Abstract
System noise was analyzed in 77 Affymetrix 6.0 samples from a previous clinical study of copy number variation (CNV). Twenty-three samples were classified as eligible for CNV detection, 29 samples as ineligible and 25 were classified as being of intermediate quality. New software (“noise-free-cnv”) was developed to visualize the data and reduce system noise. Fresh DNA preparations were more likely to yield eligible samples (p < 0.001). Eligible samples had higher rates of successfully genotyped SNPs (p < 0.001) and lower variance of signal intensities (p < 0.001), yielded fewer CNV findings after Birdview analysis (p < 0.001), and showed a tendency to yield fewer PennCNV calls (p = 0.053). The noise-free-cnv software visualized trend patterns of noise in the signal intensities across the ordered SNPs, including a wave pattern of noise, being co-linear with the banding pattern of metaphase chromosomes, as well as system deviations of individual probe sets (per-SNP noise). Wave noise and per-SNP noise occurred independently and could be separately removed from the samples. We recommend a two-step procedure of CNV validation, including noise reduction and visual inspection of all CNV calls, prior to molecular validation of a selected number of putative CNVs.
Highlights
Genomic copy number variation (CNV) was associated with a variety of clinical phenotypes [1,2,3,4,5,6].the study of CNV is of diagnostic importance
Our analysis had the following key findings: (1) Copy number samples may be noisy, which interferes—above a certain level of noise—with reliable identification of CNVs; (2) Eligible copy number samples were more likely when fresh DNA was used for microarray hybridization; (3) wave component and per-SNP component of noise are independent; (4) noise-free-cnv software enables noise reduction by subtracting wave and per-SNP noise components from samples; and (5) noise-free-cnv software supports the quality control of copy number data and the validation of copy number findings
The current noise-free-cnv version was developed for the analysis of SNP microarray samples and was not designed for noise reduction in array based comparative genomic hybridization samples
Summary
Genomic copy number variation (CNV) was associated with a variety of clinical phenotypes [1,2,3,4,5,6]. We focus on two major types of noise and present the noise-free-cnv software package for the visualization of copy number data and for the reduction of noise. This software enables large-scale inspection of CNV findings (produced by PennCNV [14], Birdview [15,16], or other specialized software packages). The LRR and BAF can be imported to PennCNV, to other CNV detections software packages (QuantiSNP, MAD), or to noise-free-cnv. The Affymetrix 6.0 microarrays used for CNV detection contain a total of 906,600 single nucleotide polymorphisms (SNPs) and 946,000 non-polymorphic copy number probes (CNPs) covering all human chromosomes. The notion of SNP is used for all analyzed probe sets (SNPs as well as CNPs)
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