review and non-linear dose-response meta-analysis of 230 cohort studies with 3.74 million deaths among 30.3 million participants.
abstract: To conduct a systematic review and meta-analysis of cohort studies of body mass index (BMI) and the risk of all cause mortality, and to clarify the shape and the nadir of the dose-response curve, and the influence on the results of confounding from smoking, weight loss associated with disease, and preclinical disease.
  
  
  
  PubMed and Embase databases searched up to 23 September 2015.
  
  
  
  Cohort studies that reported adjusted risk estimates for at least three categories of BMI in relation to all cause mortality.
  
  
  
  Summary relative risks were calculated with random effects models. Non-linear associations were explored with fractional polynomial models.
  
  
  
  230 cohort studies (207 publications) were included. The analysis of never smokers included 53 cohort studies (44 risk estimates) with >738 144 deaths and >9 976 077 participants. The analysis of all participants included 228 cohort studies (198 risk estimates) with >3 744 722 deaths among 30 233 329 participants. The summary relative risk for a 5 unit increment in BMI was 1.18 (95% confidence interval 1.15 to 1.21; I(2)=95%, n=44) among never smokers, 1.21 (1.18 to 1.25; I(2)=93%, n=25) among healthy never smokers, 1.27 (1.21 to 1.33; I(2)=89%, n=11) among healthy never smokers with exclusion of early follow-up, and 1.05 (1.04 to 1.07; I(2)=97%, n=198) among all participants. There was a J shaped dose-response relation in never smokers (Pnon-linearity <0.001), and the lowest risk was observed at BMI 23-24 in never smokers, 22-23 in healthy never smokers, and 20-22 in studies of never smokers with ≥20 years' follow-up. In contrast there was a U shaped association between BMI and mortality in analyses with a greater potential for bias including all participants, current, former, or ever smokers, and in studies with a short duration of follow-up (<5 years or <10 years), or with moderate study quality scores.
  
  
  
  Overweight and obesity is associated with increased risk of all cause mortality and the nadir of the curve was observed at BMI 23-24 among never smokers, 22-23 among healthy never smokers, and 20-22 with longer durations of follow-up. The increased risk of mortality observed in underweight people could at least partly be caused by residual confounding from prediagnostic disease. Lack of exclusion of ever smokers, people with prevalent and preclinical disease, and early follow-up could bias the results towards a more U shaped association.
authors.affiliation: Department of Public Health and General Practice, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway Department of Epidemiology and Biostatistics, Imperial College, London, UK.
authors.forename: Dagfinn
authors.initials: D
authors.lastname: Aune
authors.affiliation: Department of Public Health and General Practice, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Sen
authors.affiliation: Department of Community Medicine, Postgraduate Institute of Medical Sciences, Rohtak, Haryana, India.
authors.forename: Manya
authors.initials: M
authors.lastname: Prasad
authors.affiliation: Department of Epidemiology and Biostatistics, Imperial College, London, UK.
authors.forename: Teresa
authors.initials: T
authors.lastname: Norat
authors.affiliation: Department of Public Health and General Practice, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Imre
authors.initials: I
authors.lastname: Janszky
authors.affiliation: Department of Community Medicine, Postgraduate Institute of Medical Sciences, Rohtak, Haryana, India.
authors.forename: Serena
authors.initials: S
authors.lastname: Tonstad
authors.affiliation: Department of Public Health and General Practice, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Pål
authors.initials: P
authors.lastname: Romundstad
authors.affiliation: Department of Public Health and General Practice, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Lars J
authors.initials: LJ
authors.lastname: Vatten
mesh_terms: D015992:Body Mass Index; D015331:Cohort Studies; D006801:Humans; D009765:Obesity; D050177:Overweight; D012307:Risk Factors; D013851:Thinness