title: Statistical power and significance testing in large-scale genetic studies.
abstract: Significance testing was developed as an objective method for summarizing statistical evidence for a hypothesis. It has been widely adopted in genetic studies, including genome-wide association studies and, more recently, exome sequencing studies. However, significance testing in both genome-wide and exome-wide studies must adopt stringent significance thresholds to allow multiple testing, and it is useful only when studies have adequate statistical power, which depends on the characteristics of the phenotype and the putative genetic variant, as well as the study design. Here, we review the principles and applications of significance testing and power calculation, including recently proposed gene-based tests for rare variants.
authors.affiliation: Centre for Genomic Sciences, Jockey Club Building for Interdisciplinary Research; State Key Laboratory of Brain and Cognitive Sciences, and Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Pak C
authors.initials: PC
authors.lastname: Sham
authors.affiliation: 1] Center for Statistical Genetics, Icahn School of Medicine at Mount Sinai, New York 10029-6574, USA. [2] Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Shaun M
authors.initials: SM
authors.lastname: Purcell
mesh_terms: D016022:Case-Control Studies; D003627:Data Interpretation, Statistical; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing / Q000706:statistics & numerical data*; D055106:Genome-Wide Association Study / Q000592:standards / Q000706:statistics & numerical data*; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA / Q000379:methods / Q000706:statistics & numerical data
references.citation: Am J Hum Genet. 2012 Jan 13;90(1):7-24
references.pmid: 22243964
references.citation: J Natl Cancer Inst. 2004 Mar 17;96(6):434-42
references.pmid: 15026468
references.citation: Am J Hum Genet. 2013 Jul 11;93(1):42-53
references.pmid: 23768515
references.citation: Genet Epidemiol. 2008 May;32(4):381-5
references.pmid: 18348202
references.citation: Nat Rev Genet. 2009 Oct;10(10):681-90
references.pmid: 19763151
references.citation: Am J Hum Genet. 2013 Aug 8;93(2):236-48
references.pmid: 23891470
references.citation: Int J Epidemiol. 2012 Feb;41(1):273-86
references.pmid: 22253303
references.citation: Nucleic Acids Res. 2012 Apr;40(7):e53
references.pmid: 22241780
references.citation: Biometrika. 1949 Jun;36(Pt. 1-2):202-32
references.pmid: 18132092
references.citation: Am J Hum Genet. 2008 Sep;83(3):311-21
references.pmid: 18691683
references.citation: Science. 2012 Jul 6;337(6090):100-4
references.pmid: 22604722
references.citation: Am J Hum Genet. 2004 Sep;75(3):424-35
references.pmid: 15266393
references.citation: Am J Hum Genet. 2010 Jun 11;86(6):832-8
references.pmid: 20471002
references.citation: BMC Proc. 2011 Nov 29;5 Suppl 9:S33
references.pmid: 22373523
references.citation: Proc Natl Acad Sci U S A. 2014 Jan 28;111(4):E455-64
references.pmid: 24443550
references.citation: Eur J Hum Genet. 2013 Sep;21(9):1027-30
references.pmid: 23321613
references.citation: Genet Med. 2002 Mar-Apr;4(2):45-61
references.pmid: 11882781
references.citation: Ann Hum Genet. 2008 May;72(Pt 3):397-406
references.pmid: 18318785
references.citation: Am J Hum Genet. 2002 Aug;71(2):439-41
references.pmid: 12111669
references.citation: Bioinformatics. 2012 Oct 15;28(20):2703-4
references.pmid: 22914216
references.citation: Heredity (Edinb). 2005 Sep;95(3):221-7
references.pmid: 16077740
references.citation: PLoS One. 2012;7(2):e31358
references.pmid: 22348076
references.citation: PLoS Genet. 2013 Apr;9(4):e1003443
references.pmid: 23593035
references.citation: Trends Mol Med. 2003 Apr;9(4):135-8
references.pmid: 12727138
references.citation: Epidemiology. 2008 Sep;19(5):640-8
references.pmid: 18633328
references.citation: Genet Epidemiol. 2008 Apr;32(3):227-34
references.pmid: 18300295
references.citation: Nat Rev Genet. 2010 Nov;11(11):773-85
references.pmid: 20940738
references.citation: Nat Rev Genet. 2011 Sep 27;12(11):745-55
references.pmid: 21946919
references.citation: Eur J Hum Genet. 2013 Oct;21(10):1158-62
references.pmid: 23386037
references.citation: Nature. 2005 Oct 27;437(7063):1299-320
references.pmid: 16255080
references.citation: Hum Genet. 2012 May;131(5):747-56
references.pmid: 22143225
references.citation: PLoS Genet. 2013;9(8):e1003671
references.pmid: 23966865
references.citation: Behav Genet. 2009 Sep;39(5):571-9
references.pmid: 19568925
references.citation: Biometrika. 1948 May;35(Pts 1-2):157-75
references.pmid: 18867420
references.citation: PLoS Genet. 2009 Feb;5(2):e1000384
references.pmid: 19214210
references.citation: PLoS One. 2010 Dec 20;5(12):e14318
