scholarly journals Set-based rare variant association tests for biobank scale sequencing data sets

2021 ◽  
Author(s):  
Wei Zhou ◽  
Wenjian Bi ◽  
Zhangchen Zhao ◽  
Kushal K. Dey ◽  
Karthik A. Jagadeesh ◽  
...  
Keyword(s):  
Rare Variant ◽  
Error Control ◽  
Type I Error ◽  
Error Rates ◽  
Data Sets ◽  
Type I ◽  
Sequencing Data ◽  
Functional Annotations ◽  
Whole Exome ◽  
Inflated Type

UK Biobank has released the whole-exome sequencing (WES) data for 200,000 participants, but the best practices remain unclear for rare variant tests, and an existing approach, SAIGE-GENE, can have inflated type I error rates with high computation cost. Here, we propose SAIGE-GENE+ with greatly improved type I error control and computational efficiency compared to SAIGE-GENE. In the analysis of UKBB WES data of 30 quantitative and 141 binary traits, SAIGE-GENE+ identified 551 gene-phenotype associations. In addition, we showed that incorporating multiple MAF cutoffs and functional annotations can help identify novel gene-phenotype associations and SAIGE-GENE+ can facilitate this.

scholarly journals On Robust Association Testing for Quantitative Traits and Rare Variants

2016 ◽  
Vol 6 (12) ◽  
pp. 3941-3950 ◽  
Author(s):  
Peng Wei ◽  
Ying Cao ◽  
Yiwei Zhang ◽  
Zhiyuan Xu ◽  
Il-Youp Kwak ◽  
...  
Keyword(s):  
Type I Error ◽  
Rare Variants ◽  
Error Rates ◽  
Routine Practice ◽  
Type I ◽  
Sequencing Data ◽  
High Data ◽  
Association Testing ◽  
Sequencing Technologies ◽  
Inflated Type

Abstract With the advance of sequencing technologies, it has become a routine practice to test for association between a quantitative trait and a set of rare variants (RVs). While a number of RV association tests have been proposed, there is a dearth of studies on the robustness of RV association testing for nonnormal distributed traits, e.g., due to skewness, which is ubiquitous in cohort studies. By extensive simulations, we demonstrate that commonly used RV tests, including sequence kernel association test (SKAT) and optimal unified SKAT (SKAT-O), are not robust to heavy-tailed or right-skewed trait distributions with inflated type I error rates; in contrast, the adaptive sum of powered score (aSPU) test is much more robust. Here we further propose a robust version of the aSPU test, called aSPUr. We conduct extensive simulations to evaluate the power of the tests, finding that for a larger number of RVs, aSPU is often more powerful than SKAT and SKAT-O, owing to its high data-adaptivity. We also compare different tests by conducting association analysis of triglyceride levels using the NHLBI ESP whole-exome sequencing data. The QQ plots for SKAT and SKAT-O were severely inflated (λ = 1.89 and 1.78, respectively), while those for aSPU and aSPUr behaved normally. Due to its relatively high robustness to outliers and high power of the aSPU test, we recommend its use complementary to SKAT and SKAT-O. If there is evidence of inflated type I error rate from the aSPU test, we would recommend the use of the more robust, but less powerful, aSPUr test.

scholarly journals UK-Biobank Whole Exome Sequence Binary Phenome Analysis with Robust Region-based Rare Variant Test

2019 ◽  
Author(s):  
Zhangchen Zhao ◽  
Wenjian Bi ◽  
Wei Zhou ◽  
Peter VandeHaar ◽  
Lars G. Fritsche ◽  
...  
Keyword(s):  
Data Analysis ◽  
Rare Variant ◽  
Type I Error ◽  
Case Control ◽  
Error Rates ◽  
Type I ◽  
Uk Biobank ◽  
Type I Error Rates ◽  
Whole Exome ◽  
Exome Sequence

AbstractIn biobank data analysis, most binary phenotypes have unbalanced case-control ratios, which can cause inflation of type I error rates. Recently, a saddlepoint approximation (SPA) based single variant test has been developed to provide an accurate and scalable method to test for associations of such phenotypes. For gene- or region-based multiple variant tests, a few methods exist which adjust for unbalanced case-control ratios; however, these methods are either less accurate when case-control ratios are extremely unbalanced or not scalable for large data analyses. To address these problems, we propose SKAT/SKAT-O type region-based tests, where the single-variant score statistic is calibrated based on SPA and Efficient Resampling (ER). Through simulation studies, we show that the proposed method provides well-calibrated p-values. In contrast, the unadjusted approach has greatly inflated type I error rates (90 times of exome-wideα=2.5×10-6) when the case-control ratio is 1:99. Additionally, the proposed method has similar computation time as the unadjusted approaches and is scalable for large sample data. Our UK Biobank whole exome sequence data analysis of 45,596 unrelated European samples and 791 PheCode phenotypes identified 10 rare variant associations with p-value < 10-7, including the associations betweenJAK2and myeloproliferative disease,TNCand large cell lymphoma andF11and congenital coagulation defects. All analysis summary results are publicly available through a web-based visual server.

