title: Preserving biological heterogeneity with a permuted surrogate variable analysis for genomics batch correction.
abstract: BACKGROUND
  Sample source, procurement process and other technical variations introduce batch effects into genomics data. Algorithms to remove these artifacts enhance differences between known biological covariates, but also carry potential concern of removing intragroup biological heterogeneity and thus any personalized genomic signatures. As a result, accurate identification of novel subtypes from batch-corrected genomics data is challenging using standard algorithms designed to remove batch effects for class comparison analyses. Nor can batch effects be corrected reliably in future applications of genomics-based clinical tests, in which the biological groups are by definition unknown a priori.
  
  
  RESULTS
  Therefore, we assess the extent to which various batch correction algorithms remove true biological heterogeneity. We also introduce an algorithm, permuted-SVA (pSVA), using a new statistical model that is blind to biological covariates to correct for technical artifacts while retaining biological heterogeneity in genomic data. This algorithm facilitated accurate subtype identification in head and neck cancer from gene expression data in both formalin-fixed and frozen samples. When applied to predict Human Papillomavirus (HPV) status, pSVA improved cross-study validation even if the sample batches were highly confounded with HPV status in the training set.
  
  
  METHODS
  All analyses were performed using R version 2.15.0. The code and data used to generate the results of this manuscript is available from https://sourceforge.net/projects/psva.
authors.affiliation: Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21205, USA, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119333, Russia, Research Institute for Genetics and Selection of Industrial Microorganisms "GosNIIGenetika", Moscow 117545, Russia, Department of Statistics and Biostatistics, Rutgers University, NJ 08854, USA and Division of Allergy & Clinical Immunology, Department of Medicine, Johns Hopkins University, Baltimore, MD 21224, USA.
authors.forename: Hilary S
authors.initials: HS
authors.lastname: Parker
authors.affiliation: Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21205, USA, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119333, Russia, Research Institute for Genetics and Selection of Industrial Microorganisms "GosNIIGenetika", Moscow 117545, Russia, Department of Statistics and Biostatistics, Rutgers University, NJ 08854, USA and Division of Allergy & Clinical Immunology, Department of Medicine, Johns Hopkins University, Baltimore, MD 21224, USA.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Leek
authors.affiliation: Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21205, USA, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119333, Russia, Research Institute for Genetics and Selection of Industrial Microorganisms "GosNIIGenetika", Moscow 117545, Russia, Department of Statistics and Biostatistics, Rutgers University, NJ 08854, USA and Division of Allergy & Clinical Immunology, Department of Medicine, Johns Hopkins University, Baltimore, MD 21224, USA Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21205, USA, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119333, Russia, Research Institute for Genetics and Selection of Industrial Microorganisms "GosNIIGenetika", Moscow 117545, Russia, Department of Statistics and Biostatistics, Rutgers University, NJ 08854, USA and Division of Allergy & Clinical Immunology, Department of Medicine, Johns Hopkins University, Baltimore, MD 21224, USA Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21205, USA, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119333, Russia, Research Institute for Genetics and Selection of Industrial Microorganisms "GosNIIGenetika", Moscow 117545, Russia, Department of Statistics and Biostatistics, Rutgers University, NJ 08854, USA and Division of Allergy & Clinical Immunology, Department of Medicine, Johns Hopkins University, Baltimore, MD 21224, USA.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Favorov
authors.affiliation: Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21205, USA, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119333, Russia, Research Institute for Genetics and Selection of Industrial Microorganisms "GosNIIGenetika", Moscow 117545, Russia, Department of Statistics and Biostatistics, Rutgers University, NJ 08854, USA and Division of Allergy & Clinical Immunology, Department of Medicine, Johns Hopkins University, Baltimore, MD 21224, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Considine
authors.affiliation: Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21205, USA, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119333, Russia, Research Institute for Genetics and Selection of Industrial Microorganisms "GosNIIGenetika", Moscow 117545, Russia, Department of Statistics and Biostatistics, Rutgers University, NJ 08854, USA and Division of Allergy & Clinical Immunology, Department of Medicine, Johns Hopkins University, Baltimore, MD 21224, USA.
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Xia
authors.affiliation: Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21205, USA, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119333, Russia, Research Institute for Genetics and Selection of Industrial Microorganisms "GosNIIGenetika", Moscow 117545, Russia, Department of Statistics and Biostatistics, Rutgers University, NJ 08854, USA and Division of Allergy & Clinical Immunology, Department of Medicine, Johns Hopkins University, Baltimore, MD 21224, USA.
authors.forename: Sameer
authors.initials: S
authors.lastname: Chavan
authors.affiliation: Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21205, USA, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119333, Russia, Research Institute for Genetics and Selection of Industrial Microorganisms "GosNIIGenetika", Moscow 117545, Russia, Department of Statistics and Biostatistics, Rutgers University, NJ 08854, USA and Division of Allergy & Clinical Immunology, Department of Medicine, Johns Hopkins University, Baltimore, MD 21224, USA.
authors.forename: Christine H
authors.initials: CH
authors.lastname: Chung
authors.affiliation: Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21205, USA, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119333, Russia, Research Institute for Genetics and Selection of Industrial Microorganisms "GosNIIGenetika", Moscow 117545, Russia, Department of Statistics and Biostatistics, Rutgers University, NJ 08854, USA and Division of Allergy & Clinical Immunology, Department of Medicine, Johns Hopkins University, Baltimore, MD 21224, USA.
authors.forename: Elana J
authors.initials: EJ
authors.lastname: Fertig
mesh_terms: D000465:Algorithms; D016477:Artifacts; D019295:Computational Biology / Q000379:methods; D023281:Genomics / Q000379:methods*; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000821:virology; D006801:Humans; D015233:Models, Statistical; D030361:Papillomavirus Infections / Q000175:diagnosis*; D015203:Reproducibility of Results; D012984:Software