title: Association analysis using next-generation sequence data from publicly available control groups: the robust variance score statistic.
abstract: BACKGROUND
  Sufficiently powered case-control studies with next-generation sequence (NGS) data remain prohibitively expensive for many investigators. If feasible, a more efficient strategy would be to include publicly available sequenced controls. However, these studies can be confounded by differences in sequencing platform; alignment, single nucleotide polymorphism and variant calling algorithms; read depth; and selection thresholds. Assuming one can match cases and controls on the basis of ethnicity and other potential confounding factors, and one has access to the aligned reads in both groups, we investigate the effect of systematic differences in read depth and selection threshold when comparing allele frequencies between cases and controls. We propose a novel likelihood-based method, the robust variance score (RVS), that substitutes genotype calls by their expected values given observed sequence data.
  
  
  RESULTS
  We show theoretically that the RVS eliminates read depth bias in the estimation of minor allele frequency. We also demonstrate that, using simulated and real NGS data, the RVS method controls Type I error and has comparable power to the 'gold standard' analysis with the true underlying genotypes for both common and rare variants.
  
  
  METHODS
  An RVS R script and instructions can be found at strug.research.sickkids.ca, and at https://github.com/strug-lab/RVS.
  
  
  BACKGROUND
  lisa.strug@utoronto.ca
  
  
  BACKGROUND
  Supplementary data are available at Bioinformatics online.
authors.affiliation: Department of Statistical Science, University of Toronto, Toronto, ON, Canada, Program in Child Health Evaluative Sciences, the Hospital for Sick Children Research Institute, Toronto, ON, Canada, Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London, Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, Molecular and Population Genetics and NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
authors.forename: Andriy
authors.initials: A
authors.lastname: Derkach
authors.affiliation: Department of Statistical Science, University of Toronto, Toronto, ON, Canada, Program in Child Health Evaluative Sciences, the Hospital for Sick Children Research Institute, Toronto, ON, Canada, Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London, Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, Molecular and Population Genetics and NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
authors.forename: Theodore
authors.initials: T
authors.lastname: Chiang
authors.affiliation: Department of Statistical Science, University of Toronto, Toronto, ON, Canada, Program in Child Health Evaluative Sciences, the Hospital for Sick Children Research Institute, Toronto, ON, Canada, Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London, Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, Molecular and Population Genetics and NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
authors.forename: Jiafen
authors.initials: J
authors.lastname: Gong
authors.affiliation: Department of Statistical Science, University of Toronto, Toronto, ON, Canada, Program in Child Health Evaluative Sciences, the Hospital for Sick Children Research Institute, Toronto, ON, Canada, Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London, Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, Molecular and Population Genetics and NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
authors.forename: Laura
authors.initials: L
authors.lastname: Addis
authors.affiliation: Department of Statistical Science, University of Toronto, Toronto, ON, Canada, Program in Child Health Evaluative Sciences, the Hospital for Sick Children Research Institute, Toronto, ON, Canada, Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London, Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, Molecular and Population Genetics and NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
authors.forename: Sara
authors.initials: S
authors.lastname: Dobbins
authors.affiliation: Department of Statistical Science, University of Toronto, Toronto, ON, Canada, Program in Child Health Evaluative Sciences, the Hospital for Sick Children Research Institute, Toronto, ON, Canada, Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London, Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, Molecular and Population Genetics and NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
authors.affiliation: Department of Statistical Science, University of Toronto, Toronto, ON, Canada, Program in Child Health Evaluative Sciences, the Hospital for Sick Children Research Institute, Toronto, ON, Canada, Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London, Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, Molecular and Population Genetics and NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Houlston
authors.affiliation: Department of Statistical Science, University of Toronto, Toronto, ON, Canada, Program in Child Health Evaluative Sciences, the Hospital for Sick Children Research Institute, Toronto, ON, Canada, Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London, Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, Molecular and Population Genetics and NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
authors.forename: Deb K
authors.initials: DK
authors.lastname: Pal
authors.affiliation: Department of Statistical Science, University of Toronto, Toronto, ON, Canada, Program in Child Health Evaluative Sciences, the Hospital for Sick Children Research Institute, Toronto, ON, Canada, Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London, Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, Molecular and Population Genetics and NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, CanadaDepartment of Statistical Science, University of Toronto, Toronto, ON, Canada, Program in Child Health Evaluative Sciences, the Hospital for Sick Children Research Institute, Toronto, ON, Canada, Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London, Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, Molecular and Population Genetics and NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Strug
mesh_terms: D000465:Algorithms; D000704:Analysis of Variance; D016022:Case-Control Studies; D002648:Child; D019295:Computational Biology / Q000379:methods*; D035061:Control Groups; D003627:Data Interpretation, Statistical; D019305:Epilepsy, Rolandic / Q000235:genetics; D005787:Gene Frequency; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D016045:Human Genome Project; D006801:Humans; D016013:Likelihood Functions; D020641:Polymorphism, Single Nucleotide
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