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CN 34-1054/N

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Open AccessOpen Access JUSTC Original Paper

Poisson approximation variable threshold method in rare variants association study

  • Department of Statistics and Finance, School of Management, University of Science and Technology of China, Hefei 230026, China

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https://doi.org/10.3969/j.issn.0253-2778.2015.03.005
  • Received Date: 03 September 2014
  • Accepted Date: 26 February 2015
  • Rev Recd Date: 26 February 2015
  • Publish Date: 30 March 2015
    Abstract

  • Abstract

    The association study of rare genetic variants and disease traits as a supplement of genome-wide association study (GWAS) has achieved remarkable development and application. But the traditional association testing methods are not suitable for the rare variants association problem. Many new testing methods designed specifically for the rare variants have been proposed and applied. The variable-threshold (VT) method is one of them, which has achieved more power than the traditional association test methods. Here the occurrence of the mutation of rare variants was treated as a rare event. Poisson distribution was taken instead of binomial distribution and a new test statistic was proposed. Base on the VT method, a new test method was proposed, namely, the Poisson approximation variable threshold method (PAVT). Simulation results show that the new method has more power than VT method uniformly, and variant selection is more efficient.

    Abstract

    The association study of rare genetic variants and disease traits as a supplement of genome-wide association study (GWAS) has achieved remarkable development and application. But the traditional association testing methods are not suitable for the rare variants association problem. Many new testing methods designed specifically for the rare variants have been proposed and applied. The variable-threshold (VT) method is one of them, which has achieved more power than the traditional association test methods. Here the occurrence of the mutation of rare variants was treated as a rare event. Poisson distribution was taken instead of binomial distribution and a new test statistic was proposed. Base on the VT method, a new test method was proposed, namely, the Poisson approximation variable threshold method (PAVT). Simulation results show that the new method has more power than VT method uniformly, and variant selection is more efficient.
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    • References(14)
  • [1]
    Morgenthaler S, Thilly W G. A strategy to discover genes that carry multi-allelic or mono-allelic risk for common diseases: A cohort allelic sums test (CAST)[J]. Mutation Research, 2007, 615:28-56.
    [2]
    Li B, Leal S M. Methods for detecting association with rare variants for common diseases: Application to analysis of sequence data[J]. Am J Hum Genet, 2008, 83:311-321.
    [3]
    Madsen B E, Browning S R. A groupwise association test for rare mutations using a weighter sum statistic[J]. PLoS Genet, 2009, 5: e1000384.
    [4]
    Price A L, Kryukov G V, de Bakker P I W, et al. Pooled association tests for rare variants in exon-resequencing studies[J]. Am J Hum Genet, 2010, 86: 832-838.
    [5]
    Sha Q, Wang X, Wang X, et al. Detecting association of rare and common variants by testing an optimally weighted combination of variants[J]. Genetic Epidemiology, 2012, 36:561-71.
    [6]
    Fang H, Hou B, Wang Q, et al. Rare variants analysis by riskbased variable-threshold method[J]. Comput Biol Chem, 2013, 46:32-38.
    [7]
    Neale B M, Rivas M A, Voight B F, et al. Testing for an unusual distribution of rare variants[J]. PLoS Genet, 2011, 7: e1001322.
    [8]
    Wu M C, Lee S, Cai T, et al. Rare-variant association testing for sequencing data with the sequence kernel association test[J]. The American Journal of Human Genetics, 2011, 89:82-93.
    [9]
    Falk M, Hüsler J, Reiss R D. Laws of Small Numbers: Extremes and Rare Events[M]. 3rd ed. Birkhuser: Springer, 2011.
    [10]
    Pritchard J K. Are rare variants responsible for susceptibility to complex disease? [J]. Am J Hum Genet, 2001, 69:124-137.
    [11]
    Wrights S. Evolution in Mendelian populations[J]. Genetics, 1931, 16:97-159.
    [12]
    Ewens W J. Mathematical Population Genetics[M]. 2nd ed. Berlin: Springer, 2004.
    [13]
    Pritchard J K, Cox N J. The allelic architecture of human disease genes: common disease-common variant … or not?[J]. Hum Mol Genet, 2002, 11:2 417-2 423.
    [14]
    Pan W, Shen X T. Adaptive tests for association analysis of rare variants [J]. Genetic Epidemiology, 2011, 35: 381-388.
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    [1]
    Morgenthaler S, Thilly W G. A strategy to discover genes that carry multi-allelic or mono-allelic risk for common diseases: A cohort allelic sums test (CAST)[J]. Mutation Research, 2007, 615:28-56.
    [2]
    Li B, Leal S M. Methods for detecting association with rare variants for common diseases: Application to analysis of sequence data[J]. Am J Hum Genet, 2008, 83:311-321.
    [3]
    Madsen B E, Browning S R. A groupwise association test for rare mutations using a weighter sum statistic[J]. PLoS Genet, 2009, 5: e1000384.
    [4]
    Price A L, Kryukov G V, de Bakker P I W, et al. Pooled association tests for rare variants in exon-resequencing studies[J]. Am J Hum Genet, 2010, 86: 832-838.
    [5]
    Sha Q, Wang X, Wang X, et al. Detecting association of rare and common variants by testing an optimally weighted combination of variants[J]. Genetic Epidemiology, 2012, 36:561-71.
    [6]
    Fang H, Hou B, Wang Q, et al. Rare variants analysis by riskbased variable-threshold method[J]. Comput Biol Chem, 2013, 46:32-38.
    [7]
    Neale B M, Rivas M A, Voight B F, et al. Testing for an unusual distribution of rare variants[J]. PLoS Genet, 2011, 7: e1001322.
    [8]
    Wu M C, Lee S, Cai T, et al. Rare-variant association testing for sequencing data with the sequence kernel association test[J]. The American Journal of Human Genetics, 2011, 89:82-93.
    [9]
    Falk M, Hüsler J, Reiss R D. Laws of Small Numbers: Extremes and Rare Events[M]. 3rd ed. Birkhuser: Springer, 2011.
    [10]
    Pritchard J K. Are rare variants responsible for susceptibility to complex disease? [J]. Am J Hum Genet, 2001, 69:124-137.
    [11]
    Wrights S. Evolution in Mendelian populations[J]. Genetics, 1931, 16:97-159.
    [12]
    Ewens W J. Mathematical Population Genetics[M]. 2nd ed. Berlin: Springer, 2004.
    [13]
    Pritchard J K, Cox N J. The allelic architecture of human disease genes: common disease-common variant … or not?[J]. Hum Mol Genet, 2002, 11:2 417-2 423.
    [14]
    Pan W, Shen X T. Adaptive tests for association analysis of rare variants [J]. Genetic Epidemiology, 2011, 35: 381-388.
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