Sources of variation in false discovery rate estimation include sample size, correlation, and inherent differences between groups

Zhang, Jiexin; Coombes, Kevin R.

doi:10.1186/1471-2105-13-s13-s1

Cited by 40 publications

(17 citation statements)

References 22 publications

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“…The lack of differences in the endometrium between fertility-classified heifers could be due to the use of algorithms designed for fewer replicates and homogenous differences between experimental groups [47]. Therefore, the data were reanalyzed with Bioconductor Limma with no false discovery rate (FDR).…”

Section: Resultsmentioning

confidence: 99%

Effects of Fertility on Gene Expression and Function of the Bovine Endometrium

Minten

Bilby²,

Bruno

et al. 2013

PLoS ONE

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Infertility and subfertility are important and pervasive reproductive problems in both domestic animals and humans. The majority of embryonic loss occurs during the first three weeks of pregnancy in cattle and women due, in part, to inadequate endometrial receptivity for support of embryo implantation. To identify heifers of contrasting fertility, serial rounds of artificial insemination (AI) were conducted in 201 synchronized crossbred beef heifers. The heifers were then fertility classified based on number of pregnancies detected on day 35 in four AI opportunities. Heifers, classified as having high fertility, subfertility or infertility, were selected for further study. The fertility-classified heifers were superovulated and flushed, and the recovered embryos were graded and then transferred to synchronized recipients. Quantity of embryos recovered per flush, embryo quality, and subsequent recipient pregnancy rates did not differ by fertility classification. Two in vivo-produced bovine embryos (stage 4 or 5, grade 1 or 2) were then transferred into each heifer on day 7 post-estrus. Pregnancy rates were greater in high fertility than lower fertility heifers when heifers were used as embryo recipients. The reproductive tracts of the classified heifers were obtained on day 14 of the estrous cycle. No obvious morphological differences in reproductive tract structures and histology of the uterus were observed in the heifers. Microarray analysis revealed differences in the endometrial transcriptome based on fertility classification. A genome-wide association study, based on SNP genotyping, detected 7 moderate associations with fertility across 6 different chromosomes. Collectively, these studies support the idea that innate differences in uterine function underlie fertility and early pregnancy loss in ruminants. Cattle with defined early pregnancy success or loss is useful to elucidate the complex biological and genetic mechanisms governing endometrial receptivity and uterine competency for pregnancy.

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Section: Resultsmentioning

confidence: 99%

Effects of Fertility on Gene Expression and Function of the Bovine Endometrium

Minten

Bilby²,

Bruno

et al. 2013

PLoS ONE

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“…Its high level of technical reproducibility has also been demonstrated [4][5][6]. Despite these advantages, recent analyses have revealed larger technical variability for the quantification of genes expressed at lower levels [7] and biases introduced by RNA-Seq technologies and the normalization methods [8][9][10]. However, most of these studies lack the absolute "truth" to objectively assess the performance and biases of RNA-Seq technology and the impact of data analysis approaches.…”

mentioning

confidence: 99%

mRNA enrichment protocols determine the quantification characteristics of external RNA spike-in controls in RNA-Seq studies

Qing

et al. 2013

Sci. China Life Sci.

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RNA-Seq promises to be used in clinical settings as a gene-expression profiling tool; however, questions about its variability and biases remain and need to be addressed. Thus, RNA controls with known concentrations and sequence identities originally developed by the External RNA Control Consortium (ERCC) for microarray and qPCR platforms have recently been proposed for RNA-Seq platforms, but only with a limited number of samples. In this study, we report our analysis of RNA-Seq data from 92 ERCC controls spiked in a diverse collection of 447 RNA samples from eight ongoing studies involving five species (human, rat, mouse, chicken, and Schistosoma japonicum) and two mRNA enrichment protocols, i.e., poly(A) and RiboZero. The entire collection of datasets consisted of 15650143175 short sequence reads, 131603796 (i.e., 0.84%) of which were mapped to the 92 ERCC references. The overall ERCC mapping ratio of 0.84% is close to the expected value of 1.0% when assuming a 2.0% mRNA fraction in total RNA, but showed a difference of 2.8-fold across studies and 4.3-fold among samples from the same study with one tissue type. This level of fluctuation may prevent the ERCC controls from being used for cross-sample normalization in RNA-Seq. Furthermore, we observed striking biases of quantification between poly(A) and RiboZero which are transcript-specific. For example, ERCC-00116 showed a 7.3-fold under-enrichment in poly(A) compared to RiboZero. Extra care is needed in integrative analysis of multiple datasets and technical artifacts of protocol differences should not be taken as true biological findings. RNA-Seq

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“…To evaluate the performance of the different metrics, we generated artificial gene expression datasets representing scenarios that differed in the number of latent subgroups present and in the within ( σ g ) and between ( σ p ) tumor sample variance using the R package Umpire [ 20 ]. In each scenario, the log expression level for each gene was generated by a hierarchical model, in which σ g controls the within-tumor variance and σ p controls the variance across patients in the cohort [ 21 ].…”

Section: Resultsmentioning

confidence: 99%

Statistical measures of transcriptional diversity capture genomic heterogeneity of cancer

et al. 2014

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BackgroundMolecular heterogeneity of tumors suggests the presence of multiple different subclones that may limit response to targeted therapies and contribute to acquisition of drug resistance, but its quantification has remained challenging.ResultsWe performed simulations to evaluate statistical measures that best capture the molecular diversity within a group of tumors for either continuous (gene expression) or discrete (mutations, copy number alterations) molecular data. Dispersion based metrics in the principal component space best captured the underlying heterogeneity. To demonstrate utility of these measures, we characterized the diversity in transcriptional and genomic profiles of different breast tumor subtypes, and showed that basal-like or triple-negative breast cancers (TNBC) are significantly more heterogeneous molecularly than other subtypes. Our analysis also suggests that transcriptional diversity is a global characteristic of the tumors observed across the majority of molecular pathways. Among basal-like tumors, those that were resistant to multi-agent chemotherapy showed greater transcriptional diversity compared to chemotherapy-sensitive tumors, suggesting that potentially multiple mechanisms may be contributing to chemotherapy resistance.ConclusionsWe proposed and validated measures of transcriptional and genomic diversity that can quantify the molecular diversity of tumors. We applied the new measures to genomic data from breast tumors and demonstrated that basal-like breast cancers are significantly more diverse than other breast cancers. The observation that chemo-resistant tumors are significantly more diverse molecularly than chemosensitive tumors implies that multiple resistance mechanisms may be active, thus limiting the sensitivity and accuracy of predictive markers of chemotherapy response.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-876) contains supplementary material, which is available to authorized users.

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Sources of variation in false discovery rate estimation include sample size, correlation, and inherent differences between groups

Cited by 40 publications

References 22 publications

Effects of Fertility on Gene Expression and Function of the Bovine Endometrium

Effects of Fertility on Gene Expression and Function of the Bovine Endometrium

mRNA enrichment protocols determine the quantification characteristics of external RNA spike-in controls in RNA-Seq studies

Statistical measures of transcriptional diversity capture genomic heterogeneity of cancer

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