scholarly journals Meta-MultiSKAT: Multiple phenotype meta-analysis for region-based association test

2019 ◽  
Author(s):  
Diptavo Dutta ◽  
Sarah A. Gagliano Taliun ◽  
Joshua S. Weinstock ◽  
Matthew Zawistowski ◽  
Carlo Sidore ◽  
...  
Keyword(s):  
Type I Error ◽  
Rare Variants ◽  
Meta Analysis ◽  
Region Of Interest ◽  
Type I ◽  
Association Analyses ◽  
Component Test ◽  
Multiple Phenotype ◽  
Meta Analyses ◽  
Single Phenotype

AbstractThe power of genetic association analyses can be increased by jointly meta-analyzing multiple correlated phenotypes. Here, we develop a meta-analysis framework, Meta-MultiSKAT, that uses summary statistics to test for association between multiple continuous phenotypes and variants in a region of interest. Our approach models the heterogeneity of effects between studies through a kernel matrix and performs a variance component test for association. Using a genotype kernel, our approach can test for rare-variants and the combined effects of both common and rare-variants. To achieve robust power, within Meta-MultiSKAT, we developed fast and accurate omnibus tests combining different models of genetic effects, functional genomic annotations, multiple correlated phenotypes and heterogeneity across studies. Additionally, Meta-MultiSKAT accommodates situations where studies do not share exactly the same set of phenotypes or have differing correlation patterns among the phenotypes. Simulation studies confirm that Meta-MultiSKAT can maintain type-I error rate at exome-wide level of 2.5×10−6. Further simulations under different models of association show that Meta-MultiSKAT can improve power of detection from 23% to 38% on average over single phenotype-based meta-analysis approaches. We demonstrate the utility and improved power of Meta-MultiSKAT in the meta-analyses of four white blood cell subtype traits from the Michigan Genomics Initiative (MGI) and SardiNIA studies.

scholarly journals Multi-SKAT: General framework to test multiple phenotype associations of rare variants

2017 ◽  
Author(s):  
Diptavo Dutta ◽  
Laura Scott ◽  
Michael Boehnke ◽  
Seunggeun Lee
Keyword(s):  
General Framework ◽  
Type I Error ◽  
Rare Variants ◽  
Simulated Data ◽  
P Value ◽  
Type I ◽  
Component Test ◽  
Multiple Phenotype ◽  
Causal Variants ◽  
Multivariate Kernel Regression

In genetic association analysis, a joint test of multiple distinct phenotypes can increase power to identify sets of trait-associated variants within genes or regions of interest. Existing multi-phenotype tests for rare variants make specific assumptions about the patterns of association of underlying causal variants, and the violation of these assumptions can reduce power to detect association. Here we develop a general framework for testing pleiotropic effects of rare variants based on multivariate kernel regression (Multi-SKAT). Multi-SKAT models effect sizes of variants on the phenotypes through a kernel matrix and performs a variance component test of association. We show that many existing tests are equivalent to specific choices of kernel matrices with the Multi-SKAT framework. To increase power to detect association across tests with different kernel matrices, we developed a fast and accurate approximation of the significance of the minimum observed p-value across tests. To account for related individuals, our framework uses a random effects for the kinship matrix. Using simulated data and amino acid and exome-array data from the METSIM study, we show that Multi-SKAT can improve power over single-phenotype SKAT-O test and existing multiple phenotype tests, while maintaining type I error rate.

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 Cannons and sparrows II: the enhanced Bernoulli exact method for determining statistical significance and effect size in the meta-analysis of k 2 × 2 tables

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Lawrence M. Paul
Keyword(s):  
Effect Size ◽  
Type I Error ◽  
Meta Analysis ◽  
Statistical Significance ◽  
Statistical Error ◽  
Exact Method ◽  
Type I ◽  
Exact Test ◽  
Inverse Variance ◽  
Meta Analyses

