Dataset Information

Literature aided determination of data quality and statistical significance threshold for gene expression studies.

ABSTRACT:

Background

Gene expression data are noisy due to technical and biological variability. Consequently, analysis of gene expression data is complex. Different statistical methods produce distinct sets of genes. In addition, selection of expression p-value (EPv) threshold is somewhat arbitrary. In this study, we aimed to develop novel literature based approaches to integrate functional information in analysis of gene expression data.

Methods

Functional relationships between genes were derived by Latent Semantic Indexing (LSI) of Medline abstracts and used to calculate the function cohesion of gene sets. In this study, literature cohesion was applied in two ways. First, Literature-Based Functional Significance (LBFS) method was developed to calculate a p-value for the cohesion of differentially expressed genes (DEGs) in order to objectively evaluate the overall biological significance of the gene expression experiments. Second, Literature Aided Statistical Significance Threshold (LASST) was developed to determine the appropriate expression p-value threshold for a given experiment.

Results

We tested our methods on three different publicly available datasets. LBFS analysis demonstrated that only two experiments were significantly cohesive. For each experiment, we also compared the LBFS values of DEGs generated by four different statistical methods. We found that some statistical tests produced more functionally cohesive gene sets than others. However, no statistical test was consistently better for all experiments. This reemphasizes that a statistical test must be carefully selected for each expression study. Moreover, LASST analysis demonstrated that the expression p-value thresholds for some experiments were considerably lower (p < 0.02 and 0.01), suggesting that the arbitrary p-values and false discovery rate thresholds that are commonly used in expression studies may not be biologically sound.

Conclusions

We have developed robust and objective literature-based methods to evaluate the biological support for gene expression experiments and to determine the appropriate statistical significance threshold. These methods will assist investigators to more efficiently extract biologically meaningful insights from high throughput gene expression experiments.

SUBMITTER: Xu L

PROVIDER: S-EPMC3535704 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Publications

Literature aided determination of data quality and statistical significance threshold for gene expression studies.

Xu Lijing L Cheng Cheng C George E Olusegun EO Homayouni Ramin R

BMC genomics 20121217

<h4>Background</h4>Gene expression data are noisy due to technical and biological variability. Consequently, analysis of gene expression data is complex. Different statistical methods produce distinct sets of genes. In addition, selection of expression p-value (EPv) threshold is somewhat arbitrary. In this study, we aimed to develop novel literature based approaches to integrate functional information in analysis of gene expression data.<h4>Methods</h4>Functional relationships between genes were ...[more]

PMID: 23282414

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Project description:MOTIVATION:There are a number of well-established methods such as principal component analysis (PCA) for automatically capturing systematic variation due to latent variables in large-scale genomic data. PCA and related methods may directly provide a quantitative characterization of a complex biological variable that is otherwise difficult to precisely define or model. An unsolved problem in this context is how to systematically identify the genomic variables that are drivers of systematic variation captured by PCA. Principal components (PCs) (and other estimates of systematic variation) are directly constructed from the genomic variables themselves, making measures of statistical significance artificially inflated when using conventional methods due to over-fitting. RESULTS:We introduce a new approach called the jackstraw that allows one to accurately identify genomic variables that are statistically significantly associated with any subset or linear combination of PCs. The proposed method can greatly simplify complex significance testing problems encountered in genomics and can be used to identify the genomic variables significantly associated with latent variables. Using simulation, we demonstrate that our method attains accurate measures of statistical significance over a range of relevant scenarios. We consider yeast cell-cycle gene expression data, and show that the proposed method can be used to straightforwardly identify genes that are cell-cycle regulated with an accurate measure of statistical significance. We also analyze gene expression data from post-trauma patients, allowing the gene expression data to provide a molecularly driven phenotype. Using our method, we find a greater enrichment for inflammatory-related gene sets compared to the original analysis that uses a clinically defined, although likely imprecise, phenotype. The proposed method provides a useful bridge between large-scale quantifications of systematic variation and gene-level significance analyses. AVAILABILITY AND IMPLEMENTATION:An R software package, called jackstraw, is available in CRAN. CONTACT:jstorey@princeton.edu.

