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Vol. 73, No. 3, 2012
Issue release date: July 2012
Section title: Original Paper
Free Access
Hum Hered 2012;73:139–147

Two-Stage Extreme Phenotype Sequencing Design for Discovering and Testing Common and Rare Genetic Variants: Efficiency and Power

Kang G.a, c · Lin D.a · Hakonarson H.b · Chen J.a
aDepartment of Biostatistics and Epidemiology, University of Pennsylvania, and bCenter for Applied Genomics, The Joseph Stokes Jr. Research Institute, The Children’s Hospital of Philadelphia, Philadelphia, Pa., and cDepartment of Biostatistics, St. Jude Children’s Research Hospital, Memphis, Tenn., USA
email Corresponding Author

Jinbo Chen, PhD

Department of Biostatistics and Epidemiology

University of Pennsylvania Perelman School of Medicine

Philadelphia, PA 19104 (USA)

Tel. +1 215 746 3915, E-Mail


  1. Stankiewicz P, Lupski JR: Structural variation in the human genome and its role in disease. Ann Rev Med 2010;61:437–455.
  2. Schaid DJ, Sinnwell JP: Two-stage case-control designs for rare genetic variants. Hum Genet 2010;127:659–668.

    External Resources

  3. Bansal V, Tewhey R, LeProust EM, Schork NJ: Efficient and cost effective population resequencing by pooling and in-solution hybridization. PLoS One 2011;6:e18353.
  4. Kim SY, Li Y, Guo Y, Li R, Holmkvist J, et al: Design of association studies with pooled or un-pooled next-generation sequencing data. Genet Epidemiol 2010;34:479–491.
  5. Cirulli ET, Goldstein DB: Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nature Rev Genet 2010;11:415–425.
  6. Guey LT, Kravic J, Melander O, Burtt NP, Laramie JM, Lyssenko V, Jonsson A, Lindholm E, Tuomi T, Isomaa B, Nilsson P, Almgren P, Kathiresan S, Groop L, Seymour AB, Altshuler D, Voight BF: Power in the phenotypic extremes: a simulation study of power in discovery and replication of rare variants. Genet Epidemiol 2011;32:236–246.
  7. Almasy L, Dyer TD, Peralta JM, Kent JW Jr, Charlesworth JC, Curran JE, Blangero J: Genetic Analysis Workshop 17 mini-exome simulation. BMC Proc 2011;5(suppl 9):S2.

    External Resources

  8. Basu S, Pan W: Comparison of statistical tests for disease association with rare variants. Genet Epidemiol 2011;35:606–619.

    External Resources

  9. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, Maller J, Sklar P, de Bakker PIW, Daly MJ, Sham PC: PLINK: a tool set for whole-genome association and population-based linkage analysis. Am J Hum Genet 2007;81:559–575.
  10. Li B, Leal SM: Methods for detecting associations with rare variants for common diseases: application to analysis of sequence data. Am J Hum Genet 2008;83:311–321.
  11. Pan W: Asymptotic tests of association with multiple SNPs in linkage disequilibrium. Genet Epidemiol 2009;33:497–507.
  12. Wang T, Elston RC: Improved power by use of a weighted score test for linkage disequilibrium mapping. Am J Hum Genet 2007;80:353–360.
  13. Ionita-Laza I, Buxbaum JD, Laird NM, Lange C: A new testing strategy to identify rare variants with either risk or protective effect on disease. PLoS Genet 2011;7:e1001289.
  14. Pritchard JK: Are rare variants responsible for susceptibility to common diseases? Am J Hum Genet 2001;69:124–137.
  15. Madsen BE, Browning SR: A groupwise association test for rare mutations using a weighted sum statistic. PLoS Genet 2009;5:e1000384.
  16. Dickson SP, Wang K, Krantz I, Hakonarson H, Goldstein DB: Rare variants create synthetic genome-wide associations. PLoS Biol 2010;8:e1000294.
  17. Siu H, Zhu Y, Jin L, Xiong M: Implication of next-generation sequencing on association studies. BMC Genomics 2011;12:322.

    External Resources

  18. Wu MC, Lee S, Cai T, Li Y, Boehnke M, Lin X: Rare-variant association testing for sequencing data with the sequence kernel association test. Am J Hum Genet 2011;89:82–93.
  19. Li BS, Leal SM: Discovery of rare variants via sequencing: implications for the design of complex trait association studies. PLoS Genet 2009;5:e1000481.
  20. Ionita-Laza I, Lange C, Laird NM: Estimating the number of unseen variants in the human genome. Proc Natl Acad Sci USA 2009;106:5008–5013.
  21. Liu D, Ghosh D, Lin X: Estimation and testing for the effect of a genetic pathway on a disease outcome using logistic kernel machine regression via logistic mixed models. BMC Bioinformatics 2008;9:292.
  22. Neale BM, Rivas MA, Voight BF, Altshuler D, Devlin B, Ogho-Melander M, Katherisan S, Purcell SM, Roeder K, Daly MJ: Testing for an unusual distribution of rare variants. PLoS Genet 2011;7:e1001322.
  23. Han F, Pan W: A data-adaptive sum test for disease association with multiple common or rare variants. Hum Hered 2010;70:42–54.