Abstract Background The use of meta-analysis to aggregate the results of multiple studies has increased dramatically over the last 40 years. For homogeneous meta-analysis, the Mantel–Haenszel technique has typically been utilized. In such meta-analyses, the effect size across the contributing studies of the meta-analysis differs only by statistical error. If homogeneity cannot be assumed or established, the most popular technique developed to date is the inverse-variance DerSimonian and Laird (DL) technique (DerSimonian and Laird, in Control Clin Trials 7(3):177–88, 1986). However, both of these techniques are based on large sample, asymptotic assumptions. At best, they are approximations especially when the number of cases observed in any cell of the corresponding contingency tables is small. Results This research develops an exact, non-parametric test for evaluating statistical significance and a related method for estimating effect size in the meta-analysis of k 2 × 2 tables for any level of heterogeneity as an alternative to the asymptotic techniques. Monte Carlo simulations show that even for large values of heterogeneity, the Enhanced Bernoulli Technique (EBT) is far superior at maintaining the pre-specified level of Type I Error than the DL technique. A fully tested implementation in the R statistical language is freely available from the author. In addition, a second related exact test for estimating the Effect Size was developed and is also freely available. Conclusions This research has developed two exact tests for the meta-analysis of dichotomous, categorical data. The EBT technique was strongly superior to the DL technique in maintaining a pre-specified level of Type I Error even at extremely high levels of heterogeneity. As shown, the DL technique demonstrated many large violations of this level. Given the various biases towards finding statistical significance prevalent in epidemiology today, a strong focus on maintaining a pre-specified level of Type I Error would seem critical. In addition, a related exact method for estimating the Effect Size was developed.

Visual Inference for the Funnel Plot in Meta-Analysis

2019 ◽  
Vol 227 (1) ◽  
pp. 83-89 ◽  
Author(s):  
Michael Kossmeier ◽  
Ulrich S. Tran ◽  
Martin Voracek
Keyword(s):  
Visual Inspection ◽  
Type I Error ◽  
Statistical Tests ◽  
Meta Analysis ◽  
Real Data ◽  
Type I ◽  
Funnel Plot ◽  
Funnel Plots ◽  
Meta Analyses ◽  
Open Nature

Abstract. The funnel plot is widely used in meta-analyses to assess potential publication bias. However, experimental evidence suggests that informal, mere visual, inspection of funnel plots is frequently prone to incorrect conclusions, and formal statistical tests (Egger regression and others) entirely focus on funnel plot asymmetry. We suggest using the visual inference framework with funnel plots routinely, including for didactic purposes. In this framework, the type I error is controlled by design, while the explorative, holistic, and open nature of visual graph inspection is preserved. Specifically, the funnel plot of the actually observed data is presented simultaneously, in a lineup, with null funnel plots showing data simulated under the null hypothesis. Only when the real data funnel plot is identifiable from all the funnel plots presented, funnel plot-based conclusions might be warranted. Software to implement visual funnel plot inference is provided via a tailored R function.

scholarly journals A permutation method for detecting trend correlations in rare variant association studies

2019 ◽  
Vol 101 ◽  
Author(s):  
Lifeng Liu ◽  
Pengfei Wang ◽  
Jingbo Meng ◽  
Lili Chen ◽  
Wensheng Zhu ◽  
...  
Keyword(s):  
Rare Variant ◽  
Type I Error ◽  
Rare Variants ◽  
Association Studies ◽  
Complex Diseases ◽  
Type I ◽  
Phenotypic Variance ◽  
Rare Variant Association ◽  
Significance Level ◽  
Association Analyses

Abstract In recent years, there has been an increasing interest in detecting disease-related rare variants in sequencing studies. Numerous studies have shown that common variants can only explain a small proportion of the phenotypic variance for complex diseases. More and more evidence suggests that some of this missing heritability can be explained by rare variants. Considering the importance of rare variants, researchers have proposed a considerable number of methods for identifying the rare variants associated with complex diseases. Extensive research has been carried out on testing the association between rare variants and dichotomous, continuous or ordinal traits. So far, however, there has been little discussion about the case in which both genotypes and phenotypes are ordinal variables. This paper introduces a method based on the γ-statistic, called OV-RV, for examining disease-related rare variants when both genotypes and phenotypes are ordinal. At present, little is known about the asymptotic distribution of the γ-statistic when conducting association analyses for rare variants. One advantage of OV-RV is that it provides a robust estimation of the distribution of the γ-statistic by employing the permutation approach proposed by Fisher. We also perform extensive simulations to investigate the numerical performance of OV-RV under various model settings. The simulation results reveal that OV-RV is valid and efficient; namely, it controls the type I error approximately at the pre-specified significance level and achieves greater power at the same significance level. We also apply OV-RV for rare variant association studies of diastolic blood pressure.

