title: A computational method for genotype calling in family-based sequencing data.
abstract: BACKGROUND
  As sequencing technologies can help researchers detect common and rare variants across the human genome in many individuals, it is known that jointly calling genotypes across multiple individuals based on linkage disequilibrium (LD) can facilitate the analysis of low to modest coverage sequence data. However, genotype-calling methods for family-based sequence data, particularly for complex families beyond parent-offspring trios, are still lacking.
  
  
  RESULTS
  In this study, first, we proposed an algorithm that considers both linkage disequilibrium (LD) patterns and familial transmission in nuclear and multi-generational families while retaining the computational efficiency. Second, we extended our method to incorporate external reference panels to analyze family-based sequence data with a small sample size. In simulation studies, we show that modeling multiple offspring can dramatically increase genotype calling accuracy and reduce phasing and Mendelian errors, especially at low to modest coverage. In addition, we show that using external panels can greatly facilitate genotype calling of sequencing data with a small number of individuals. We applied our method to a whole genome sequencing study of 1339 individuals at ~10X coverage from the Minnesota Center for Twin and Family Research.
  
  
  CONCLUSIONS
  The aggregated results show that our methods significantly outperform existing ones that ignore family constraints or LD information. We anticipate that our method will be useful for many ongoing family-based sequencing projects. We have implemented our methods efficiently in a C++ program FamLDCaller, which is available from http://www.pitt.edu/~wec47/famldcaller.html.
authors.affiliation: Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, 20892, USA. lun-ching.chang@nih.gov.
authors.forename: Lun-Ching
authors.initials: LC
authors.lastname: Chang
authors.affiliation: Department of Molecular Physiology & Biophysics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. bingshan.li@vanderbilt.edu.
authors.forename: Bingshan
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, 15261, USA. zhf9@pitt.edu.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Fang
authors.affiliation: Department of Psychology & Neuroscience, Institute for Behavioral Genetics, University of Colorado, Boulder, CO, 80309, USA. scott.vrieze@colorado.edu.
authors.forename: Scott
authors.initials: S
authors.lastname: Vrieze
authors.affiliation: Department of Psychology, University of Minnesota, Minneapolis, MN, 55455, USA. mcgue001@umn.edu.
authors.forename: Matt
authors.initials: M
authors.lastname: McGue
authors.affiliation: Department of Psychology, University of Minnesota, Minneapolis, MN, 55455, USA. wiacono@umn.edu.
authors.forename: William G
authors.initials: WG
authors.lastname: Iacono
authors.affiliation: Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, 15261, USA. ctseng@pitt.edu.
authors.forename: George C
authors.initials: GC
authors.lastname: Tseng
authors.affiliation: Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, 15261, USA. wei.chen@chp.edu.|Division of Pulmonary Medicine, Allergy and Immunology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, 15224, USA. wei.chen@chp.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
mesh_terms: D000465:Algorithms; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D030541:Databases, Genetic; D015894:Genome, Human; D060005:Genotyping Techniques / Q000379:methods*; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA