Dataset Information

Assessing the Power of Exome Chips.

ABSTRACT: Genotyping chips for rare and low-frequent variants have recently gained popularity with the introduction of exome chips, but the utility of these chips remains unclear. These chips were designed using exome sequencing data from mainly American-European individuals, enriched for a narrow set of common diseases. In addition, it is well-known that the statistical power of detecting associations with rare and low-frequent variants is much lower compared to studies exclusively involving common variants. We developed a simulation program adaptable to any exome chip design to empirically evaluate the power of the exome chips. We implemented the main properties of the Illumina HumanExome BeadChip array. The simulated data sets were used to assess the power of exome chip based studies for varying effect sizes and causal variant scenarios. We applied two widely-used statistical approaches for rare and low-frequency variants, which collapse the variants into genetic regions or genes. Under optimal conditions, we found that a sample size between 20,000 to 30,000 individuals were needed in order to detect modest effect sizes (0.5% < PAR > 1%) with 80% power. For small effect sizes (PAR <0.5%), 60,000-100,000 individuals were needed in the presence of non-causal variants. In conclusion, we found that at least tens of thousands of individuals are necessary to detect modest effects under optimal conditions. In addition, when using rare variant chips on cohorts or diseases they were not originally designed for, the identification of associated variants or genes will be even more challenging.

SUBMITTER: Page CM

PROVIDER: S-EPMC4593624 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Assessing the Power of Exome Chips.

Page Christian Magnus CM Baranzini Sergio E SE Mevik Bjørn-Helge BH Bos Steffan Daniel SD Harbo Hanne F HF Andreassen Bettina Kulle BK

PloS one 20151005 10

Genotyping chips for rare and low-frequent variants have recently gained popularity with the introduction of exome chips, but the utility of these chips remains unclear. These chips were designed using exome sequencing data from mainly American-European individuals, enriched for a narrow set of common diseases. In addition, it is well-known that the statistical power of detecting associations with rare and low-frequent variants is much lower compared to studies exclusively involving common varia ...[more]

PMID: 26437075

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Project description:BackgroundReproducibility is receiving increased attention across many domains of science and genomics is no exception. Efforts to identify copy number variations (CNVs) from exome sequence (ES) data have been increasing. Many algorithms have been published to discover CNVs from exomes and a major challenge is the reproducibility in other datasets. Here we test exome CNV calling reproducibility under three conditions: data generated by different sequencing centers; varying sample sizes; and varying capture methodology.MethodsFour CNV tools were tested: eXome Hidden Markov Model (XHMM), Copy Number Inference From Exome Reads (CoNIFER), EXCAVATOR, and Copy Number Analysis for Targeted Resequencing (CONTRA). To examine the reproducibility, we ran the callers on four datasets, varying sample sizes of N = 10, 30, 75, 100, 300, and data with different capture methodology. We examined the false negative (FN) calls and false positive (FP) calls for potential limitations of the CNV callers. The positive predictive value (PPV) was measured by checking the CNV call concordance against single nucleotide polymorphism array.ResultsUsing independently generated datasets, we examined the PPV for each dataset and observed wide range of PPVs. The PPV values were highly data dependent (p <0.001). For the sample sizes and capture method analyses, we tested the callers in triplicates. Both analyses resulted in wide ranges of PPVs, even for the same test. Interestingly, negative correlations between the PPV and the sample sizes were observed for CoNIFER (ρ = -0.80). Further examination of FN calls showed that 44 % of these were missed by all callers and were attributed to the CNV size (46 % spanned ≤3 exons). Overlap of the FP calls showed that FPs were unique to each caller, indicative of algorithm dependency.ConclusionsOur results demonstrate that further improvements in CNV callers are necessary to improve reproducibility and to include wider spectrum of CNVs (including the small CNVs). These CNV callers should be evaluated on multiple independent, heterogeneously generated datasets of varying size to increase robustness and utility. These approaches to the evaluation of exome CNV are essential to support wide utility and applicability of CNV discovery in exome studies.

Project description:There are two major sequencing technologies for investigating the microbiome: the amplicon sequencing that generates the OTU (operational taxonomic unit) tables of marker genes (e.g., bacterial 16S-rRNA), and the metagenomic shotgun sequencing that generates metagenomic gene abundance (MGA) tables. The OTU table is the counterpart of species abundance tables in macrobial ecology of plants and animals, and has been the target of numerous ecological and network analyses in recent gold rush for microbiome research and in great efforts for establishing an inclusive theoretical ecology. Nevertheless, MGA analyses have been largely limited to bioinformatics pipelines and ad hoc statistical methods, and systematic approaches to MGAs guided by classic ecological theories are still few. Here, we argue that, the difference between "gene kinds" and "gene species" are nominal, and the metagenome that a microbiota carries is essentially a 'community' of metagenomic genes (MGs). Each row of a MGA table represents a metagenome of a microbiota, and the whole MGA table represents a 'meta-metagenome' (or an assemblage of metagenomes) of N microbiotas (microbiome samples). Consequently, the same ecological/network analyses used in OTU analyses should be equally applicable to MGA tables. Here we choose to analyze the heterogeneity of metagenome by introducing classic Taylor's power law (TPL) and its recent extensions in community ecology. Heterogeneity is a fundamental property of metagenome, particularly in the context of human microbiomes. Recent studies have shown that the heterogeneity of human metagenomes is far more significant than that of human genomes. Therefore, without deep understanding of the human metagenome heterogeneity, personalized medicine of the human microbiome-associated diseases is hardly feasible. The TPL extensions have been successfully applied to measure the heterogeneity of human microbiome based on amplicon-sequencing reads of marker genes (e.g., 16s-rRNA). In this article, we demonstrate the analysis of the metagenomic heterogeneity of human gut microbiome at whole metagenome scale (with type-I power law extension) and metagenomic gene scale (type-III), as well as the heterogeneity of gene clusters, respectively. We further examine the influences of obesity, IBD and diabetes on the heterogeneity, which is of important ramifications for the diagnosis and treatment of human microbiome-associated diseases.

Dataset Information

Assessing the Power of Exome Chips.

Publications

Assessing the Power of Exome Chips.

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