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A multilevel model to address batch effects in copy number estimation using SNP arrays

BIOSTATISTICS 2011年第1期12卷 33-50页

作者： Scharpf, Robert B. Ruczinski, Ingo Carvalho, Benilton Doan, Betty Chakravarti, Aravinda Irizarry, Rafael A. Johns Hopkins Univ Sch Med Dept Oncol Baltimore MD 21205 USA Johns Hopkins Bloomberg Sch Publ Hlth Dept Biostat Baltimore MD 21205 USA Johns Hopkins Univ Sch Med Inst Med Genet Baltimore MD 21205 USA

Submicroscopic changes in chromosomal DNA copy number dosage are common and have been implicated in many heritable diseases and cancers. Recent high-throughput technologies have a resolution that permits the detection of segmental changes in DNA copy number that span thousands of base pairs in the genome. Genomewide association studies (GWAS) may simultaneously screen for copy number phenotype and single nucleotide polymorphism (SNP) phenotype associations as part of the analytic strategy. However, genomewide array analyses are particularly susceptible to batch effects as the logistics of preparing DNA and processing thousands of arrays often involves multiple laboratories and technicians, or changes over calendar time to the reagents and laboratory equipment. Failure to adjust for batch effects can lead to incorrect inference and requires inefficient post hoc quality control procedures to exclude regions that are associated with batch. Our work extends previous model-based approaches for copy number estimation by explicitly modeling batch and using shrinkage to improve locus-specific estimates of copy number uncertainty. Key features of this approach include the use of biallelic genotype calls from experimental data to estimate batch-specific and locus-specific parameters of background and signal without the requirement of training data. We illustrate these ideas using a study of bipolar disease and a study of chromosome 21 trisomy. The former has batch effects that dominate much of the observed variation in the quantile-normalized intensities, while the latter illustrates the robustness of our approach to a data set in which approximately 27% of the samples have altered copy number. Locus-specific estimates of copy number can be plotted on the copy number scale to investigate mosaicism and guide the choice of appropriate downstream approaches for smoothing the copy number as a function of physical position. The software is open source and implemented in the R pack

关键词： Bioinformatics Hierarchical models DNA copy number variations single nucleotide polymorphism array

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A forward-backward fragment assembling algorithm for the identification of genomic amplification and deletion breakpoints using high-density single nucleotide polymorphism (SNP) array

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BMC BIOINFORMATICS 2007年第1期8卷 1-11页

作者： Yu, Tianwei Ye, Hui Sun, Wei Li, Ker-Chau Chen, Zugen Jacobs, Sharoni Bailey, Dione K. Wong, David T. Zhou, Xiaofeng Univ Illinois Coll Dent Ctr Mol Biol Oral Dis Chicago IL 60680 USA Univ Illinois Rollins Sch Publ Hlth Dept Biostat Chicago IL 60680 USA Shanghai Jiao Tong Univ Shanghai Childrens Med Ctr Shanghai Peoples R China Univ Calif Los Angeles Dept Stat Los Angeles CA 90024 USA Univ Calif Los Angeles Dept Human Genet & Microarray Core Los Angeles CA 90024 USA Affymetrix Inc Santa Clara CA USA Univ Calif Los Angeles Dent Res Inst Sch Dent David Geffen Sch Med Los Angeles CA 90024 USA Univ Calif Los Angeles Henry Samueli Sch Engn Los Angeles CA 90024 USA Univ Calif Los Angeles Jonsson Comprehens Canc Ctr Los Angeles CA 90024 USA Sun Yat Sen Univ Guanghua Sch Guangzhou Peoples R China Sun Yat Sen Univ Res Inst Stomatol Guangzhou Peoples R China

Background: DNA copy number aberration (CNA) is one of the key characteristics of cancer cells. Recent studies demonstrated the feasibility of utilizing high density single nucleotide polymorphism (SNP) genotyping arrays to detect CNA. Compared with the two-color array-based comparative genomic hybridization (array-CGH), the SNP arrays offer much higher probe density and lower signal-to-noise ratio at the single SNP level. To accurately identify small segments of CNA from SNP array data, segmentation methods that are sensitive to CNA while resistant to noise are required. Results: We have developed a highly sensitive algorithm for the edge detection of copy number data which is especially suitable for the SNP array-based copy number data. The method consists of an over-sensitive edge-detection step and a test-based forward-backward edge selection step. Conclusion: Using simulations constructed from real experimental data, the method shows high sensitivity and specificity in detecting small copy number changes in focused regions. The method is implemented in an R package FASeg, which includes data processing and visualization utilities, as well as libraries for processing Affymetrix SNP array data.

