title: The Repertoire Dissimilarity Index as a method to compare lymphocyte receptor repertoires.
abstract: BACKGROUND
  The B and T cells of the human adaptive immune system leverage a highly diverse repertoire of antigen-specific receptors to protect the human body from pathogens. The sequencing and analysis of immune repertoires is emerging as an important tool to understand immune responses, whether beneficial or harmful (in the case of autoimmunity). However, methods for studying these repertoires, and for directly comparing different immune repertoires, are lacking.
  
  
  RESULTS
  In this paper, we present a non-parametric method for directly comparing sequencing repertoires, with the goal of rigorously quantifying differences in V, D, and J gene segment utilization. This method, referred to as the Repertoire Dissimilarity Index (RDI), uses a bootstrapped subsampling approach to account for variance in sequencing depth, and, coupled with a data simulation approach, allows for direct quantification of the average variation between repertoires. We use the RDI method to recapitulate known differences in the formation of the CD4+and CD8+T cell repertoires, and further show that antigen-driven activation of naïve CD8+T cells is more selective than in the CD4+repertoire, resulting in a more specialized CD8+memory repertoire.
  
  
  CONCLUSIONS
  We prove that the RDI method is an accurate and versatile method for comparisons of immune repertoires. The RDI method has been implemented as an R package, and is available for download through Bitbucket.
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, 94305, CA, USA.|Genentech, Inc., 1 DNA Way, MS 93, South San Francisco, 94080, CA, USA.
authors.forename: Christopher R
authors.identifier: http://orcid.org/0000-0003-2270-5565
authors.initials: CR
authors.lastname: Bolen
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, 94305, CA, USA.
authors.forename: Florian
authors.initials: F
authors.lastname: Rubelt
authors.affiliation: Interdepartmental Program in Computational Biology and Bioinformatics, Department of Computational Biology & Bioinformatics, Yale University, New Haven, 06520, CT, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Vander Heiden
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, 94305, CA, USA. mmdavis@stanford.edu.|Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, 94305, CA, USA. mmdavis@stanford.edu.|Institute of Immunity, Department of Microbiology and Immunology, Transplantation and Infection, Stanford University School of Medicine, Stanford, 94305, CA, USA. mmdavis@stanford.edu.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Davis
mesh_terms: D000465:Algorithms; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D015329:Gene Rearrangement, T-Lymphocyte; D014644:Genetic Variation; D006801:Humans; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000235:genetics; D017423:Sequence Analysis, RNA / Q000379:methods*; D060152:V(D)J Recombination
chemical_list: D011948:Receptors, Antigen, T-Cell
keywords: Immunology; Nonparametric methods; Repertoire sequencing