Tomasz Gambin, Pawel Stankiewicz, Maciej Sykulski, Anna Gambin


Array-comparative genomic hybridization (aCGH) technology enables rapid, high-resolution analysis of genomic rearrangements. With the use of it, genome copy number changes and rearrangement breakpoints can be detected and analyzed at resolutions down to a few kilobases. An exon array CGH approach proposed recently accurately measures copy-number changes of individual exons in the human genome. The crucial and highly non-trivial starting task is the design of an array, i.e. the choice of appropriate (multi)set of oligos. The success of the whole high-level analysis depends on the quality of the design. Also, the comparison of several alternative designs of array CGH constitutes an important step in development of new diagnostic chip. In this paper we deal with these two often neglected issues. We propose new approach to measure the quality of array CGH designs. Our measures reflect the robustness of rearrangements detection to the noise (mostly experimental measurement error). The method is parametrized by the segmentation algorithm used to identify aberrations. We implemented the efficient Monte Carlo method for testing noise robustness within DNAcopy procedure. Developed framework has been applied to evaluation of functional quality of several optimized array designs.


  1. Baldocchi, R. A., Glynne, R. J., Chin, K., Kowbel, D., Collins, C., Mack, D. H., and Gray, J. W. (2005). Design considerations for array CGH to oligonucleotide arrays. Cytometry. Part A: The Journal of the International Society for Analytical Cytology, 67(2):129- 136.
  2. Barrett, M. T., Scheffer, A., Ben-Dor, A., Sampas, N., Lipson, D., Kincaid, R., Tsang, P., Curry, B., Baird, K., Meltzer, P. S., Yakhini, Z., Bruhn, L., and Laderman, S. (2004). Comparative genomic hybridization using oligonucleotide microarrays and total genomic DNA. Proceedings of the National Academy of Sciences of the United States of America, 101(51):1776517770.
  3. Ben-Yaacov, E. and Eldar, Y. C. (2008). A fast and flexible method for the segmentation of aCGH data. Bioinformatics (Oxford, England), 24(16):i139-145.
  4. Cahan, P., Godfrey, L. E., Eis, P. S., Richmond, T. A., Selzer, R. R., Brent, M., McLeod, H. L., Ley, T. J., and Graubert, T. A. (2008). wuHMM: a robust algorithm to detect DNA copy number variation using long oligonucleotide microarray data. Nucleic Acids Research, 36(7):e41.
  5. Carter (2002). Comparative analysis of comparative genomic hybridization micro array technologies: report of a workshop sponsored by the wellcome trust. Cytometry, 49(2):43-48.
  6. Caserta, D., Benkhalifa, M., Baldi, M., Fiorentino, F., Qumsiyeh, M., and Moscarini, M. (2008). Genome profiling of ovarian adenocarcinomas using pangenomic BACs microarray comparative genomic hybridization. Molecular Cytogenetics, 1:10.
  7. Chen, H. H., Hsu, F., Jiang, Y., Tsai, M., Yang, P., Meltzer, P. S., Chuang, E. Y., and Chen, Y. (2008). A probedensity-based analysis method for array CGH data: sim ulation, normalization and centralization. Bioinformatics (Oxford, England), 24(16):1749-1756.
  8. Coe, B. P., Ylstra, B., Carvalho, B., Meijer, G. A., Macaulay, C., and Lam, W. L. (2007). Resolving the resolution of array CGH. Genomics, 89(5):647-653.
  9. Daz-Uriarte, R. and Rueda, O. M. (2007). ADaCGH: a parallelized web-based application and r package for the analysis of aCGH data. PloS One, 2(1):e737.
  10. Hampel, F. R., Ronchetti, E. M., Rousseeuw, P. J., and Stahel, W. A. (2005). Robust Statistics: The Approach Based on Influence Functions. Wiley Series in Probability and Statistics.
  11. Hijum, S. A. F. T. V., Baerends, R. J. S., Zomer, A. L., Karsens, H. A., Martin-Requena, V., Trelles, O., Kok, J., and Kuipers, O. P. (2008). Supervised lowess normalization of comparative genome hybridization data-application to lactococcal strain comparisons. BMC Bioinformatics, 9:93.
  12. Iourov, I. Y., Vorsanova, S. G., and Yurov, Y. B. (2008). Chromosomal mosaicism goes global. Molecular Cytogenetics, 1:26.
  13. Kreil, D. P. and Russell, R. R. (2005). There is no silver bullet-a guide to low-level data transforms and normalisation methods for microarray data. Briefings in Bioinformatics, 6(1):86-97.
  14. Lai, C., Horlings, H. M., de Vijver, M. J. V., Beers, E. H. V., Nederlof, P. M., Wessels, L. F., and Reinders, M. J. (2007). SIRAC: supervised identification of regions of aberration in aCGH datasets. BMC Bioinformatics, 8:422.