references.pmid: 21187953
references.citation: Biostatistics. 2008 Oct;9(4):621-34
references.pmid: 18310059
references.citation: Nat Genet. 2012 Jul 22;44(8):848-51
references.pmid: 22820511
references.citation: Genet Epidemiol. 2011;35 Suppl 1:S18-21
references.pmid: 22128053
references.citation: Biostatistics. 2012 Sep;13(4):762-75
references.pmid: 22699862
references.citation: Genet Epidemiol. 2009 Jan;33(1):79-86
references.pmid: 18642345
references.citation: Am J Hum Genet. 2000 May;66(5):1616-30
references.pmid: 10762547
references.citation: Am J Hum Genet. 1999 Jan;64(1):259-67
references.pmid: 9915965
references.citation: Am J Hum Genet. 2010 Dec 10;87(6):790-801
references.pmid: 21129725
references.citation: PLoS Genet. 2011 Mar;7(3):e1001322
references.pmid: 21408211
references.citation: Nat Genet. 2012 Feb 05;44(3):243-6
references.pmid: 22306651
references.citation: Int J Epidemiol. 2001 Oct;30(5):1035-40
references.pmid: 11689518
references.citation: Nat Rev Genet. 2006 Oct;7(10):781-91
references.pmid: 16983374
references.citation: Nat Genet. 2012 May 29;44(6):623-30
references.pmid: 22641211
references.citation: Am J Hum Genet. 2005 Mar;76(3):399-408
references.pmid: 15645388
references.citation: Nature. 2010 Jul 15;466(7304):368-72
references.pmid: 20531469
references.citation: Psychol Methods. 2000 Jun;5(2):241-301
references.pmid: 10937333
references.citation: Am J Hum Genet. 2011 Sep 9;89(3):354-67
references.pmid: 21885029
references.citation: Am J Hum Genet. 2004 Apr;74(4):765-9
references.pmid: 14997420
references.citation: Nat Rev Genet. 2005 Feb;6(2):109-18
references.pmid: 15716907
references.citation: Nat Rev Genet. 2005 Feb;6(2):95-108
references.pmid: 15716906
references.citation: Genet Epidemiol. 2008 Apr;32(3):246-54
references.pmid: 18228557
references.citation: PLoS One. 2009 Dec 02;4(12):e7969
references.pmid: 19956539
references.citation: Am J Hum Genet. 2007 Apr;80(4):727-39
references.pmid: 17357078
references.citation: Nat Methods. 2010 Apr;7(4):248-9
references.pmid: 20354512
references.citation: PLoS Genet. 2012;8(8):e1002793
references.pmid: 22876189
references.citation: Stat Med. 2002 Jan 15;21(1):35-50
references.pmid: 11782049
references.citation: BMC Genomics. 2008 Oct 31;9:516
references.pmid: 18976480
references.citation: Bioinformatics. 2003 Jan;19(1):149-50
references.pmid: 12499305
references.citation: Am J Hum Genet. 2007 Sep;81(3):559-75
references.pmid: 17701901
references.citation: Br J Psychiatry. 2014 Feb;204(2):108-14
references.pmid: 24311552
references.citation: Nat Rev Genet. 2008 May;9(5):356-69
references.pmid: 18398418
references.citation: BMC Proc. 2011 Nov 29;5 Suppl 9:S44
references.pmid: 22373328
references.citation: Neuron. 2012 Apr 26;74(2):285-99
references.pmid: 22542183
references.citation: Nat Genet. 2006 Aug;38(8):904-9
references.pmid: 16862161
references.citation: Nat Genet. 2010 Sep;42(9):790-3
references.pmid: 20711175
references.citation: PLoS One. 2011;6(8):e23221
references.pmid: 21850262
references.citation: Am J Hum Genet. 2011 Jul 15;89(1):82-93
references.pmid: 21737059
references.citation: Am J Hum Genet. 2007 Apr;80(4):605-15
references.pmid: 17357068
references.citation: Genet Epidemiol. 2011 Nov;35(7):606-19
references.pmid: 21769936
references.citation: Am J Hum Genet. 2008 May;82(5):1064-74
references.pmid: 18423522
references.citation: Hum Hered. 2011;72(4):228-36
references.pmid: 22189465
references.citation: Genet Epidemiol. 2008 Feb;32(2):179-85
references.pmid: 18200594
references.citation: Genome Biol. 2011 Sep 14;12(9):227
references.pmid: 21920052
references.citation: Nature. 2013 Jan 10;493(7431):216-20
references.pmid: 23201682
references.citation: Genet Epidemiol. 2011 Dec;35(8):790-9
references.pmid: 21922541
references.citation: Am J Hum Genet. 2003 Feb;72(2):498-9
references.pmid: 12596795
references.citation: PLoS Genet. 2012 Feb;8(2):e1002496
references.pmid: 22319458
references.citation: Am J Epidemiol. 2002 Mar 1;155(5):478-84
references.pmid: 11867360
references.citation: Science. 2009 Apr 17;324(5925):387-9
references.pmid: 19264985
references.citation: Behav Genet. 2011 Sep;41(5):768-75
references.pmid: 21305351
references.citation: Neuron. 2013 Jan 23;77(2):235-42
references.pmid: 23352160
references.citation: Genet Epidemiol. 2008 Sep;32(6):567-73
references.pmid: 18425821
references.citation: Genet Epidemiol. 2009 Nov;33(7):559-68
references.pmid: 19217024
references.citation: Hum Mol Genet. 2012 Dec 1;21(23):5209-21
references.pmid: 22936693
references.citation: Am J Hum Genet. 1999 Aug;65(2):578-80
references.pmid: 10417304
references.citation: PLoS Genet. 2009 May;5(5):e1000481
references.pmid: 19436704