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Evaluation of sample size effect on the identification of haplotype blocks.

ABSTRACT: BACKGROUND: Genome-wide maps of linkage disequilibrium (LD) and haplotypes have been created for different populations. Substantial sharing of the boundaries and haplotypes among populations was observed, but haplotype variations have also been reported across populations. Conflicting observations on the extent and distribution of haplotypes require careful examination. The mechanisms that shape haplotypes have not been fully explored, although the effect of sample size has been implicated. We present a close examination of the effect of sample size on haplotype blocks using an original computational simulation. RESULTS: A region spanning 19.31 Mb on chromosome 20q was genotyped for 1,147 SNPs in 725 Japanese subjects. One region of 445 kb exhibiting a single strong LD value (average |D'|; 0.94) was selected for the analysis of sample size effect on haplotype structure. Three different block definitions (recombination-based, LD-based, and diversity-based) were exploited to create simulations for block identification with theta value from real genotyping data. As a result, it was quite difficult to estimate a haplotype block for data with less than 200 samples. Attainment of a reliable haplotype structure with 50 samples was not possible, although the simulation was repeated 10,000 times. CONCLUSION: These analyses underscored the difficulties of estimating haplotype blocks. To acquire a reliable result, it would be necessary to increase sample size more than 725 and to repeat the simulation 3,000 times. Even in one genomic region showing a high LD value, the haplotype block might be fragile. We emphasize the importance of applying careful confidence measures when using the estimated haplotype structure in biomedical research.

SUBMITTER: Osabe D

PROVIDER: S-EPMC1913927 | biostudies-literature | 2007

REPOSITORIES: biostudies-literature

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Evaluation of sample size effect on the identification of haplotype blocks.

Osabe Dai D Tanahashi Toshihito T Nomura Kyoko K Shinohara Shuichi S Nakamura Naoto N Yoshikawa Toshikazu T Shiota Hiroshi H Keshavarz Parvaneh P Yamaguchi Yuka Y Kunika Kiyoshi K Moritani Maki M Inoue Hiroshi H Itakura Mitsuo M

BMC bioinformatics 20070614

<h4>Background</h4>Genome-wide maps of linkage disequilibrium (LD) and haplotypes have been created for different populations. Substantial sharing of the boundaries and haplotypes among populations was observed, but haplotype variations have also been reported across populations. Conflicting observations on the extent and distribution of haplotypes require careful examination. The mechanisms that shape haplotypes have not been fully explored, although the effect of sample size has been implicate ...[more]

PMID: 17567919

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Project description:In modern plant breeding, genomic selection is becoming the gold standard for selection of superior genotypes. The basis for genomic prediction models is a set of phenotyped lines along with their genotypic profile. With high marker density and linkage disequilibrium (LD) between markers, genotype data in breeding populations tends to exhibit considerable redundancy. Therefore, interest is growing in the use of haplotype blocks to overcome redundancy by summarizing co-inherited features. Moreover, haplotype blocks can help to capture local epistasis caused by interacting loci. Here, we compared genomic prediction methods that either used single SNPs or haplotype blocks with regards to their prediction accuracy for important traits in crop datasets. We used four published datasets from canola, maize, wheat and soybean. Different approaches to construct haplotype blocks were compared, including blocks based on LD, physical distance, number of adjacent markers and the algorithms implemented in the software "Haploview" and "HaploBlocker". The tested prediction methods included Genomic Best Linear Unbiased Prediction (GBLUP), Extended GBLUP to account for additive by additive epistasis (EGBLUP), Bayesian LASSO and Reproducing Kernel Hilbert Space (RKHS) regression. We found improved prediction accuracy in some traits when using haplotype blocks compared to SNP-based predictions, however the magnitude of improvement was very trait- and model-specific. Especially in settings with low marker density, haplotype blocks can improve genomic prediction accuracy. In most cases, physically large haplotype blocks yielded a strong decrease in prediction accuracy. Especially when prediction accuracy varies greatly across different prediction models, prediction based on haplotype blocks can improve prediction accuracy of underperforming models. However, there is no "best" method to build haplotype blocks, since prediction accuracy varied considerably across methods and traits. Hence, criteria used to define haplotype blocks should not be viewed as fixed biological parameters, but rather as hyperparameters that need to be adjusted for every dataset.

Project description:BackgroundAn appropriate sample size is essential for obtaining a precise and reliable outcome of a study. In machine learning (ML), studies with inadequate samples suffer from overfitting of data and have a lower probability of producing true effects, while the increment in sample size increases the accuracy of prediction but may not cause a significant change after a certain sample size. Existing statistical approaches using standardized mean difference, effect size, and statistical power for determining sample size are potentially biased due to miscalculations or lack of experimental details. This study aims to design criteria for evaluating sample size in ML studies. We examined the average and grand effect sizes and the performance of five ML methods using simulated datasets and three real datasets to derive the criteria for sample size. We systematically increase the sample size, starting from 16, by randomly sampling and examine the impact of sample size on classifiers' performance and both effect sizes. Tenfold cross-validation was used to quantify the accuracy.ResultsThe results demonstrate that the effect sizes and the classification accuracies increase while the variances in effect sizes shrink with the increment of samples when the datasets have a good discriminative power between two classes. By contrast, indeterminate datasets had poor effect sizes and classification accuracies, which did not improve by increasing sample size in both simulated and real datasets. A good dataset exhibited a significant difference in average and grand effect sizes. We derived two criteria based on the above findings to assess a decided sample size by combining the effect size and the ML accuracy. The sample size is considered suitable when it has appropriate effect sizes (≥ 0.5) and ML accuracy (≥ 80%). After an appropriate sample size, the increment in samples will not benefit as it will not significantly change the effect size and accuracy, thereby resulting in a good cost-benefit ratio.ConclusionWe believe that these practical criteria can be used as a reference for both the authors and editors to evaluate whether the selected sample size is adequate for a study.

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Evaluation of sample size effect on the identification of haplotype blocks.

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Evaluation of sample size effect on the identification of haplotype blocks.

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