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      Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies

      research-article
      , PhD a , * , , PhD a , , PhD a , , MD a , b , , PhD a , , MMath a , , PhD c , , PhD a , , PhD a , , PhD a , d , , PhD a , , PhD a , , MSc a , , PhD e , , PhD f , , Prof, PhD g , h , , Prof, MD i , , Prof, MD j , , Prof, PhD k , l , m , , Prof, MD o , , Prof, MD p , q , , Prof, MBBS r , s , t , , Prof, PhD u , , Prof, MD v , , Prof, MD w , , PhD x , , Prof, FMedSci y , , Prof, MD z , aa , , Prof, MD ab , , Prof, FMedSci ac , , MD ad , , Prof, MD ae , , MD af , , Prof, PhD ag , , MD ah , , Prof, MD ai ,   , PhD aj , , PhD ak , , PhD al , , PhD am , , Prof, PhD h , , Prof, MD ad , , MD an , , MD ao , ap , aq , , PhD ae , , PhD g , , Prof, DPhil k , , MD ar , , PhD as , at , , PhD au , , MD av , , PhD aw , , Prof, MD ax , , MD ay , , Prof, MD az , , MD ba , , Prof, MD q , , MD bb , , MD bc , , PhD bd , , PhD be , , Prof, MD bf , bg ,   , Prof, PhD be , bh , bi , bj , , Prof, PhD bk , , Prof, MD bl , bm , , Prof, PhD bn , bo ,   , MSc bp , bq , , Prof, MD b , , Prof, MD br , , BSc bs , , MD bt ,   , PhD bq , bu , , Prof, MD bv , , Prof, MD bw , , MD bq , bx , , Prof, MD by , bz , , DPhil k , , Prof, PhD ca , , MD ao , ap , , Prof, MD ao , ap , , PhD ad , , Prof, MD h , , MD cb , , MD cc , , Prof, PhD al ,   , Prof, MD aj , cd , , Prof, MD ce , , Prof, MD cf , , MD cf , , Prof, PhD cf , , PhD af , , Prof, DPhil cg , , Prof, MD ch , , MSc y , , Prof, MD ci , cj , , MD ck , , PhD cl , , Prof, PhD cm , cn , , PhD ae , , Prof, MD co , , MD cp , , Prof, MD ad , cq , , PhD cr , , MD cs , , Prof, PhD y , , Prof, MD ct , , MD cu , , MD cv , , Prof, PhD cw , , Prof, FMedSci cw , , MD n , , Prof, FMedSci a , , PhD cx , , Prof, PhD u ,   , Prof, MD cy , , Prof, FRS k , , Prof, PhD cz , , Prof, PhD c , , MD a , , Prof, FMedSci a , ** , Emerging Risk Factors Collaboration/EPIC-CVD/UK Biobank Alcohol Study Group
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          Summary

          Background

          Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease.

          Methods

          We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose–response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th–95th percentile 1·04–13·5]) from 71 011 participants from 37 studies.

          Findings

          In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10–1·17), coronary disease excluding myocardial infarction (1·06, 1·00–1·11), heart failure (1·09, 1·03–1·15), fatal hypertensive disease (1·24, 1·15–1·33); and fatal aortic aneurysm (1·15, 1·03–1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91–0·97). In comparison to those who reported drinking >0–≤100 g per week, those who reported drinking >100–≤200 g per week, >200–≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1–2 years, or 4–5 years, respectively.

          Interpretation

          In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines.

          Funding

          UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

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          Most cited references57

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          Bias in meta-analysis detected by a simple, graphical test

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            Quantifying heterogeneity in a meta-analysis.

            The extent of heterogeneity in a meta-analysis partly determines the difficulty in drawing overall conclusions. This extent may be measured by estimating a between-study variance, but interpretation is then specific to a particular treatment effect metric. A test for the existence of heterogeneity exists, but depends on the number of studies in the meta-analysis. We develop measures of the impact of heterogeneity on a meta-analysis, from mathematical criteria, that are independent of the number of studies and the treatment effect metric. We derive and propose three suitable statistics: H is the square root of the chi2 heterogeneity statistic divided by its degrees of freedom; R is the ratio of the standard error of the underlying mean from a random effects meta-analysis to the standard error of a fixed effect meta-analytic estimate, and I2 is a transformation of (H) that describes the proportion of total variation in study estimates that is due to heterogeneity. We discuss interpretation, interval estimates and other properties of these measures and examine them in five example data sets showing different amounts of heterogeneity. We conclude that H and I2, which can usually be calculated for published meta-analyses, are particularly useful summaries of the impact of heterogeneity. One or both should be presented in published meta-analyses in preference to the test for heterogeneity. Copyright 2002 John Wiley & Sons, Ltd.
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              UK Biobank: An Open Access Resource for Identifying the Causes of a Wide Range of Complex Diseases of Middle and Old Age