  15. Lemoine, S., Combes, F., and Crom, S. L. (2009). An evaluation of custom microarray applications: the oligonucleotide design challenge. Nucleic Acids Research, 37(6):17261739.
  16. Lipson, D., Aumann, Y., Ben-Dor, A., Linial, N., and Yakhini, Z. (2006). Efficient calculation of interval scores for DNA copy number data analysis. Journal of Computational Biology: A Journal of Computational Molecular Cell Biology, 13(2):215-228.
  17. Lipson, D., Webb, P., and Yakhini, Z. (2002). Designing specific oligonucleotide probes for the entire s. cerevisiae transcriptome. Algorithms in Bioinformatics, pages 491-505.
  18. Lipson, D., Yakhini, Z., and Aumann, Y. (2007). Optimization of probe coverage for high-resolution oligonucleotide acgh. Bioinformatics, 23:e77-83.
  19. Liu, J., Mohammed, J., Carter, J., Ranka, S., Kahveci, T., and Baudis, M. (2006). Distance-based clustering of CGH data. Bioinformatics, 22(16):1971-1978.
  20. Lupski, J. R. (2009). Genomic disorders ten years on. Genome Medicine, 1(4):42.
  21. O'Hagan, R. C., Brennan, C. W., Strahs, A., Zhang, X., Kannan, K., Donovan, M., Cauwels, C., Sharpless, N. E., Wong, W. H., and Chin, L. (2003). Array comparative genome hybridization for tumor classification and gene discovery in mouse models of malignant melanoma. Cancer Res, 63:5352-5356.
  22. Olshen, A. B., Venkatraman, E. S., Lucito, R., and Wigler, M. (2004). Circular binary segmentation for the analysis of array-based dna copy number data. Biostatistics (Oxford, England), 5:557-72.
  23. Perry, G. H., Ben-Dor, A., Tsalenko, A., Sampas, N., Rodriguez-Revenga, L., Tran, C. W., Scheffer, A., Steinfeld, I., Tsang, P., Yamada, N. A., Park, H. S., Kim, J.-I., Seo, J.-S., Yakhini, Z., Laderman, S., Bruhn, L., and Lee, C. (2008). The fine-scale and complex architecture of human copy-number variation. American journal of human genetics, 82:685-95.
  24. Pollack, J. R., Perou, C. M., Alizadeh, A. A., Eisen, M. B., Pergamenschikov, A., Williams, C. F., Jeffrey, S. S., Botstein, D., and Brown, P. O. (1999). Genome-wide analysis of dna copy-number changes using cdna microarrays. Nature genetics, 23:41-6.
  25. Shaw, C. J., Shaw, C. A., Yu, W., Stankiewicz, P., White, L. D., Beaudet, A. L., and Lupski, J. R. (2004). Comparative genomic hybridisation using a proximal 17p bac/pac array detects rearrangements responsible for four genomic disorders. J Med Genet, 41:113-119.
  26. Snijders, A. M., Schmidt, B. L., Fridlyand, J., Dekker, N., Pinkel, D., Jordan, R. C. K., and Albertson, D. G. (2005). Rare amplicons implicate frequent deregulation of cell fate specification pathways in oral squamous cell carcinoma. Oncogene, 24:4232-42.
  27. Staaf, J., Jonsson, G., Ringner, M., and Vallon-Christersson, J. (2007). Normalization of array-cgh data: influence of copy number imbalances. BMC Genomics, 8:382.
  28. Thomas, R., Scott, A., Langford, C. F., Fosmire, S. P., Jubala, C. M., Lorentzen, T. D., Hitte, C., Karlsson, E. K., Kirkness, E., Ostrander, E. A., Galibert, F., Lindblad-Toh, K., Modiano, J. F., and Breen, M. (2005). Construction of a 2-Mb resolution BAC microarray for CGH analysis of canine tumors. Genome Research, 15(12):18311837.
  29. Wang, Y., Makedon, F., and Pearlman, J. (2006). Tumor classification based on dna copy number aberrations determined using snp arrays. Oncology reports, 15 Spec no.:1057-9.
  30. Willenbrock, H. and Fridlyand, J. (2005). A comparison study: applying segmentation to array cgh data for downstream analyses. Bioinformatics, 21:4084-4091.
  31. Xia, X.-Q., Jia, Z., Porwollik, S., Long, F., Hoemme, C., Ye, K., Muller-Tidow, C., McClelland, M., and Wang, Y. (2010). Evaluating oligonucleotide properties for DNA microarray probe design. Nucl. Acids Res., 38(11):e121.

Paper Citation

in Harvard Style

Gambin T., Stankiewicz P., Sykulski M. and Gambin A. (2011). ROBUSTNESS OF EXON CGH ARRAY DESIGNS . In Proceedings of the International Conference on Bioinformatics Models, Methods and Algorithms - Volume 1: BIOINFORMATICS, (BIOSTEC 2011) ISBN 978-989-8425-36-2, pages 173-182. DOI: 10.5220/0003153201730182

in Bibtex Style

author={Tomasz Gambin and Pawel Stankiewicz and Maciej Sykulski and Anna Gambin},
booktitle={Proceedings of the International Conference on Bioinformatics Models, Methods and Algorithms - Volume 1: BIOINFORMATICS, (BIOSTEC 2011)},

in EndNote Style

JO - Proceedings of the International Conference on Bioinformatics Models, Methods and Algorithms - Volume 1: BIOINFORMATICS, (BIOSTEC 2011)
SN - 978-989-8425-36-2
AU - Gambin T.
AU - Stankiewicz P.
AU - Sykulski M.
AU - Gambin A.
PY - 2011
SP - 173
EP - 182
DO - 10.5220/0003153201730182