scholarly journals De novo detection of differentially bound regions for ChIP-seq data using peaks and windows: controlling error rates correctly

2014 ◽  
Vol 42 (11) ◽  
pp. e95-e95 ◽  
Author(s):  
Aaron T.L. Lun ◽  
Gordon K. Smyth
Keyword(s):  
False Discovery Rate ◽  
Error Control ◽  
De Novo ◽  
Hybrid Approach ◽  
Careful Consideration ◽  
Error Rates ◽  
Type I ◽  
Data Set ◽  
False Discovery ◽  
Differential Binding

Abstract A common aim in ChIP-seq experiments is to identify changes in protein binding patterns between conditions, i.e. differential binding. A number of peak- and window-based strategies have been developed to detect differential binding when the regions of interest are not known in advance. However, careful consideration of error control is needed when applying these methods. Peak-based approaches use the same data set to define peaks and to detect differential binding. Done improperly, this can result in loss of type I error control. For window-based methods, controlling the false discovery rate over all detected windows does not guarantee control across all detected regions. Misinterpreting the former as the latter can result in unexpected liberalness. Here, several solutions are presented to maintain error control for these de novo counting strategies. For peak-based methods, peak calling should be performed on pooled libraries prior to the statistical analysis. For window-based methods, a hybrid approach using Simes’ method is proposed to maintain control of the false discovery rate across regions. More generally, the relative advantages of peak- and window-based strategies are explored using a range of simulated and real data sets. Implementations of both strategies also compare favourably to existing programs for differential binding analyses.

Application of the False Discovery Rate to Quantitative Trait Loci Interval Mapping With Multiple Traits

Genetics ◽  
2002 ◽  
Vol 161 (2) ◽  
pp. 905-914 ◽  
Author(s):  
Hakkyo Lee ◽  
Jack C M Dekkers ◽  
M Soller ◽  
Massoud Malek ◽  
Rohan L Fernando ◽  
...  
Keyword(s):  
Quantitative Trait Loci ◽  
False Discovery Rate ◽  
Error Rate ◽  
Quantitative Trait ◽  
Interval Mapping ◽  
Error Rates ◽  
Multiple Traits ◽  
Test Statistic ◽  
False Discovery ◽  
Trait Loci

Abstract Controlling the false discovery rate (FDR) has been proposed as an alternative to controlling the genomewise error rate (GWER) for detecting quantitative trait loci (QTL) in genome scans. The objective here was to implement FDR in the context of regression interval mapping for multiple traits. Data on five traits from an F2 swine breed cross were used. FDR was implemented using tests at every 1 cM (FDR1) and using tests with the highest test statistic for each marker interval (FDRm). For the latter, a method was developed to predict comparison-wise error rates. At low error rates, FDR1 behaved erratically; FDRm was more stable but gave similar significance thresholds and number of QTL detected. At the same error rate, methods to control FDR gave less stringent significance thresholds and more QTL detected than methods to control GWER. Although testing across traits had limited impact on FDR, single-trait testing was recommended because there is no theoretical reason to pool tests across traits for FDR. FDR based on FDRm was recommended for QTL detection in interval mapping because it provides significance tests that are meaningful, yet not overly stringent, such that a more complete picture of QTL is revealed.

scholarly journals Comparison of haplotype-based tests for detecting gene–environment interactions with rare variants

2019 ◽  
Vol 21 (3) ◽  
pp. 851-862 ◽  
Author(s):  
Charalampos Papachristou ◽  
Swati Biswas
Keyword(s):  
Lung Cancer ◽  
Rare Variants ◽  
Practical Interest ◽  
Serum Triglyceride ◽  
Error Rates ◽  
Type I ◽  
Rare Haplotype ◽  
Data Set ◽  
Cancer Data ◽  
Gene Environment

Abstract Dissecting the genetic mechanism underlying a complex disease hinges on discovering gene–environment interactions (GXE). However, detecting GXE is a challenging problem especially when the genetic variants under study are rare. Haplotype-based tests have several advantages over the so-called collapsing tests for detecting rare variants as highlighted in recent literature. Thus, it is of practical interest to compare haplotype-based tests for detecting GXE including the recent ones developed specifically for rare haplotypes. We compare the following methods: haplo.glm, hapassoc, HapReg, Bayesian hierarchical generalized linear model (BhGLM) and logistic Bayesian LASSO (LBL). We simulate data under different types of association scenarios and levels of gene–environment dependence. We find that when the type I error rates are controlled to be the same for all methods, LBL is the most powerful method for detecting GXE. We applied the methods to a lung cancer data set, in particular, in region 15q25.1 as it has been suggested in the literature that it interacts with smoking to affect the lung cancer susceptibility and that it is associated with smoking behavior. LBL and BhGLM were able to detect a rare haplotype–smoking interaction in this region. We also analyzed the sequence data from the Dallas Heart Study, a population-based multi-ethnic study. Specifically, we considered haplotype blocks in the gene ANGPTL4 for association with trait serum triglyceride and used ethnicity as a covariate. Only LBL found interactions of haplotypes with race (Hispanic). Thus, in general, LBL seems to be the best method for detecting GXE among the ones we studied here. Nonetheless, it requires the most computation time.

