scholarly journals Tissue specificity-aware TWAS (TSA-TWAS) framework identifies novel associations with metabolic, immunologic, and virologic traits in HIV-positive adults

PLoS Genetics ◽  
2021 ◽  
Vol 17 (4) ◽  
pp. e1009464
Author(s):  
Binglan Li ◽  
Yogasudha Veturi ◽  
Anurag Verma ◽  
Yuki Bradford ◽  
Eric S. Daar ◽  
...  
Keyword(s):  
Tissue Specificity ◽  
Type I Error ◽  
Density Lipoprotein ◽  
Error Rates ◽  
Gene Prioritization ◽  
Type I ◽  
Uridine Diphosphate ◽  
Analytic Framework ◽  
Type I Error Rates ◽  
Transcriptional Regulatory Mechanisms

As a type of relatively new methodology, the transcriptome-wide association study (TWAS) has gained interest due to capacity for gene-level association testing. However, the development of TWAS has outpaced statistical evaluation of TWAS gene prioritization performance. Current TWAS methods vary in underlying biological assumptions about tissue specificity of transcriptional regulatory mechanisms. In a previous study from our group, this may have affected whether TWAS methods better identified associations in single tissues versus multiple tissues. We therefore designed simulation analyses to examine how the interplay between particular TWAS methods and tissue specificity of gene expression affects power and type I error rates for gene prioritization. We found that cross-tissue identification of expression quantitative trait loci (eQTLs) improved TWAS power. Single-tissue TWAS (i.e., PrediXcan) had robust power to identify genes expressed in single tissues, but, often found significant associations in the wrong tissues as well (therefore had high false positive rates). Cross-tissue TWAS (i.e., UTMOST) had overall equal or greater power and controlled type I error rates for genes expressed in multiple tissues. Based on these simulation results, we applied a tissue specificity-aware TWAS (TSA-TWAS) analytic framework to look for gene-based associations with pre-treatment laboratory values from AIDS Clinical Trial Group (ACTG) studies. We replicated several proof-of-concept transcriptionally regulated gene-trait associations, including UGT1A1 (encoding bilirubin uridine diphosphate glucuronosyltransferase enzyme) and total bilirubin levels (p = 3.59×10−12), and CETP (cholesteryl ester transfer protein) with high-density lipoprotein cholesterol (p = 4.49×10−12). We also identified several novel genes associated with metabolic and virologic traits, as well as pleiotropic genes that linked plasma viral load, absolute basophil count, and/or triglyceride levels. By highlighting the advantages of different TWAS methods, our simulation study promotes a tissue specificity-aware TWAS analytic framework that revealed novel aspects of HIV-related traits.

scholarly journals Tissue specificity-aware TWAS (TSA-TWAS) framework identifies novel associations with metabolic, immunologic, and virologic traits in HIV-positive adults

2020 ◽  
Author(s):  
Binglan Li ◽  
Yogasudha Veturi ◽  
Anurag Verma ◽  
Yuki Bradford ◽  
Eric S. Daar ◽  
...  
Keyword(s):  
Tissue Specificity ◽  
Type I Error ◽  
Density Lipoprotein ◽  
Error Rates ◽  
Gene Prioritization ◽  
Type I ◽  
Uridine Diphosphate ◽  
Analytic Framework ◽  
Type I Error Rates ◽  
Transcriptional Regulatory Mechanisms

AbstractAs a type of relatively new methodology, the transcriptome-wide association study (TWAS) has gained interest due to capacity for gene-level association testing. However, the development of TWAS has outpaced statistical evaluation of TWAS gene prioritization performance. Current TWAS methods vary in underlying biological assumptions about tissue specificity of transcriptional regulatory mechanisms. In a previous study from our group, this may have affected whether TWAS methods better identified associations in single tissues versus multiple tissues. We therefore designed simulation analyses to examine how the interplay between particular TWAS methods and tissue specificity of gene expression affects power and type I error rates for gene prioritization. We found that cross-tissue identification of expression quantitative trait loci (eQTLs) improved TWAS power. Single-tissue TWAS (i.e., PrediXcan) had robust power to identify genes expressed in single tissues, but, had high false positive rates for genes that are expressed in multiple tissues. Cross-tissue TWAS (i.e., UTMOST) had overall equal or greater power and controlled type I error rates for genes expressed in multiple tissues. Based on these simulation results, we applied a tissue specificity-aware TWAS (TSA-TWAS) analytic framework to look for gene-based associations with pre-treatment laboratory values from AIDS Clinical Trial Group (ACTG) studies. We replicated several proof-of-concept transcriptionally regulated gene-trait associations, including UGT1A1 (encoding bilirubin uridine diphosphate glucuronosyl transferase enzyme) and total bilirubin levels (p = 3.59×10−12), and CETP (cholesteryl ester transfer protein) with high-density lipoprotein cholesterol (p = 4.49×10−12). We also identified several novel genes associated with metabolic and virologic traits, as well as pleiotropic genes that linked plasma viral load, absolute basophil count, and/or triglyceride levels. By highlighting the advantages of different TWAS methods, our simulation study promotes a tissue specificity-aware TWAS analytic framework that revealed novel aspects of HIV-related traits.publicly available.

