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Detecting genomic aberrations using products in a multiscale analysis.

ABSTRACT: Genomic instability, such as copy-number losses and gains, occurs in many genetic diseases. Recent technology developments enable researchers to measure copy numbers at tens of thousands of markers simultaneously. In this article, we propose a nonparametric approach for detecting the locations of copy-number changes and provide a measure of significance for each change point. The proposed test is based on seeking scale-based changes in the sequence of copy numbers, which is ordered by the marker locations along the chromosome. The method leads to a natural way to estimate the null distribution for the test of a change point and adjusted p-values for the significance of a change point using a step-down maxT permutation algorithm to control the family-wise error rate. A simulation study investigates the finite sample performance of the proposed method and compares it with a more standard sequential testing method. The method is illustrated using two real data sets.

SUBMITTER: Yu X

PROVIDER: S-EPMC2942992 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Detecting genomic aberrations using products in a multiscale analysis.

Yu Xuesong X Randolph Timothy W TW Tang Hua H Hsu Li L

Biometrics 20100901 3

Genomic instability, such as copy-number losses and gains, occurs in many genetic diseases. Recent technology developments enable researchers to measure copy numbers at tens of thousands of markers simultaneously. In this article, we propose a nonparametric approach for detecting the locations of copy-number changes and provide a measure of significance for each change point. The proposed test is based on seeking scale-based changes in the sequence of copy numbers, which is ordered by the marker ...[more]

PMID: 19817738

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Project description:Multiscale signal processing techniques such as wavelet filtering have proved to be particularly successful in predicting exon sequences. Traditional wavelet predictor is domain filtering, and enforces exon features by weighting nucleotide values with coefficients. Such a measure performs linear filtering and is not suitable for preserving the short coding exons and the exon-intron boundaries. This paper describes a prediction framework that is capable of non-linearly processing DNA sequences while achieving high prediction rates. There are two key contributions. The first is the introduction of a genomic-inspired multiscale bilateral filtering (MSBF) which exploits both weighting coefficients in the spatial domain and nucleotide similarity in the range. Similarly to wavelet transform, the MSBF is also defined as a weighted sum of nucleotides. The difference is that the MSBF takes into account the variation of nucleotides at a specific codon position. The second contribution is the exploitation of inter-scale correlation in MSBF domain to find the inter-scale dependency on the differences between the exon signal and the background noise. This favourite property is used to sharp the important structures while weakening noise. Three benchmark data sets have been used in the evaluation of considered methods. By comparison with four existing techniques, the prediction results demonstrate that: the proposed method reveals at least improvement of 4.1%, 50.5%, 25.6%, 2.5%, 10.8%, 15.5%, 11.1%, 12.3%, 9.2% and 2.4% on the exons length of 1-24, 25-49, 50-74, 75-99, 100-124, 125-149, 150-174, 175-199, 200-299 and 300-300+, respectively. The MSBF of its nonlinear nature is good at energy compaction, which makes it capable of locating the sharp variations around short exons. The direct scale multiplication of coefficients at several adjacent scales obviously enhanced exon features while the noise contents were suppressed. We show that the non-linear nature and correlation-based property achieved in proposed predictor is greater than that for traditional filtering, which leads to better exon prediction performance. There are some possible applications of this predictor. Its good localization and protection of sharp variations will make the predictor be suitable to perform fault diagnosis of aero-engine.

Project description:Genomic aberrations recurrent in a particular cancer type can be important prognostic markers for tumor progression. Typically in early tumorigenesis, cells incur a breakdown of the DNA replication machinery that results in an accumulation of genomic aberrations in the form of duplications, deletions, translocations, and other genomic alterations. Microarray methods allow for finer mapping of these aberrations than has previously been possible; however, data processing and analysis methods have not taken full advantage of this higher resolution. Attention has primarily been given to analysis on the single sample level, where multiple adjacent probes are necessarily used as replicates for the local region containing their target sequences. However, regions of concordant aberration can be short enough to be detected by only one, or very few, array elements. We describe a method called Multiple Sample Analysis for assessing the significance of concordant genomic aberrations across multiple experiments that does not require a-priori definition of aberration calls for each sample. If there are multiple samples, representing a class, then by exploiting the replication across samples our method can detect concordant aberrations at much higher resolution than can be derived from current single sample approaches. Additionally, this method provides a meaningful approach to addressing population-based questions such as determining important regions for a cancer subtype of interest or determining regions of copy number variation in a population. Multiple Sample Analysis also provides single sample aberration calls in the locations of significant concordance, producing high resolution calls per sample, in concordant regions. The approach is demonstrated on a dataset representing a challenging but important resource: breast tumors that have been formalin-fixed, paraffin-embedded, archived, and subsequently UV-laser capture microdissected and hybridized to two-channel BAC arrays using an amplification protocol. We demonstrate the accurate detection on simulated data, and on real datasets involving known regions of aberration within subtypes of breast cancer at a resolution consistent with that of the array. Similarly, we apply our method to previously published datasets, including a 250K SNP array, and verify known results as well as detect novel regions of concordant aberration. The algorithm has been fully implemented and tested and is freely available as a Java application at http://www.cbil.upenn.edu/MSA.

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Detecting genomic aberrations using products in a multiscale analysis.

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Detecting genomic aberrations using products in a multiscale analysis.

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