scholarly journals Considering Both Statistical and Clinical Significance

2016 ◽  
Vol 5 (5) ◽  
pp. 16 ◽  
Author(s):  
Guolong Zhao
Keyword(s):  
Clinical Significance ◽  
Null Hypothesis ◽  
Type I Error ◽  
Statistical Significance ◽  
Error Rates ◽  
Type I ◽  
Data Set ◽  
Type I Error Rates ◽  
Empirical Coverage ◽  
Superiority Trials

To evaluate a drug, statistical significance alone is insufficient and clinical significance is also necessary. This paper explains how to analyze clinical data with considering both statistical and clinical significance. The analysis is practiced by combining a confidence interval under null hypothesis with that under non-null hypothesis. The combination conveys one of the four possible results: (i) both significant, (ii) only significant in the former, (iii) only significant in the latter or (iv) neither significant. The four results constitute a quadripartite procedure. Corresponding tests are mentioned for describing Type I error rates and power. The empirical coverage is exhibited by Monte Carlo simulations. In superiority trials, the four results are interpreted as clinical superiority, statistical superiority, non-superiority and indeterminate respectively. The interpretation is opposite in inferiority trials. The combination poses a deflated Type I error rate, a decreased power and an increased sample size. The four results may helpful for a meticulous evaluation of drugs. Of these, non-superiority is another profile of equivalence and so it can also be used to interpret equivalence. This approach may prepare a convenience for interpreting discordant cases. Nevertheless, a larger data set is usually needed. An example is taken from a real trial in naturally acquired influenza.

scholarly journals Three New Methods for Analysis of Answer Changes

2016 ◽  
Vol 77 (1) ◽  
pp. 54-81 ◽  
Author(s):  
Sandip Sinharay ◽  
Matthew S. Johnson
Keyword(s):  
Normal Distribution ◽  
Null Hypothesis ◽  
Type I Error ◽  
Error Rates ◽  
Standard Normal Distribution ◽  
Type I ◽  
Data Set ◽  
Continuity Correction ◽  
Type I Error Rates ◽  
Standard Normal

In a pioneering research article, Wollack and colleagues suggested the “erasure detection index” (EDI) to detect test tampering. The EDI can be used with or without a continuity correction and is assumed to follow the standard normal distribution under the null hypothesis of no test tampering. When used without a continuity correction, the EDI often has inflated Type I error rates. When used with a continuity correction, the EDI has satisfactory Type I error rates, but smaller power compared with the EDI without a continuity correction. This article suggests three methods for detecting test tampering that do not rely on the assumption of a standard normal distribution under the null hypothesis. It is demonstrated in a detailed simulation study that the performance of each suggested method is slightly better than that of the EDI. The EDI and the suggested methods were applied to a real data set. The suggested methods, although more computation intensive than the EDI, seem to be promising in detecting test tampering.

scholarly journals Testing Mediation Effects in High-Dimensional Microbiome Data with False Discovery Rate Control

2021 ◽  
Author(s):  
Ye Yue ◽  
Yijuan Hu
Keyword(s):  
False Discovery Rate ◽  
Relative Abundance ◽  
Mediation Analysis ◽  
Type I Error ◽  
New Method ◽  
Type I ◽  
Inverse Regression ◽  
Global Test ◽  
Mediation Effects ◽  
False Discovery

Abstract Background: Understanding whether and which microbes played a mediating role between an exposure and a disease outcome are essential for researchers to develop clinical interventions to treat the disease by modulating the microbes. Existing methods for mediation analysis of the microbiome are often limited to a global test of community-level mediation or selection of mediating microbes without control of the false discovery rate (FDR). Further, while the null hypothesis of no mediation at each microbe is a composite null that consists of three types of null (no exposure-microbe association, no microbe-outcome association given the exposure, or neither), most existing methods for the global test such as MedTest and MODIMA treat the microbes as if they are all under the same type of null. Results: We propose a new approach based on inverse regression that regresses the (possibly transformed) relative abundance of each taxon on the exposure and the exposure-adjusted outcome to assess the exposure-taxon and taxon-outcome associations simultaneously. Then the association p-values are used to test mediation at both the community and individual taxon levels. This approach fits nicely into our Linear Decomposition Model (LDM) framework, so our new method is implemented in the LDM and enjoys all the features of the LDM, i.e., allowing an arbitrary number of taxa to be tested, supporting continuous, discrete, or multivariate exposures and outcomes as well as adjustment of confounding covariates, accommodating clustered data, and offering analysis at the relative abundance or presence-absence scale. We refer to this new method as LDM-med. Using extensive simulations, we showed that LDM-med always controlled the type I error of the global test and had compelling power over existing methods; LDM-med always preserved the FDR of testing individual taxa and had much better sensitivity than alternative approaches. In contrast, MedTest and MODIMA had severely inflated type I error when different taxa were under different types of null. The flexibility of LDM-med for a variety of mediation analyses is illustrated by the application to a murine microbiome dataset, which identified a plausible mediator.Conclusions: Inverse regression coupled with the LDM is a strategy that performs well and is capable of handling mediation analysis in a wide variety of microbiome studies.

