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Kernel-Based Aggregation of Marker-Level Genetic Association Tests Involving Copy-Number Variation
Microarrays 2013, 2(4), 284-303; doi:10.3390/microarrays2040284

Copy Number Studies in Noisy Samples

1 Neurology Department, University of Heidelberg, INF 400, Heidelberg D69120, Germany 2 Division of Molecular Genetic Epidemiology, German Cancer Research Center, INF 280, Heidelberg D69120, Germany 3 Stroke Unit and Department of Neurology, University Hospital Basel, Petersgraben 4, Basel CH4031, Switzerland These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 20 September 2013 / Revised: 24 October 2013 / Accepted: 25 October 2013 / Published: 6 November 2013
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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.
Keywords: copy number variation (CNV); variance; wave noise; per-SNP noise; noise-free-cnv software; noise reduction; validation of CNV findings copy number variation (CNV); variance; wave noise; per-SNP noise; noise-free-cnv software; noise reduction; validation of CNV findings
This is an open access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Ginsbach, P.; Chen, B.; Jiang, Y.; Engelter, S.T.; Grond-Ginsbach, C. Copy Number Studies in Noisy Samples. Microarrays 2013, 2, 284-303.

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