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Gene-based Higher Criticism methods for large-scale exonic single-nucleotide polymorphism data.

ABSTRACT: In genome-wide association studies, gene-based methods measure potential joint genetic effects of loci within genes and are promising for detecting causative genetic variations. Following recent theoretical research in statistical multiple-hypothesis testing, we propose to adapt the Higher Criticism procedures to develop novel gene-based methods that use the information of linkage disequilibrium for detecting weak and sparse genetic signals. With the large-scale exonic single-nucleotide polymorphism data from Genetic Analysis Workshop 17, we show that the new Higher-Criticism-type gene-based methods have higher statistical power to detect causative genes than the minimal P-value method, ridge regression, and the prototypes of Higher Criticism do.

SUBMITTER: He S

PROVIDER: S-EPMC3287904 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Gene-based Higher Criticism methods for large-scale exonic single-nucleotide polymorphism data.

He Shiquan S Wu Zheyang Z

BMC proceedings 20111129

In genome-wide association studies, gene-based methods measure potential joint genetic effects of loci within genes and are promising for detecting causative genetic variations. Following recent theoretical research in statistical multiple-hypothesis testing, we propose to adapt the Higher Criticism procedures to develop novel gene-based methods that use the information of linkage disequilibrium for detecting weak and sparse genetic signals. With the large-scale exonic single-nucleotide polymorp ...[more]

PMID: 22373436

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Project description:BackgroundThe development of second generation sequencing methods has enabled large scale DNA variation studies at moderate cost. For the high throughput discovery of single nucleotide polymorphisms (SNPs) in species lacking a sequenced reference genome, we set-up an analysis pipeline based on a short read de novo sequence assembler and a program designed to identify variation within short reads. To illustrate the potential of this technique, we present the results obtained with a randomly sheared, enzymatically generated, 2-3 kbp genome fraction of six pooled Meleagris gallopavo (turkey) individuals.ResultsA total of 100 million 36 bp reads were generated, representing approximately 5-6% (approximately 62 Mbp) of the turkey genome, with an estimated sequence depth of 58. Reads consisting of bases called with less than 1% error probability were selected and assembled into contigs. Subsequently, high throughput discovery of nucleotide variation was performed using sequences with more than 90% reliability by using the assembled contigs that were 50 bp or longer as the reference sequence. We identified more than 7,500 SNPs with a high probability of representing true nucleotide variation in turkeys. Increasing the reference genome by adding publicly available turkey BAC-end sequences increased the number of SNPs to over 11,000. A comparison with the sequenced chicken genome indicated that the assembled turkey contigs were distributed uniformly across the turkey genome. Genotyping of a representative sample of 340 SNPs resulted in a SNP conversion rate of 95%. The correlation of the minor allele count (MAC) and observed minor allele frequency (MAF) for the validated SNPs was 0.69.ConclusionWe provide an efficient and cost-effective approach for the identification of thousands of high quality SNPs in species currently lacking a sequenced genome and applied this to turkey. The methodology addresses a random fraction of the genome, resulting in an even distribution of SNPs across the targeted genome.

Project description:BACKGROUND: This paper introduces and applies a genome wide predictive study to learn a model that predicts whether a new subject will develop breast cancer or not, based on her SNP profile. RESULTS: We first genotyped 696 female subjects (348 breast cancer cases and 348 apparently healthy controls), predominantly of Caucasian origin from Alberta, Canada using Affymetrix Human SNP 6.0 arrays. Then, we applied EIGENSTRAT population stratification correction method to remove 73 subjects not belonging to the Caucasian population. Then, we filtered any SNP that had any missing calls, whose genotype frequency was deviated from Hardy-Weinberg equilibrium, or whose minor allele frequency was less than 5%. Finally, we applied a combination of MeanDiff feature selection method and KNN learning method to this filtered dataset to produce a breast cancer prediction model. LOOCV accuracy of this classifier is 59.55%. Random permutation tests show that this result is significantly better than the baseline accuracy of 51.52%. Sensitivity analysis shows that the classifier is fairly robust to the number of MeanDiff-selected SNPs. External validation on the CGEMS breast cancer dataset, the only other publicly available breast cancer dataset, shows that this combination of MeanDiff and KNN leads to a LOOCV accuracy of 60.25%, which is significantly better than its baseline of 50.06%. We then considered a dozen different combinations of feature selection and learning method, but found that none of these combinations produces a better predictive model than our model. We also considered various biological feature selection methods like selecting SNPs reported in recent genome wide association studies to be associated with breast cancer, selecting SNPs in genes associated with KEGG cancer pathways, or selecting SNPs associated with breast cancer in the F-SNP database to produce predictive models, but again found that none of these models achieved accuracy better than baseline. CONCLUSIONS: We anticipate producing more accurate breast cancer prediction models by recruiting more study subjects, providing more accurate labelling of phenotypes (to accommodate the heterogeneity of breast cancer), measuring other genomic alterations such as point mutations and copy number variations, and incorporating non-genetic information about subjects such as environmental and lifestyle factors.

Dataset Information

Gene-based Higher Criticism methods for large-scale exonic single-nucleotide polymorphism data.

Publications

Gene-based Higher Criticism methods for large-scale exonic single-nucleotide polymorphism data.

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