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.

scholarly journals Generalized additive models and inflated type I error rates of smoother significance tests

2011 ◽  
Vol 55 (1) ◽  
pp. 366-374 ◽  
Author(s):  
Robin L. Young ◽  
Janice Weinberg ◽  
Verónica Vieira ◽  
Al Ozonoff ◽  
Thomas F. Webster
Keyword(s):  
Type I Error ◽  
Generalized Additive Models ◽  
Error Rates ◽  
Additive Models ◽  
Type I ◽  
Significance Tests ◽  
Type I Error Rates ◽  
Inflated Type

scholarly journals A comparative analysis of cell-type adjustment methods for epigenome-wide association studies based on simulated and real data sets

2018 ◽  
Vol 20 (6) ◽  
pp. 2055-2065 ◽  
Author(s):  
Johannes Brägelmann ◽  
Justo Lorenzo Bermejo
Keyword(s):  
Statistical Power ◽  
Type I Error ◽  
Association Studies ◽  
Real Data ◽  
Error Rates ◽  
Data Sets ◽  
Type I ◽  
Cell Type ◽  
Type I Error Rates

Abstract Technological advances and reduced costs of high-density methylation arrays have led to an increasing number of association studies on the possible relationship between human disease and epigenetic variability. DNA samples from peripheral blood or other tissue types are analyzed in epigenome-wide association studies (EWAS) to detect methylation differences related to a particular phenotype. Since information on the cell-type composition of the sample is generally not available and methylation profiles are cell-type specific, statistical methods have been developed for adjustment of cell-type heterogeneity in EWAS. In this study we systematically compared five popular adjustment methods: the factored spectrally transformed linear mixed model (FaST-LMM-EWASher), the sparse principal component analysis algorithm ReFACTor, surrogate variable analysis (SVA), independent SVA (ISVA) and an optimized version of SVA (SmartSVA). We used real data and applied a multilayered simulation framework to assess the type I error rate, the statistical power and the quality of estimated methylation differences according to major study characteristics. While all five adjustment methods improved false-positive rates compared with unadjusted analyses, FaST-LMM-EWASher resulted in the lowest type I error rate at the expense of low statistical power. SVA efficiently corrected for cell-type heterogeneity in EWAS up to 200 cases and 200 controls, but did not control type I error rates in larger studies. Results based on real data sets confirmed simulation findings with the strongest control of type I error rates by FaST-LMM-EWASher and SmartSVA. Overall, ReFACTor, ISVA and SmartSVA showed the best comparable statistical power, quality of estimated methylation differences and runtime.

scholarly journals Dynamic Scan Procedure for Detecting Rare-Variant Association Regions in Whole Genome Sequencing Studies

2019 ◽  
Author(s):  
Zilin Li ◽  
Xihao Li ◽  
Yaowu Liu ◽  
Jincheng Shen ◽  
Han Chen ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Rare Variant ◽  
Type I Error ◽  
Rare Variants ◽  
Error Rates ◽  
Type I ◽  
Whole Genome ◽  
Rare Variant Association ◽  
Dynamic Scan

AbstractWhole genome sequencing (WGS) studies are being widely conducted to identify rare variants associated with human diseases and disease-related traits. Classical single-marker association analyses for rare variants have limited power, and variant-set based analyses are commonly used to analyze rare variants. However, existing variant-set based approaches need to pre-specify genetic regions for analysis, and hence are not directly applicable to WGS data due to the large number of intergenic and intron regions that consist of a massive number of non-coding variants. The commonly used sliding window method requires pre-specifying fixed window sizes, which are often unknown as a priori, are difficult to specify in practice and are subject to limitations given genetic association region sizes are likely to vary across the genome and phenotypes. We propose a computationally-efficient and dynamic scan statistic method (Scan the Genome (SCANG)) for analyzing WGS data that flexibly detects the sizes and the locations of rare-variants association regions without the need of specifying a prior fixed window size. The proposed method controls the genome-wise type I error rate and accounts for the linkage disequilibrium among genetic variants. It allows the detected rare variants association region sizes to vary across the genome. Through extensive simulated studies that consider a wide variety of scenarios, we show that SCANG substantially outperforms several alternative rare-variant association detection methods while controlling for the genome-wise type I error rates. We illustrate SCANG by analyzing the WGS lipids data from the Atherosclerosis Risk in Communities (ARIC) study.

scholarly journals Type I Error Control for Cluster Randomized Trials Under Varying Small Sample Structures

2019 ◽  
Author(s):  
Joshua Nugent ◽  
Ken Kleinman
Keyword(s):  
Cluster Size ◽  
Error Control ◽  
Type I Error ◽  
Error Rates ◽  
Small Sample ◽  
Type I ◽  
Number Of Clusters ◽  
Type I Error Rates ◽  
Wald Tests ◽  
Cluster Randomized