              Cathie Sudlow and colleagues describe the UK Biobank, a large population-based prospective study, established to allow investigation of the genetic and non-genetic determinants of the diseases of middle and old age.
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                Author and article information

                Contributors
                Journal
                Lancet
                Lancet
                Lancet (London, England)
                Elsevier
                0140-6736
                1474-547X
                14 April 2018
                14 April 2018
                : 391
                : 10129
                : 1513-1523
                Affiliations
                [a ]Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
                [b ]Medical University Innsbruck, Innsbruck, Austria
                [c ]National Centre for Epidemiology and Population Health, Australian National University, Canberra, Australia
                [d ]MRC Biostatistics Unit, Cambridge Institute of Public Health, University of Cambridge, Cambridge, UK
                [e ]NIHR BRC Nutritional Biomarker Laboratory, University of Cambridge, Cambridge, UK
                [f ]Norwegian Institute of Public Health, Oslo, Norway
                [g ]National Institute for Public Health and the Environment, Bilthoven, Netherlands
                [h ]Julius Centre for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands
                [i ]Chiba Prefectural Institute of Public Health, Chiba, Japan
                [j ]Department of Community Medicine, University of Tromsø, Tromsø, Norway
                [k ]Nuffield Department of Population Health, Medical Sciences Division, University of Oxford, Oxford, UK
                [l ]The George Institute for Global Health, University of Sydney, Sydney, NSW, Australia
                [m ]Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
                [n ]School of Medicine, Johns Hopkins University, Baltimore, MD, USA
                [o ]THL-National Institute for Health and Welfare, Helsinki, Finland
                [p ]Copenhagen University Hospital, Copenhagen, Denmark
                [q ]Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
                [r ]School of Medicine, University of Western Australia, Perth, WA, Australia
                [s ]Fiona Stanley Hospital, Perth, WA, Australia
                [t ]Harry Perkins Institute of Medical Research, Perth, WA, Australia
                [u ]London School of Hygiene & Tropical Medicine, London, UK
                [v ]Department of Clinical Sciences, Malmö, Lund University, Malmö, Sweden
                [w ]Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
                [x ]CESP INSERM UMRS 1018, Villejuif Cedex, France
                [y ]Department of Epidemiology and Public Health, University College London, London, UK
                [z ]92 Deutsches Herzzentrum München, Technische Universität München, Munich, Germany, DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
                [aa ]University of Ulm Medical Center, Ulm, Germany
                [ab ]Department of Medicine, University of Padua, Padua, Italy
                [ac ]MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK
                [ad ]German Cancer Research Center (DKFZ), Heidelberg, Germany
                [ae ]Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
                [af ]Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
                [ag ]Department of Primary Care and Public Health, Cardiff University, Cardiff, UK
                [ah ]12 de Octubre Research Institute, CIBERESP, Madrid, Spain
                [ai ]Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
                [aj ]Department of Public Health, Aarhus University, Aarhus, Denmark
                [ak ]Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London, London, UK
                [al ]German Institute of Human Nutrition, Potsdam–Rehbrüke, Germany
                [am ]School of Community Health, Portland State University, Portland, OR, USA
                [an ]St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia
                [ao ]Hellenic Health Foundation, Athens, Greece
                [ap ]National and Kapodistrian University of Athens, Athens, Greece
                [aq ]Harvard TH Chan School of Public Health, Boston, MA, USA
                [ar ]Office of Public Health Studies, University of Hawaii, Honolulu, HI, USA
                [as ]Instituto de Salud Pública de Navarra, IdiSNA - Navarra Institute for Health Research, Pamplona, Spain
                [at ]Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Pamplona, Spain
                [au ]Columbia University Irving Medical Center, New York, NY, USA
                [av ]East Boston Neighborhood Health Center, Boston, MA, USA
                [aw ]Città della Salute e della Scienza di Torino Hospital, Turin, Italy
                [ax ]College of Public Health, The University of Iowa, Iowa City, IA, USA
                [ay ]Consejería de Sanidad del Principado de Asturias, Oviedo, Asturias, Spain
                [az ]Civic - M. Arezzo Hospital, ASP Ragusa, Italy
                [ba ]Duke Divinity School, Duke University, Durham, NC, USA
                [bb ]Department of Endocrinology and Metabolism, Hirosaki University, Hirosaki, Japan
