title: Assessment of copy number variation using the Illumina Infinium 1M SNP-array: a comparison of methodological approaches in the Spanish Bladder Cancer/EPICURO study.
abstract: High-throughput single nucleotide polymorphism (SNP)-array technologies allow to investigate copy number variants (CNVs) in genome-wide scans and specific calling algorithms have been developed to determine CNV location and copy number. We report the results of a reliability analysis comparing data from 96 pairs of samples processed with CNVpartition, PennCNV, and QuantiSNP for Infinium Illumina Human 1Million probe chip data. We also performed a validity assessment with multiplex ligation-dependent probe amplification (MLPA) as a reference standard. The number of CNVs per individual varied according to the calling algorithm. Higher numbers of CNVs were detected in saliva than in blood DNA samples regardless of the algorithm used. All algorithms presented low agreement with mean Kappa Index (KI) <66. PennCNV was the most reliable algorithm (KI(w=) 98.96) when assessing the number of copies. The agreement observed in detecting CNV was higher in blood than in saliva samples. When comparing to MLPA, all algorithms identified poorly known copy aberrations (sensitivity = 0.19-0.28). In contrast, specificity was very high (0.97-0.99). Once a CNV was detected, the number of copies was truly assessed (sensitivity >0.62). Our results indicate that the current calling algorithms should be improved for high performance CNV analysis in genome-wide scans. Further refinement is required to assess CNVs as risk factors in complex diseases.
authors.affiliation: Centro Nacional de Investigaciones Oncológicas (CNIO) Madrid, Spain.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Marenne
authors.forename: Benjamín
authors.initials: B
authors.lastname: Rodríguez-Santiago
authors.forename: Montserrat García
authors.initials: MG
authors.lastname: Closas
authors.forename: Luis
authors.initials: L
authors.lastname: Pérez-Jurado
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Rothman
authors.forename: Daniel
authors.initials: D
authors.lastname: Rico
authors.forename: Guillermo
authors.initials: G
authors.lastname: Pita
authors.forename: David G
authors.initials: DG
authors.lastname: Pisano
authors.forename: Manolis
authors.initials: M
authors.lastname: Kogevinas
authors.forename: Debra T
authors.initials: DT
authors.lastname: Silverman
authors.forename: Alfonso
authors.initials: A
authors.lastname: Valencia
authors.forename: Francisco X
authors.initials: FX
authors.lastname: Real
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Génin
authors.forename: Núria
authors.initials: N
authors.lastname: Malats
mesh_terms: D000465:Algorithms; D056915:DNA Copy Number Variations; D015894:Genome, Human; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D001749:Urinary Bladder Neoplasms / Q000235:genetics*