scholarly journals Optimal testing of statistical hypotheses and multiple familywise error rates

Filomat ◽  
2016 ◽  
Vol 30 (3) ◽  
pp. 681-688
Author(s):  
Farshin Hormozinejad
Keyword(s):  
Error Control ◽  
Hypothesis Test ◽  
Probability Distributions ◽  
Test Procedure ◽  
Functional Relation ◽  
Error Rates ◽  
Type I ◽  
Hypotheses Testing ◽  
Statistical Hypotheses ◽  
Statistical Hypotheses Testing

In this article the author considers the statistical hypotheses testing to make decision among hypotheses concerning many families of probability distributions. The statistician would like to control the overall error rate relative to draw statistically valid conclusions from each test, while being as efficient as possible. The familywise error (FWE) rate metric and the hypothesis test procedure while controlling both the type I and II FWEs are generalized. The proposed procedure shows simultaneous more reliability and less conservative error control relative to fixed sample and other recently proposed sequential procedures. Also, the characteristics of logarithmically asymptotically optimal (LAO) hypotheses testing are studied. The purpose of research is to express the optimal functional relation among the reliabilities of LAO hypotheses testing and to judge with FWE metric.

scholarly journals A permutation test for assessing the presence of individual differences in treatment effects

2021 ◽  
pp. 096228022110336
Author(s):  
Chi Chang ◽  
Thomas Jaki ◽  
Muhammad Saad Sadiq ◽  
Alena Kuhlemeier ◽  
Daniel Feaster ◽  
...  
Keyword(s):  
Random Forests ◽  
Error Control ◽  
Treatment Effects ◽  
Type I Error ◽  
Permutation Test ◽  
Individual Treatment ◽  
Significant Heterogeneity ◽  
Type I ◽  
Data Set ◽  
Show Evidence

An important goal of personalized medicine is to identify heterogeneity in treatment effects and then use that heterogeneity to target the intervention to those most likely to benefit. Heterogeneity is assessed using the predicted individual treatment effects framework, and a permutation test is proposed to establish if significant heterogeneity is present given the covariates and predictive model or algorithm used for predicted individual treatment effects. We first show evidence for heterogeneity in the effects of treatment across an illustrative example data set. We then use simulations with two different predictive methods (linear regression model and Random Forests) to show that the permutation test has adequate type-I error control. Next, we use an example dataset as the basis for simulations to demonstrate the ability of the permutation test to find heterogeneity in treatment effects for a predicted individual treatment effects estimate as a function of both effect size and sample size. We find that the proposed test has good power for detecting heterogeneity in treatment effects when the heterogeneity was due primarily to a single predictor, or when it was spread across the predictors. Power was found to be greater for predictions from a linear model than from random forests. This non-parametric permutation test can be used to test for significant differences across individuals in predicted individual treatment effects obtained with a given set of covariates using any predictive method with no additional assumptions.

scholarly journals Protein functional annotation of simultaneously improved stability, accuracy and false discovery rate achieved by a sequence-based deep learning

2019 ◽  
Vol 21 (4) ◽  
pp. 1437-1447 ◽  
Author(s):  
Jiajun Hong ◽  
Yongchao Luo ◽  
Yang Zhang ◽  
Junbiao Ying ◽  
Weiwei Xue ◽  
...  
Keyword(s):  
Deep Learning ◽  
False Discovery Rate ◽  
Protein Function ◽  
Functional Annotation ◽  
De Novo ◽  
Learning Algorithm ◽  
Function Annotation ◽  
False Discovery ◽  
Protein Function Annotation ◽  
Annotation Accuracy

Abstract Functional annotation of protein sequence with high accuracy has become one of the most important issues in modern biomedical studies, and computational approaches of significantly accelerated analysis process and enhanced accuracy are greatly desired. Although a variety of methods have been developed to elevate protein annotation accuracy, their ability in controlling false annotation rates remains either limited or not systematically evaluated. In this study, a protein encoding strategy, together with a deep learning algorithm, was proposed to control the false discovery rate in protein function annotation, and its performances were systematically compared with that of the traditional similarity-based and de novo approaches. Based on a comprehensive assessment from multiple perspectives, the proposed strategy and algorithm were found to perform better in both prediction stability and annotation accuracy compared with other de novo methods. Moreover, an in-depth assessment revealed that it possessed an improved capacity of controlling the false discovery rate compared with traditional methods. All in all, this study not only provided a comprehensive analysis on the performances of the newly proposed strategy but also provided a tool for the researcher in the fields of protein function annotation.

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