关键词： single nucleotide polymorphism Marker Copy Number Change single nucleotide polymorphism array Copy Number Aberration True Edge

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Landscape of somatic allelic imbalances and copy number alterations in HER2-amplified breast cancer

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BREAST CANCER RESEARCH 2011年第6期13卷 1-15页

作者： Staaf, Johan Jonsson, Goran Ringner, Markus Baldetorp, Bo Borg, Ake Lund Univ Dept Oncol SE-22185 Lund Sweden Skane Univ Hosp SE-22185 Lund Sweden Lund Univ CREATE Hlth Strateg Ctr Translat Canc Res SE-22184 Lund Sweden Lund Univ Biomed Ctr Lund Strateg Res Ctr Stem Cell Biol & Cell Therap SE-22184 Lund Sweden

Introduction: Human epidermal growth factor receptor 2 (HER2)-amplified breast cancer represents a clinically well-defined subgroup due to availability of targeted treatment. However, HER2-amplified tumors have been shown to be heterogeneous at the genomic level by genome-wide microarray analyses, pointing towards a need of further investigations for identification of recurrent copy number alterations and delineation of patterns of allelic imbalance. Methods: High-density whole genome array-based comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) array data from 260 HER2-amplified breast tumors or cell lines, and 346 HER2-negative breast cancers with molecular subtype information were assembled from different repositories. Copy number alteration (CNA), loss-of-heterozygosity (LOH), copy number neutral allelic imbalance (CNN-AI), subclonal CNA and patterns of tumor DNA ploidy were analyzed using bioinformatical methods such as genomic identification of significant targets in cancer (GISTIC) and genome alteration print (GAP). The patterns of tumor ploidy were confirmed in 338 unrelated breast cancers analyzed by DNA flow cytometry with concurrent BAC aCGH and gene expression data. Results: A core set of 36 genomic regions commonly affected by copy number gain or loss was identified by integrating results with a previous study, together comprising > 400 HER2-amplified tumors. While CNN-AI frequency appeared evenly distributed over chromosomes in HER2-amplified tumors, not targeting specific regions and often < 20% in frequency, the occurrence of LOH was strongly associated with regions of copy number loss. HER2-amplified and HER2-negative tumors stratified by molecular subtypes displayed different patterns of LOH and CNN-AI, with basal-like tumors showing highest frequencies followed by HER2-amplified and luminal B cases. Tumor aneuploidy was strongly associated with increasing levels of LOH, CNN-AI, CNAs and occurrence of subclonal copy

关键词： Breast Cancer single nucleotide polymorphism array Copy Number Loss PAM50 Subtype Tumor Ploidy

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Laser capture microdissection (LCM) and whole genome amplification (WGA) of DNA from normal breast tissue - Optimization for genome wide array analyses

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BMC Research Notes 2011年第1期4卷 1-7页

作者： Aaltonen, Kristina E. Ebbesson, Anna Wigerup, Caroline Hedenfalk, Ingrid Department of Oncology Clinical Sciences Lund Lund University Barngatan 2B Lund SE-221 85 Sweden Department of Laboratory Medicine Center for Molecular Pathology Lund University University Hospital MAS Malmö SE-20502 Sweden

Background: Laser capture microdissection (LCM) can be applied to tissues where cells of interest are distinguishable from surrounding cell populations. Here, we have optimized LCM for fresh frozen normal breast tissue where large amounts of fat can cause problems during microdissection. Since the amount of DNA needed for genome wide analyses, such as single nucleotide polymorphism (SNP) arrays, is often greater than what can be obtained from the dissected tissue, we have compared three different whole genome amplification (WGA) kits for amplification of DNA from LCM material. In addition, the genome wide profiling methods commonly used today require extremely high DNA quality compared to PCR based techniques and DNA quality is thus critical for successful downstream analyses. Findings: We found that by using FrameSlides without glass backing for LCM and treating the slides with acetone after staining, the problems caused by excessive fat could be significantly decreased. The amount of DNA obtained after extraction from LCM tissue was not sufficient for direct SNP array analysis in our material. However, the two WGA kits based on Phi29 polymerase technology (Repli-g^® (Qiagen) and GenomiPhi (GE Healthcare)) gave relatively long amplification products, and amplified DNA from Repli-g^® gave call rates in the subsequent SNP analysis close to those from non-amplified DNA. Furthermore, the quality of the input DNA for WGA was found to be essential for successful SNP array results and initial DNA fragmentation problems could be reduced by switching from a regular halogen lamp to a VIS-LED lamp during LCM. Conclusions: LCM must be optimized to work satisfactorily in difficult tissues. We describe a work flow for fresh frozen normal breast tissue where fat is inclined to cause problems if sample treatment is not adapted to this tissue. We also show that the Phi29-based Repli-g^® WGA kit (Qiagen) is a feasible approach to amplify DNA of high qua

