title: Likelihood-based complex trait association testing for arbitrary depth sequencing data.
abstract: In next generation sequencing (NGS)-based genetic studies, researchers typically perform genotype calling first and then apply standard genotype-based methods for association testing. However, such a two-step approach ignores genotype calling uncertainty in the association testing step and may incur power loss and/or inflated type-I error. In the recent literature, a few robust and efficient likelihood based methods including both likelihood ratio test (LRT) and score test have been proposed to carry out association testing without intermediate genotype calling. These methods take genotype calling uncertainty into account by directly incorporating genotype likelihood function (GLF) of NGS data into association analysis. However, existing LRT methods are computationally demanding or do not allow covariate adjustment; while existing score tests are not applicable to markers with low minor allele frequency (MAF). We provide an LRT allowing flexible covariate adjustment, develop a statistically more powerful score test and propose a combination strategy (UNC combo) to leverage the advantages of both tests. We have carried out extensive simulations to evaluate the performance of our proposed LRT and score test. Simulations and real data analysis demonstrate the advantages of our proposed combination strategy: it offers a satisfactory trade-off in terms of computational efficiency, applicability (accommodating both common variants and variants with low MAF) and statistical power, particularly for the analysis of quantitative trait where the power gain can be up to ∼60% when the causal variant is of low frequency (MAF < 0.01).
  
  
  METHODS
  UNC combo and the associated R files, including documentation, examples, are available at http://www.unc.edu/∼yunmli/UNCcombo/
  
  
  BACKGROUND
  yunli@med.unc.edu
  
  
  BACKGROUND
  Supplementary data are available at Bioinformatics online.
authors.affiliation: Department of Biostatistics, Department of Genetics, Department of Computer Science, University of North Carolina, Chapel Hill, NC 27599 USA, Merck Research Laboratories, North Wales, PA, USA, School of Statistics, Renmin University of China, Beijing, People's Republic of China, Department of Statistics, North Carolina State University, Raleigh, NC, 27607 USA, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA and Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA Department of Biostatistics, Department of Genetics, Department of Computer Science, University of North Carolina, Chapel Hill, NC 27599 USA, Merck Research Laboratories, North Wales, PA, USA, School of Statistics, Renmin University of China, Beijing, People's Republic of China, Department of Statistics, North Carolina State University, Raleigh, NC, 27607 USA, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA and Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA Department of Biostatistics, Department of Genetics, Department of Computer Science, University of North Carolina, Chapel Hill, NC 27599 USA, Merck Research Laboratories, North Wales, PA, USA, School of Statistics, Renmin University of China, Beijing, People's Republic of China, Department of Statistics, North Carolina State University, Raleigh, NC, 27607 USA, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA and Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Yan
authors.affiliation: Department of Biostatistics, Department of Genetics, Department of Computer Science, University of North Carolina, Chapel Hill, NC 27599 USA, Merck Research Laboratories, North Wales, PA, USA, School of Statistics, Renmin University of China, Beijing, People's Republic of China, Department of Statistics, North Carolina State University, Raleigh, NC, 27607 USA, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA and Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA.
authors.forename: Shuai
authors.initials: S
authors.lastname: Yuan
authors.affiliation: Department of Biostatistics, Department of Genetics, Department of Computer Science, University of North Carolina, Chapel Hill, NC 27599 USA, Merck Research Laboratories, North Wales, PA, USA, School of Statistics, Renmin University of China, Beijing, People's Republic of China, Department of Statistics, North Carolina State University, Raleigh, NC, 27607 USA, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA and Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA Department of Biostatistics, Department of Genetics, Department of Computer Science, University of North Carolina, Chapel Hill, NC 27599 USA, Merck Research Laboratories, North Wales, PA, USA, School of Statistics, Renmin University of China, Beijing, People's Republic of China, Department of Statistics, North Carolina State University, Raleigh, NC, 27607 USA, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA and Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA Department of Biostatistics, Department of Genetics, Department of Computer Science, University of North Carolina, Chapel Hill, NC 27599 USA, Merck Research Laboratories, North Wales, PA, USA, School of Statistics, Renmin University of China, Beijing, People's Republic of China, Department of Statistics, North Carolina State University, Raleigh, NC, 27607 USA, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA and Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Biostatistics, Department of Genetics, Department of Computer Science, University of North Carolina, Chapel Hill, NC 27599 USA, Merck Research Laboratories, North Wales, PA, USA, School of Statistics, Renmin University of China, Beijing, People's Republic of China, Department of Statistics, North Carolina State University, Raleigh, NC, 27607 USA, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA and Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA.
authors.forename: Baqun
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Biostatistics, Department of Genetics, Department of Computer Science, University of North Carolina, Chapel Hill, NC 27599 USA, Merck Research Laboratories, North Wales, PA, USA, School of Statistics, Renmin University of China, Beijing, People's Republic of China, Department of Statistics, North Carolina State University, Raleigh, NC, 27607 USA, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA and Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Biostatistics, Department of Genetics, Department of Computer Science, University of North Carolina, Chapel Hill, NC 27599 USA, Merck Research Laboratories, North Wales, PA, USA, School of Statistics, Renmin University of China, Beijing, People's Republic of China, Department of Statistics, North Carolina State University, Raleigh, NC, 27607 USA, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA and Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA.
authors.forename: Guolian
authors.initials: G
authors.lastname: Kang
authors.affiliation: Department of Biostatistics, Department of Genetics, Department of Computer Science, University of North Carolina, Chapel Hill, NC 27599 USA, Merck Research Laboratories, North Wales, PA, USA, School of Statistics, Renmin University of China, Beijing, People's Republic of China, Department of Statistics, North Carolina State University, Raleigh, NC, 27607 USA, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA and Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Byrnes
authors.affiliation: Department of Biostatistics, Department of Genetics, Department of Computer Science, University of North Carolina, Chapel Hill, NC 27599 USA, Merck Research Laboratories, North Wales, PA, USA, School of Statistics, Renmin University of China, Beijing, People's Republic of China, Department of Statistics, North Carolina State University, Raleigh, NC, 27607 USA, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA and Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA Department of Biostatistics, Department of Genetics, Department of Computer Science, University of North Carolina, Chapel Hill, NC 27599 USA, Merck Research Laboratories, North Wales, PA, USA, School of Statistics, Renmin University of China, Beijing, People's Republic of China, Department of Statistics, North Carolina State University, Raleigh, NC, 27607 USA, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA and Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA Department of Biostatistics, Department of Genetics, Department of Computer Science, University of North Carolina, Chapel Hill, NC 27599 USA, Merck Research Laboratories, North Wales, PA, USA, School of Statistics, Renmin University of China, Beijing, People's Republic of China, Department of Statistics, North Carolina State University, Raleigh, NC, 27607 USA, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA and Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
mesh_terms: D003198:Computer Simulation; D005787:Gene Frequency; D056726:Genetic Association Studies; D005819:Genetic Markers; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D016013:Likelihood Functions; D010641:Phenotype; D040641:Quantitative Trait Loci; D017422:Sequence Analysis, DNA / Q000379:methods*
chemical_list: D005819:Genetic Markers