                [bc ]Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy
                [bd ]Department of Biology, Tuskegee University, AL, USA
                [be ]Department of Community Medicine, UiT The Arctic University of Norway, Tromsø, Norway
                [bf ]University of Helsinki and Helsinki University Hospital, Helsinki, Finland
                [bg ]Center for Life Course Health Research, University of Oulu, Oulu, Finland
                [bh ]Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway
                [bi ]Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
                [bj ]Genetic Epidemiology Group, Folkhälsan Research Center, Faculty of Medicine, University of Helsinki, Helsinki, Finland
                [bk ]Medical University of South Carolina, Charleston, SC, USA
                [bl ]Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA, USA
                [bm ]Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA
                [bn ]Department of Agrotechnology and Food Sciences, University of Wageningen, Wageningen, Netherlands
                [bo ]Faculty of Medical Sciences, University of Groningen, Groningen, Netherlands
                [bp ]Escuela Andaluza de Salud Pública, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain
                [bq ]CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
                [br ]School of Medicine, Yale University, New Haven, CT, USA
                [bs ]Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
                [bt ]Cancer Research and Prevention Institute (ISPO), Florence, Italy
                [bu ]Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain
                [bv ]Usher Institute, University of Edinburgh, Edinburgh, UK
                [bw ]Department of Medical Sciences, Uppsala University, Uppsala, Sweden
                [bx ]Instituto BIO-Donostia, Basque Government, San Sebastian, Spain
                [by ]The University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia
                [bz ]Department of Preventive Medicine and Public Health, Kyushu University, Fukuoka, Japan
                [ca ]School of Health Science and Education, Harokopio University, Athens, Greece
                [cb ]Department of Family Medicine and Public Health, University of California, San Diego, CA, USA
                [cc ]EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, Netherlands
                [cd ]Aalborg University Hospital, Aalborg, Denmark
                [ce ]Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
                [cf ]Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, UK
                [cg ]Department of Kinesiology, Laval University, Quebec City, QC, Canada
                [ch ]Department of Medicine, University of Vermont, Burlington, VT, USA
                [ci ]Wake Forest University School of Medicine, Winston-Salem, NC, USA
                [cj ]Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
                [ck ]Department of Social and Environmental Medicine, Kanazawa Medical University, Ishikawa, Japan
                [cl ]Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia
                [cm ]Busselton Population Medical Research Institute, Busselton, WA, Australia
                [cn ]School of Population and Global Health, The University of Western Australia, Perth, WA, Australia
                [co ]Helmholtz Zentrum München German Research Center for Environmental Health, Germany
                [cp ]Danish Cancer Society Research Center, Copenhagen, Denmark
                [cq ]Division of Clinical Epidemiology and Aging Research, University of Heidelberg, Heidelberg, Germany
                [cr ]Istituto Superiore di Sanità, Rome, Italy
                [cs ]Institut Pasteur de Lille, Lille, France
                [ct ]Assmann-Stiftung für Prävention, Münster, Germany
                [cu ]The City College of New York, New York, NY, USA
                [cv ]Howard University Hospital, Washington DC, USA
                [cw ]Institute of Cardiovascular & Medical Sciences, University of Glasgow, Glasgow, UK
                [cx ]International Agency for Research on Cancer, Lyon, France
                [cy ]MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK
                [cz ]School of Population Health, The University of Auckland, Auckland, New Zealand
                Author notes
                [* ]Correspondence to: Dr Angela Wood, Emerging Risk Factors Collaboration and EPIC-CVD Coordinating Centres, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, CB1 8RN, UK amw79@ 123456medschl.cam.ac.uk
                [** ]Professor John Danesh, Emerging Risk Factors Collaboration and EPIC-CVD Coordinating Centres, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge CB1 8RN, UK jd292@ 123456medschl.cam.ac.uk
                [†]

                Other investigators of the Emerging Risk Factors Collaboration are listed in the appendix p 48

                Article
                S0140-6736(18)30134-X
                10.1016/S0140-6736(18)30134-X
                5899998
                29676281
                d5248696-e30e-47dc-a532-28a6cd5a809a
                © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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