Project description:BackgroundA challenge in gene expression studies is the reliable identification of differentially expressed genes. In many high-throughput studies, genes are accepted as differentially expressed only if they satisfy simultaneously a p value criterion and a fold change criterion. A statistical method, TREAT, has been developed for microarray data to assess formally if fold changes are significantly higher than a predefined threshold. We have recently applied the NanoString digital platform to study expression of mouse odorant receptor genes, which form with 1,200 members the largest gene family in the mouse genome. Our objectives are, on these data, to decrease false discoveries when formally assessing the genes relative to a fold change threshold, and to provide a guided selection in the choice of this threshold.ResultsStatistical tests have been developed for microarray data to identify genes that are differentially expressed relative to a fold change threshold. Here we report that another approach, which we refer to as tTREAT, is more appropriate for our NanoString data, where false discoveries lead to costly and time-consuming follow-up experiments. Methods that we refer to as tTREAT2 and the running fold change model improve the performance of the statistical tests by protecting or selecting the fold change threshold more objectively. We show the benefits on simulated and real data.ConclusionsGene-wise statistical analyses of gene expression data, for which the significance relative to a fold change threshold is important, give reproducible and reliable results on NanoString data of mouse odorant receptor genes. Because it can be difficult to set in advance a fold change threshold that is meaningful for the available data, we developed methods that enable a better choice (thus reducing false discoveries and/or missed genes) or avoid this choice altogether. This set of tools may be useful for the analysis of other types of gene expression data.

Project description:PurposeEvidenced-based decision-making is rooted in comparative clinical studies; however, a small number of outcome event reversals have the potential to change study significance. The purpose of this study was to determine the utility of applying fragility analysis to comparative studies in the published orthopaedic shoulder literature.MethodsComparative clinical shoulder research studies reporting 1:1 dichotomous categorical data were analyzed in 6 leading orthopaedic journals between 2006 and 2016. Statistical significance was defined as a P value of less than .05. The fragility index (FI) for each study outcome was determined by the number of event reversals required to change the P value to either greater or less than 0.05, thus changing the study conclusions. The associated fragility quotient (FQ) was determined by dividing the FI by the total population comprising a particular outcome.ResultsOf the 23,897 studies screened, 3,591 met search criteria, with 198 comparative studies ultimately included for analysis, 67 of which were randomized controlled trials. There were 357 total outcome events with 74 reported as significant and 283 as not significant. The FI was 4 (IQR 2-6) with an associated FQ of 0.066 (interquartile range [IQR] 0.038-0.102). There was no difference in statistical fragility between randomized and nonrandomized trials with both revealing a FI of 4 and FQ of 0.068 (IQR 0.044-0.107) and 0.065 (IQR 0.031-0.101), respectively.ConclusionsThis current analysis reveals that comparative shoulder studies published in six leading orthopaedic journals are at risk of statistical fragility. As such, contemporary clinical shoulder literature may not be as robust as traditionally perceived with the reversal of only a few outcome events required to change study significance. Therefore, we advocate the reporting of both FI and FQ in addition to the P value as statistical complements to all comparative investigations to provide a more comprehensive understanding of trial stability and significance in the published shoulder literature.Clinical relevanceComparative study designs are commonly employed in shoulder research. Several studies in both the general medical and orthopaedic literature have identified a lack of statistical robustness through comprehensive fragility analysis. Our findings demonstrate the P value may be an inadequate independent statistical metric requiring the complement of a FI and FQ to aid in the interpretation and understanding of study significance for clinical decision-making.

Dataset Information

Literature aided determination of data quality and statistical significance threshold for gene expression studies.

Background

Methods

Results

Conclusions

Publications

Literature aided determination of data quality and statistical significance threshold for gene expression studies.

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