title: Dynamic model based algorithms for screening and genotyping over 100 K SNPs on oligonucleotide microarrays.
abstract: BACKGROUND
  A high density of single nucleotide polymorphism (SNP) coverage on the genome is desirable and often an essential requirement for population genetics studies. Region-specific or chromosome-specific linkage studies also benefit from the availability of as many high quality SNPs as possible. The availability of millions of SNPs from both Perlegen and the public domain and the development of an efficient microarray-based assay for genotyping SNPs has brought up some interesting analytical challenges. Effective methods for the selection of optimal subsets of SNPs spanning the genome and methods for accurately calling genotypes from probe hybridization patterns have enabled the development of a new microarray-based system for robustly genotyping over 100,000 SNPs per sample.
  
  
  RESULTS
  We introduce a new dynamic model-based algorithm (DM) for screening over 3 million SNPs and genotyping over 100,000 SNPs. The model is based on four possible underlying states: Null, A, AB and B for each probe quartet. We calculate a probe-level log likelihood for each model and then select between the four competing models with an SNP-level statistical aggregation across multiple probe quartets to provide a high-quality genotype call along with a quality measure of the call. We assess performance with HapMap reference genotypes, informative Mendelian inheritance relationship in families, and consistency between DM and another genotype classification method. At a call rate of 95.91% the concordance with reference genotypes from the HapMap Project is 99.81% based on over 1.5 million genotypes, the Mendelian error rate is 0.018% based on 10 trios, and the consistency between DM and MPAM is 99.90% at a comparable rate of 97.18%. We also develop methods for SNP selection and optimal probe selection.
  
  
  BACKGROUND
  The DM algorithm is available in Affymetrix's Genotyping Tools software package and in Affymetrix's GDAS software package. See http://www.affymetrix.com for further information. 10 K and 100 K mapping array data are available on the Affymetrix website.
authors.affiliation: Affymetrix, Inc., Santa Clara, CA 95051, USA. xiaojun_di@affymetrix.com
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Di
authors.forename: Hajime
authors.initials: H
authors.lastname: Matsuzaki
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Webster
authors.forename: Earl
authors.initials: E
authors.lastname: Hubbell
authors.forename: Guoying
authors.initials: G
authors.lastname: Liu
authors.forename: Shoulian
authors.initials: S
authors.lastname: Dong
authors.forename: Dan
authors.initials: D
authors.lastname: Bartell
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.forename: Richard
authors.initials: R
authors.lastname: Chiles
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Yang
authors.forename: Mei-mei
authors.initials: MM
authors.lastname: Shen
authors.forename: David
authors.initials: D
authors.lastname: Kulp
authors.forename: Giulia C
authors.initials: GC
authors.lastname: Kennedy
authors.forename: Rui
authors.initials: R
authors.lastname: Mei
authors.forename: Keith W
authors.initials: KW
authors.lastname: Jones
authors.forename: Simon
authors.initials: S
authors.lastname: Cawley
mesh_terms: D000465:Algorithms; D003198:Computer Simulation; D004252:DNA Mutational Analysis / Q000379:methods*; D005820:Genetic Testing / Q000379:methods*; D005838:Genotype; D006801:Humans; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016415:Sequence Alignment / Q000379:methods*; D017422:Sequence Analysis, DNA / Q000379:methods*; D012984:Software