scholarly journals Control of Type I Error Rates in Bayesian Sequential Designs

2019 ◽  
Vol 14 (2) ◽  
pp. 399-425 ◽  
Author(s):  
Haolun Shi ◽  
Guosheng Yin
Keyword(s):  
Type I Error ◽  
Error Rates ◽  
Type I ◽  
Sequential Designs ◽  
Type I Error Rates

scholarly journals Sisvar: a Guide for its Bootstrap procedures in multiple comparisons

2014 ◽  
Vol 38 (2) ◽  
pp. 109-112 ◽  
Author(s):  
Daniel Furtado Ferreira
Keyword(s):  
Scientific Community ◽  
Type I Error ◽  
Multiple Comparisons ◽  
Error Rates ◽  
Type I ◽  
Type I Error Rates ◽  
Statistical Analysis System ◽  
Scientific Results ◽  
Analysis System ◽  
Multiple Comparison Procedures

Sisvar is a statistical analysis system with a large usage by the scientific community to produce statistical analyses and to produce scientific results and conclusions. The large use of the statistical procedures of Sisvar by the scientific community is due to it being accurate, precise, simple and robust. With many options of analysis, Sisvar has a not so largely used analysis that is the multiple comparison procedures using bootstrap approaches. This paper aims to review this subject and to show some advantages of using Sisvar to perform such analysis to compare treatments means. Tests like Dunnett, Tukey, Student-Newman-Keuls and Scott-Knott are performed alternatively by bootstrap methods and show greater power and better controls of experimentwise type I error rates under non-normal, asymmetric, platykurtic or leptokurtic distributions.

scholarly journals Cluster Wild Bootstrapping to Handle Dependent Effect Sizes in Meta-Analysis with a Small Number of Studies

2021 ◽  
Author(s):  
Megha Joshi ◽  
James E Pustejovsky ◽  
S. Natasha Beretvas
Keyword(s):  
Effect Size ◽  
Type I Error ◽  
Meta Analysis ◽  
Error Rates ◽  
Small Sample ◽  
Type I ◽  
Hypothesis Tests ◽  
Type I Error Rates ◽  
Meta Analyses ◽  
Small Sample Correction

The most common and well-known meta-regression models work under the assumption that there is only one effect size estimate per study and that the estimates are independent. However, meta-analytic reviews of social science research often include multiple effect size estimates per primary study, leading to dependence in the estimates. Some meta-analyses also include multiple studies conducted by the same lab or investigator, creating another potential source of dependence. An increasingly popular method to handle dependence is robust variance estimation (RVE), but this method can result in inflated Type I error rates when the number of studies is small. Small-sample correction methods for RVE have been shown to control Type I error rates adequately but may be overly conservative, especially for tests of multiple-contrast hypotheses. We evaluated an alternative method for handling dependence, cluster wild bootstrapping, which has been examined in the econometrics literature but not in the context of meta-analysis. Results from two simulation studies indicate that cluster wild bootstrapping maintains adequate Type I error rates and provides more power than extant small sample correction methods, particularly for multiple-contrast hypothesis tests. We recommend using cluster wild bootstrapping to conduct hypothesis tests for meta-analyses with a small number of studies. We have also created an R package that implements such tests.

scholarly journals Another Warning about Median Reaction Time --- Version of 11 Feb 2020

2020 ◽  
Author(s):  
Jeff Miller
Keyword(s):  
Type I Error ◽  
Reaction Times ◽  
Error Rates ◽  
Type I ◽  
Experimental Conditions ◽  
Type I Error Rates ◽  
Correction Technique ◽  
Inflated Type ◽  
The Mean ◽  
Rt Distributions

Contrary to the warning of Miller (1988), Rousselet and Wilcox (2020) argued that it is better to summarize each participant’s single-trial reaction times (RTs) in a given condition with the median than with the mean when comparing the central tendencies of RT distributions across experimental conditions. They acknowledged that median RTs can produce inflated Type I error rates when conditions differ in the number of trials tested, consistent with Miller’s warning, but they showed that the bias responsible for this error rate inflation could be eliminated with a bootstrap bias correction technique. The present simulations extend their analysis by examining the power of bias-corrected medians to detect true experimental effects and by comparing this power with the power of analyses using means and regular medians. Unfortunately, although bias-corrected medians solve the problem of inflated Type I error rates, their power is lower than that of means or regular medians in many realistic situations. In addition, even when conditions do not differ in the number of trials tested, the power of tests (e.g., t-tests) is generally lower using medians rather than means as the summary measures. Thus, the present simulations demonstrate that summary means will often provide the most powerful test for differences between conditions, and they show what aspects of the RT distributions determine the size of the power advantage for means.

Sign in / Sign up

Export Citation Format

Share Document