Abstract Background: Linear mixed models (LMM) are a common approach to analyzing data from cluster randomized trials (CRTs). Inference on parameters can be performed via Wald tests or likelihood ratio tests (LRT), but both approaches may give incorrect Type I error rates in common finite sample settings. The impact of interactions of cluster size, number of clusters, intraclass correlation coefficient (ICC), and analysis approach on Type I error rates have not been well studied. Reviews of published CRTs find that small sample sizes are not uncommon, so the performance of different inferential approaches in these settings can guide data analysts to the best choices. Methods: Using a random-intercept LMM stucture, we use simulations to study Type I error rates with the LRT and Wald test with different degrees of freedom (DF) choices across different combinations of cluster size, number of clusters, and ICC.Results: Our simulations show that the LRT can be anti-conservative when the ICC is large and the number of clusters is small, with the effect most pronouced when the cluster size is relatively large. Wald tests with the Between-Within DF method or the Satterthwaite DF approximation maintain Type I error control at the stated level, though they are conservative when the number of clusters, the cluster size, and the ICC are small. Conclusions: Depending on the structure of the CRT, analysts should choose a hypothesis testing approach that will maintain the appropriate Type I error rate for their data. Wald tests with the Satterthwaite DF approximation work well in many circumstances, but in other cases the LRT may have Type I error rates closer to the nominal level.

scholarly journals Type I Error Control for Cluster Randomized Trials Under Varying Small Sample Structures

2020 ◽  
Author(s):  
Joshua Nugent ◽  
Ken Kleinman
Keyword(s):  
Cluster Size ◽  
Error Control ◽  
Type I Error ◽  
Error Rates ◽  
Small Sample ◽  
Type I ◽  
Number Of Clusters ◽  
Type I Error Rates ◽  
Wald Tests ◽  
Cluster Randomized

Abstract Background: Linear mixed models (LMM) are a common approach to analyzing data from cluster randomized trials (CRTs). Inference on parameters can be performed via Wald tests or likelihood ratio tests (LRT), but both approaches may give incorrect Type I error rates in common finite sample settings. The impact of different combinations of cluster size, number of clusters, intraclass correlation coefficient (ICC), and analysis approach on Type I error rates has not been well studied. Reviews of published CRTs nd that small sample sizes are not uncommon, so the performance of different inferential approaches in these settings can guide data analysts to the best choices.Methods: Using a random-intercept LMM stucture, we use simulations to study Type I error rates with the LRT and Wald test with different degrees of freedom (DF) choices across different combinations of cluster size, number of clusters, and ICC.Results: Our simulations show that the LRT can be anti-conservative when the ICC is large and the number of clusters is small, with the effect most pronounced when the cluster size is relatively large. Wald tests with the between-within DF method or the Satterthwaite DF approximation maintain Type I error control at the stated level, though they are conservative when the number of clusters, the cluster size, and the ICC are small.Conclusions: Depending on the structure of the CRT, analysts should choose a hypothesis testing approach that will maintain the appropriate Type I error rate for their data. Wald tests with the Satterthwaite DF approximation work well in many circumstances, but in other cases the LRT may have Type I error rates closer to the nominal level.

scholarly journals Assessing Treatment Effects with Pharmacometric Models: A New Method that Addresses Problems with Standard Assessments

2021 ◽  
Vol 23 (3) ◽  
Author(s):  
Estelle Chasseloup ◽  
Adrien Tessier ◽  
Mats O. Karlsson
Keyword(s):  
Multiple Testing ◽  
Type I Error ◽  
Drug Effect ◽  
Model Averaging ◽  
Clinical Trial Data ◽  
Real Data ◽  
Data Sets ◽  
Type I ◽  
Data Types ◽  
Inflated Type

AbstractLongitudinal pharmacometric models offer many advantages in the analysis of clinical trial data, but potentially inflated type I error and biased drug effect estimates, as a consequence of model misspecifications and multiple testing, are main drawbacks. In this work, we used real data to compare these aspects for a standard approach (STD) and a new one using mixture models, called individual model averaging (IMA). Placebo arm data sets were obtained from three clinical studies assessing ADAS-Cog scores, Likert pain scores, and seizure frequency. By randomly (1:1) assigning patients in the above data sets to “treatment” or “placebo,” we created data sets where any significant drug effect was known to be a false positive. Repeating the process of random assignment and analysis for significant drug effect many times (N = 1000) for each of the 40 to 66 placebo-drug model combinations, statistics of the type I error and drug effect bias were obtained. Across all models and the three data types, the type I error was (5th, 25th, 50th, 75th, 95th percentiles) 4.1, 11.4, 40.6, 100.0, 100.0 for STD, and 1.6, 3.5, 4.3, 5.0, 6.0 for IMA. IMA showed no bias in the drug effect estimates, whereas in STD bias was frequently present. In conclusion, STD is associated with inflated type I error and risk of biased drug effect estimates. IMA demonstrated controlled type I error and no bias.

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