关键词： Normal Breast Tissue Laser Capture Microdissection single nucleotide polymorphism array Whole Genome Amplification Multiple Displacement Amplification

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A response to Yu et al.: "A forward-backward fragment assembling algorithm for the identification of genomic amplification and deletion breakpoints using high-density single nucleotide polymorphism (SNP) array", BMC Bioinformatics 2007, 8: 145

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BMC BIOINFORMATICS 2007年第1期8卷 1-9页

作者： Rueda, Oscar M. Diaz-Uriarte, Ramon Spanish Nat Canc Ctr CNIO Stat Comp Team Struct Biol & Biocomp Programme Madrid 28029 Spain

Background: Yu et al. (BMC Bioinformatics 2007,8: 145+) have recently compared the performance of several methods for the detection of genomic amplification and deletion breakpoints using data from high-density single nucleotide polymorphism arrays. One of the methods compared is our non-homogenous Hidden Markov Model approach. Our approach uses Markov Chain Monte Carlo for inference, but Yu et al. ran the sampler for a severely insufficient number of iterations for a Markov Chain Monte Carlo-based method. Moreover, they did not use the appropriate reference level for the non-altered state. Methods: We rerun the analysis in Yu et al. using appropriate settings for both the Markov Chain Monte Carlo iterations and the reference level. Additionally, to show how easy it is to obtain answers to additional specific questions, we have added a new analysis targeted specifically to the detection of breakpoints. Results: The reanalysis shows that the performance of our method is comparable to that of the other methods analyzed. In addition, we can provide probabilities of a given spot being a breakpoint, something unique among the methods examined. Conclusion: Markov Chain Monte Carlo methods require using a sufficient number of iterations before they can be assumed to yield samples from the distribution of interest. Running our method with too small a number of iterations cannot be representative of its performance. Moreover, our analysis shows how our original approach can be easily adapted to answer specific additional questions (e. g., identify edges).

关键词： Markov Chain Monte Carlo Hide State Markov Chain Monte Carlo Algorithm Viterbi Algorithm single nucleotide polymorphism array

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Genomic study of the response of chicken to highly pathogenic avian influenza virus

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BMC Proceedings 2011年第4期5卷 1-4页

作者： Sironi, Laura Williams, John L. Stella, Alessandra Minozzi, Giulietta Moreno, Ana Ramelli, Paola Han, Jianlin Weigend, Steffen Wan, Junxing Lombardi, Guerino Cordioli, Paolo Mariani, Paola Parco Tecnologico Padano Lodi 26900 Italy Animal Health Department Istituto Zooprofilattico Sperimentale della Lombardia e dell'Emilia Romagna Bruno Ubertini Brescia 25124 Italy CAAS-ILRI Joint Laboratory on Livestock and Forage Genetic Resources Institute of Animal Science Chinese Academy of Agricultural Sciences (CAAS) Beijing 100193 China Institute of Farm Animal Genetics Friedrich Loeffler Institut Mariensee D-31535 Germany DIPAV Università degli Studi di Milano Milano 20133 Italy IBBACNR Lodi 26900 Italy

Background: The host mounts an immune response to pathogens, but few data are currently available on the role of host genetics in variation in response to avian influenza (AI). The study presented here investigated the role of the host genetic background in response to in vivo infection with AI virus (AIV). Methods: Experimental lines of chicken and commercial crosses were experimentally infected intratracheally with 10³ EID₅₀/bird of A/Chicken/Italy/13474/99 H7N1 highly pathogenic avian influenza virus (HPAIV). Chickens were genotyped for the Mx polymorphism causing the S631N mutation, and for the Major Histocompatibility Complex (MHC). Whole-genome genotyping was carried out using 60 k single nucleotide polymorphism (SNP) array developed by the poultry Genome-Wide Marker-Assisted Selection Consortium (GWMASC). Results: Variability in response of different chicken lines to the HPAIV infections and some degree of resistance to AI were observed: a statistically significant effect of chicken line on the response to infection was found. There was no association between survival in healthy conditions and polymorphisms at the Mx gene and the MHC-B region. The analysis based on the 60 k SNPs provided a good clustering of the chicken lines, but no specific genetic cluster associated with response to AIV was identified. Conclusions: Neither the genotype at the Mx gene or MHC-B locus, nor for SNP spanning the whole-genome identified loci involved in variations to response to AIV infection. These results point towards the possibility that either the genetic factors affecting the response of chickens to the H7N1 HPAIV are weak, or relevant alleles were not segregating in the studied populations. © 2011 Sironi et al;licensee BioMed Central Ltd.

