title: Evaluating power and type 1 error in large pedigree analyses of binary traits.
abstract: Studying population isolates with large, complex pedigrees has many advantages for discovering genetic susceptibility loci; however, statistical analyses can be computationally challenging. Allelic association tests need to be corrected for relatedness among study participants, and linkage analyses require subdividing and simplifying the pedigree structures. We have extended GenomeSIMLA to simulate SNP data in complex pedigree structures based on an Amish pedigree to generate the same structure and distribution of sampled individuals. We evaluated type 1 error rates when no disease SNP was simulated and power when disease SNPs with recessive, additive, and dominant modes of inheritance and odds ratios of 1.1, 1.5, 2.0, and 5.0 were simulated. We generated subpedigrees with a maximum bit-size of 24 using PedCut and performed two-point and multipoint linkage using Merlin. We also ran MQLS on the subpedigrees and unified pedigree. We saw no inflation of type 1 error when running MQLS on either the whole pedigrees or the sub-pedigrees, and we saw low type 1 error for two-point and multipoint linkage. Power was reduced when running MQLS on the subpedigrees versus the whole pedigree, and power was low for two-point and multipoint linkage analyses of the subpedigrees. These data suggest that MQLS has appropriate type 1 error rates in our Amish pedigree structure, and while type 1 error does not seem to be affected when dividing the pedigree prior to linkage analysis, power to detect linkage is diminished when the pedigree is divided.
authors: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America.
authors: Anna C
authors: AC
authors: Cummings
authors: Eric
authors: E
authors: Torstenson
authors: Mary F
authors: MF
authors: Davis
authors: Laura N
authors: LN
authors: D'Aoust
authors: William K
authors: WK
authors: Scott
authors: Margaret A
authors: MA
authors: Pericak-Vance
authors: William S
authors: WS
authors: Bush
authors: Jonathan L
authors: JL
authors: Haines
mesh_terms: D000483:Alleles; D061365:Amish / Q000235:genetics*; D003198:Computer Simulation; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D040582:Inheritance Patterns; D008297:Male; D008957:Models, Genetic; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012984:Software
references: BMC Med Genet. 2006 Mar 03;7:19
references: 16515697
references: Nat Genet. 1995 Dec;11(4):402-8
references: 7493020
references: Hum Hered. 2007;64(4):234-42
references: 17570925
references: Am J Hum Genet. 2007 Jul;81(1):17-31
references: 17564960
references: Am J Hum Genet. 1993 Mar;52(3):506-16
references: 8447318
references: Am J Hum Genet. 2010 Feb 12;86(2):172-84
references: 20137780
references: Bioinformatics. 2002;18 Suppl 1:S189-98
references: 12169547
references: Nat Genet. 2002 Jan;30(1):97-101
references: 11731797
references: Am J Hum Genet. 1996 Jun;58(6):1347-63
references: 8651312
references: Am J Med Genet C Semin Med Genet. 2003 Aug 15;121C(1):32-7
references: 12888984
references: J Comput Biol. 2004;11(2-3):263-75
references: 15285892
references: Nat Genet. 2005 Oct;37(10):1015-6
references: 16195711
references: Ann Hum Genet. 2012 Sep;76(5):342-51
references: 22881374
references: Am J Med Genet B Neuropsychiatr Genet. 2006 Mar 5;141B(2):160-6
references: 16389594
references: Am J Hum Genet. 2000 Jul;67(1):146-54
references: 10825280
references: Hum Hered. 2005;59(1):41-60
references: 15802921
references: Ann Hum Genet. 2011 May;75(3):351-8
references: 21488853
references: Ann Hum Genet. 2006 Nov;70(Pt 6):965-70
references: 17044871
references: Hum Hered. 2000 Jul-Aug;50(4):211-23
references: 10782012
references: Am J Hum Genet. 2007 Aug;81(2):321-37
references: 17668381
references: Am J Hum Genet. 2001 Apr;68(4):1065-7
references: 11254459
references: Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):226-31
references: 19114657
references: Ann Hum Genet. 2008 Sep;72(Pt 5):621-9
references: 18505419
references: Eur J Hum Genet. 2008 Jul;16(7):854-60
references: 18301450
references: Am J Hum Genet. 2003 Sep;73(3):612-26
references: 12929084
references: Nat Genet. 2000 May;25(1):12-3
references: 10802644