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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


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          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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          UK Biobank: from concept to reality.

          The UK Biobank is a major UK collaborative research project to recruit and follow longitudinally the health of 500,000 volunteers aged between 40-69 years. It will provide important biological samples and environmental exposure data. As such, it will constitute a resource for many future investigations of the separate and combined effects of genetic, environmental and lifestyle factors on human morbidity, mortality and health.
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            What makes a good genetic association study?

            Genetic association studies are central to efforts to identify and characterise genomic variants underlying susceptibility to multifactorial disease. However, obtaining robust replication of initial association findings has proved difficult. Much of this inconsistency can be attributed to inadequacies in study design, implementation, and interpretation--inadequately powered sample groups are a major concern. Several additional factors affect the quality of any given association study, with appropriate sample-recruitment strategy, logical variant selection, minimum genotyping error, relevant data analysis, and valid interpretation all essential to generation of robust findings. Replication has a vital role in showing that associations that are identified reflect interesting biological processes rather than methodological quirks. For an unbiased view of the evidence for and against any particular association, study quality, rather than significance value, needs to play the dominant part.
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              Size matters: just how big is BIG?

              Background Despite earlier doubts, a string of recent successes indicates that if sample sizes are large enough, it is possible—both in theory and in practice—to identify and replicate genetic associations with common complex diseases. But human genome epidemiology is expensive and, from a strategic perspective, it is still unclear what ‘large enough’ really means. This question has critical implications for governments, funding agencies, bioscientists and the tax-paying public. Difficult strategic decisions with imposing price tags and important opportunity costs must be taken. Methods Conventional power calculations for case–control studies disregard many basic elements of analytic complexity—e.g. errors in clinical assessment, and the impact of unmeasured aetiological determinants—and can seriously underestimate true sample size requirements. This article describes, and applies, a rigorous simulation-based approach to power calculation that deals more comprehensively with analytic complexity and has been implemented on the web as ESPRESSO: (www.p3gobservatory.org/powercalculator.htm). Results Using this approach, the article explores the realistic power profile of stand-alone and nested case–control studies in a variety of settings and provides a robust quantitative foundation for determining the required sample size both of individual biobanks and of large disease-based consortia. Despite universal acknowledgment of the importance of large sample sizes, our results suggest that contemporary initiatives are still, at best, at the lower end of the range of desirable sample size. Insufficient power remains particularly problematic for studies exploring gene–gene or gene–environment interactions. Discussion Sample size calculation must be both accurate and realistic, and we must continue to strengthen national and international cooperation in the design, conduct, harmonization and integration of studies in human genome epidemiology.

                Author and article information

                PLoS Med
                PLoS Med
                PLoS Medicine
                Public Library of Science (San Francisco, CA USA )
                31 March 2015
                March 2015
                : 12
                : 3
                [1 ]University of Edinburgh, Edinburgh, United Kingdom
                [2 ]UK Biobank, Stockport, United Kingdom
                [3 ]University of Cardiff, Cardiff, United Kingdom
                [4 ]University of Oxford, Oxford, United Kingdom
                [5 ]University of Bristol, Bristol, United Kingdom
                [6 ]University of Cambridge, Cambridge, United Kingdom
                [7 ]Imperial College, London, United Kingdom
                [8 ]University of New South Wales, Sydney, Australia
                [9 ]University of Warwick, Warwick, United Kingdom
                [10 ]University of Glasgow, Glasgow, United Kingdom
                [11 ]University of Manchester, Manchester, United Kingdom
                Author notes

                All authors are current or past members of UK Biobank’s executive management team or steering committee, or of one of UK Biobank’s working groups. PM is a part-time employee and holder of stock and options in GlaxoSmithKline and has received attendance fees and contributed to panels convened by the Medical Research Council, a public funder of UK Biobank. JD has received research funding from The Wellcome Trust, British Heart Foundation, UK Medical Research Council, BUPA Foundation, Denka, diaDexus, European Research Council, European Union, Evelyn Trust, Fogarty International Centre, GlaxoSmithKline, Merck, National Heart, Lung and Blood Institute, National Health Service Blood and Transplant, National Institute for Health Research, National Institute of Neurological Disorders and Stroke, Novartis, Pfizer, Roche, UK Biobank. RC is the CEO and PI of UK Biobank, which is a charity set up by the MRC and Wellcome Trust to establish this prospective cohort as a resource for researchers from around the world. RC is a member of the Editorial Board of PLOS Medicine. All other authors have declared that no competing interests exist.

                Wrote the first draft of the manuscript: CS JG NA GO RC. Contributed to the writing of the manuscript: CS JG NA VB PB JD PD PE JG ML BL PM GO JP AS AY TS TP RC. ICMJE criteria for authorship read and met: CS JG NA VB PB JD PD PE JG ML BL PM GO JP AS AY TS TP RC. Agree with manuscript results and conclusions: CS JG NA VB PB JD PD PE JG ML BL PM GO JP AS AY TS TP RC.


                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                Page count
                Figures: 0, Tables: 3, Pages: 10
                UK Biobank has received funding from the UK Medical Research Council, Wellcome Trust, Department of Health, British Heart Foundation, Diabetes UK, Northwest Regional Development Agency, Scottish Government, and Welsh Assembly Government. As described in the manuscript, the MRC and Wellcome Trust played a key role in the decision to establish UK Biobank, a large, population-based, prospective, open access resource that would allow detailed investigations of the genetic and environmental determinants of the diseases of middle and old age. The MRC, Wellcome Trust, Department of Health, and Scottish Chief Scientist Office each have a representative on the UK Biobank Board. The MRC and Wellcome Trust fund the independent Ethics and Governance Council.
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