关键词： Major Histocompatibility Complex Avian Influenza single nucleotide polymorphism array Highly Pathogenic Avian Influenza Virus Chicken Line

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Evaluation of 16 loci to examine the cross-species utility of single nucleotide polymorphism arrays

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ANIMAL GENETICS 2010年第2期41卷 199-202页

作者： Sechi, T. Coltman, D. W. Kijas, J. W. CSIRO Livestock Ind St Lucia Qld 4067 Australia DiRPA AGRIS Res Unit Sardinia Italy Univ Alberta Dept Biol Sci Edmonton AB T6G 2E9 Canada

P>Large collections of single nucleotide polymorphisms (SNPs) have recently been identified from a number of livestock genomes. This raises the possibility that SNP arrays might be useful for analysis in related species for which few genetic markers are currently available. To address the likely success of such an approach, the aim of this study was to examine the threshold number and position of flanking mutations which act to prevent genotype calls being produced. Sequence diversity was measured across 16 loci containing SNPs known either to work successfully between species or fail between species. In pairwise comparisons between domestic and wild sheep, sequence divergence surrounding working SNP assays was significantly lower than that surrounding non-functional assays. In addition, the location of flanking mismatches tended to be closer to the target SNP in loci that failed to generate genotype calls across species. The magnitude of sequence divergence observed for both working and non-functional assays was compared with the divergence separating domestic sheep from European Mouflon, African Barbary, goat and cattle. The results suggest that the utility of SNP arrays for analysis of shared polymorphism will be restricted to closely related pairs of species. Analysis across more divergent species will, however, be successful for other objectives, such as the identification of the ancestral state of SNPs.

关键词： sheep single nucleotide polymorphism single nucleotide polymorphism array

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A fast and accurate method to detect allelic genomic imbalances underlying mosaic rearrangements using SNP array data

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BMC BIOINFORMATICS 2011年第1期12卷 1-11页

作者： Gonzalez, Juan R. Rodriguez-Santiago, Benjamin Caceres, Alejandro Pique-Regi, Roger Rothman, Nathaniel Chanock, Stephen J. Armengol, Lluis Perez-Jurado, Luis A. Ctr Res Environm Epidemiol CREAL Barcelona 08003 Spain IMIM Barcelona 08003 Spain UPF Dept Ciencies Expt & Salut Barcelona 08003 Spain Univ Chicago Dept Human Genet Chicago IL 60637 USA NCI Div Canc Epidemiol & Genet Rockville MD 20852 USA SAIC Frederick Core Genotyping Facil Frederick MD 21702 USA Quantitat Genom Med Labs Ltd qGenom Barcelona 08003 Spain

Background: Mosaicism for copy number and copy neutral chromosomal rearrangements has been recently identified as a relatively common source of genetic variation in the normal population. However its prevalence is poorly defined since it has been only studied systematically in one large-scale study and by using non optimal adhoc SNP array data analysis tools, uncovering rather large alterations (> 1 Mb) and affecting a high proportion of cells. Here we propose a novel methodology, Mosaic Alteration Detection-MAD, by providing a software tool that is effective for capturing previously described alterations as wells as new variants that are smaller in size and/or affecting a low percentage of cells. Results: The developed method identified all previously known mosaic abnormalities reported in SNP array data obtained from controls, bladder cancer and HapMap individuals. In addition MAD tool was able to detect new mosaic variants not reported before that were smaller in size and with lower percentage of cells affected. The performance of the tool was analysed by studying simulated data for different scenarios. Our method showed high sensitivity and specificity for all assessed scenarios. Conclusions: The tool presented here has the ability to identify mosaic abnormalities with high sensitivity and specificity. Our results confirm the lack of sensitivity of former methods by identifying new mosaic variants not reported in previously utilised datasets. Our work suggests that the prevalence of mosaic alterations could be higher than initially thought. The use of appropriate SNP array data analysis methods would help in defining the human genome mosaic map.

关键词： False Discovery Rate Allelic Imbalance single nucleotide polymorphism array Circular Binary Segmentation High False Discovery Rate

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Comparative analysis of copy number variation detection methods and database construction

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BMC GENETICS 2011年第1期12卷 29-29页

作者： Koike, Asako Nishida, Nao Yamashita, Daiki Tokunaga, Katsushi Hitachi Ltd Cent Res Lab Tokyo Japan Univ Tokyo Dept Human Genet Grad Sch Med Tokyo Japan

Background: array-based detection of copy number variations (CNVs) is widely used for identifying disease-specific genetic variations. However, the accuracy of CNV detection is not sufficient and results differ depending on the detection programs used and their parameters. In this study, we evaluated five widely used CNV detection programs, Birdsuite (mainly consisting of the Birdseye and Canary modules), Birdseye ( part of Birdsuite), PennCNV, CGHseg, and DNAcopy from the viewpoint of performance on the Affymetrix platform using HapMap data and other experimental data. Furthermore, we identified CNVs of 180 healthy Japanese individuals using parameters that showed the best performance in the HapMap data and investigated their characteristics. Results: The results indicate that Hidden Markov model-based programs PennCNV and Birdseye (part of Birdsuite), or Birdsuite show better detection performance than other programs when the high reproducibility rates of the same individuals and the low Mendelian inconsistencies are considered. Furthermore, when rates of overlap with other experimental results were taken into account, Birdsuite showed the best performance from the view point of sensitivity but was expected to include many false negatives and some false positives. The results of 180 healthy Japanese demonstrate that the ratio containing repeat sequences, not only segmental repeats but also long interspersed nuclear element (LINE) sequences both in the start and end regions of the CNVs, is higher in CNVs that are commonly detected among multiple individuals than that in randomly selected regions, and the conservation score based on primates is lower in these regions than in randomly selected regions. Similar tendencies were observed in HapMap data and other experimental data. Conclusions: Our results suggest that not only segmental repeats but also interspersed repeats, especially LINE sequences, are deeply involved in CNVs, particularly in common CNV formations. T

关键词： Long Terminal Repeat array Comparative Genomic Hybridization single nucleotide polymorphism array Long Intersperse Nuclear Element HapMap Data

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Renal cell carcinoma primary cultures maintain genomic and phenotypic profile of parental tumor tissues

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BMC CANCER 2011年第0期11卷 244-244页

作者： Cifola, Ingrid Bianchi, Cristina Mangano, Eleonora Bombelli, Silvia Frascati, Fabio Fasoli, Ester Ferrero, Stefano Di Stefano, Vitalba Zipeto, Maria A. Magni, Fulvio Signorini, Stefano Battaglia, Cristina Perego, Roberto A. Univ Milan Dipartimento Sci & Tecnol Biomed I-20090 Milan Italy Natl Res Council CNR Inst Biomed Technol ITB I-20090 Milan Italy Univ Milano Bicocca Dept Expt Med I-20052 Milan Italy Univ Milan Dept Med Surg & Dent Anat Pathol Unit Osped Maggiore Policlin I-20122 Milan Italy Univ Milano Bicocca Dept Lab Med Desio Hosp I-20033 Milan Italy

Background: Clear cell renal cell carcinoma (ccRCC) is characterized by recurrent copy number alterations (CNAs) and loss of heterozygosity (LOH), which may have potential diagnostic and prognostic applications. Here, we explored whether ccRCC primary cultures, established from surgical tumor specimens, maintain the DNA profile of parental tumor tissues allowing a more confident CNAs and LOH discrimination with respect to the original tissues. Methods: We established a collection of 9 phenotypically well-characterized ccRCC primary cell cultures. Using the Affymetrix SNP array technology, we performed the genome-wide copy number (CN) profiling of both cultures and corresponding tumor tissues. Global concordance for each culture/tissue pair was assayed evaluating the correlations between whole-genome CN profiles and SNP allelic calls. CN analysis was performed using the two CNAG v3.0 and Partek software, and comparing results returned by two different algorithms (Hidden Markov Model and Genomic Segmentation). Results: A very good overlap between the CNAs of each culture and corresponding tissue was observed. The finding, reinforced by high whole-genome CN correlations and SNP call concordances, provided evidence that each culture was derived from its corresponding tissue and maintained the genomic alterations of parental tumor. In addition, primary culture DNA profile remained stable for at least 3 weeks, till to third passage. These cultures showed a greater cell homogeneity and enrichment in tumor component than original tissues, thus enabling a better discrimination of CNAs and LOH. Especially for hemizygous deletions, primary cultures presented more evident CN losses, typically accompanied by LOH;differently, in original tissues the intensity of these deletions was weaken by normal cell contamination and LOH calls were missed. Conclusions: ccRCC primary cultures are a reliable in vitro model, well-reproducing original tumor genetics and phenotype, potentially use

关键词： single nucleotide polymorphism array Copy Number Loss Parental Tissue single nucleotide polymorphism Call Normal Cell Contamination single nucleotide polymorphism array Copy Number Loss Parental Tissue single nucleotide polymorphism Call Normal Cell Contamination

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