Random-effects meta-analysis: the number of studies matters

2015 ◽  
Vol 26 (3) ◽  
pp. 1500-1518 ◽  
Author(s):  
Annamaria Guolo ◽  
Cristiano Varin
Keyword(s):  
Random Effects ◽  
Type I Error ◽  
Meta Analysis ◽  
Practical Interest ◽  
Error Rates ◽  
Type I ◽  
Model Framework ◽  
Random Effects Models ◽  
Meta Analyses ◽  
The Impact

This paper investigates the impact of the number of studies on meta-analysis and meta-regression within the random-effects model framework. It is frequently neglected that inference in random-effects models requires a substantial number of studies included in meta-analysis to guarantee reliable conclusions. Several authors warn about the risk of inaccurate results of the traditional DerSimonian and Laird approach especially in the common case of meta-analysis involving a limited number of studies. This paper presents a selection of likelihood and non-likelihood methods for inference in meta-analysis proposed to overcome the limitations of the DerSimonian and Laird procedure, with a focus on the effect of the number of studies. The applicability and the performance of the methods are investigated in terms of Type I error rates and empirical power to detect effects, according to scenarios of practical interest. Simulation studies and applications to real meta-analyses highlight that it is not possible to identify an approach uniformly superior to alternatives. The overall recommendation is to avoid the DerSimonian and Laird method when the number of meta-analysis studies is modest and prefer a more comprehensive procedure that compares alternative inferential approaches. R code for meta-analysis according to all of the inferential methods examined in the paper is provided.

scholarly journals Investigating heterogeneity in meta-analysis of studies with rare events

METRON ◽  
2021 ◽  
Author(s):  
Dankmar Böhning ◽  
Heinz Holling ◽  
Walailuck Böhning ◽  
Patarawan Sangnawakij
Keyword(s):  
Risk Ratio ◽  
Type I Error ◽  
Rare Events ◽  
Meta Analysis ◽  
Rare Event ◽  
Control Group ◽  
Type I ◽  
Bootstrap Approach ◽  
Testing Homogeneity ◽  
Meta Analyses

AbstractIn many meta-analyses, the variable of interest is frequently a count outcome reported in an intervention and a control group. Single- or double-zero studies are often observed in this type of data. Given this setting, the well-known Cochran’s Q statistic for testing homogeneity becomes undefined. In this paper, we propose two statistics for testing homogeneity of the risk ratio, particularly for application in the case of rare events in meta-analysis. The first one is a chi-square type statistic. It is constructed based on information of the conditional probability of the number of events in the treatment group given the total number of events. The second one is a likelihood ratio statistic, derived from the logistic regression models allowing fixed and random effects for the risk ratio. Both proposed statistics are well defined even in the situation of single-zero studies. In a simulation study, the proposed tests show a performance better than the traditional test in terms of type I error and power of the test under common and rare event situations. However, as the performance of the two newly proposed tests is still unsatisfactory in the very rare events setting, we suggest a bootstrap approach that does not rely on asymptotic distributional theory and it is shown that the bootstrap approach performs well in terms of type I error. Furthermore, a number of empirical meta-analyses are used to illustrate the methods.

scholarly journals Canons and Sparrows II*: The Enhanced Bernoulli Exact Method for Determining Statistical Significance and Effect Size in the Meta-Analysis of k 2 x 2 Tables

2021 ◽  
Author(s):  
Lawrence Marc Paul
Keyword(s):  
Effect Size ◽  
Type I Error ◽  
Meta Analysis ◽  
Statistical Significance ◽  
Statistical Error ◽  
Type I ◽  
Exact Test ◽  
Strong Focus ◽  
Inverse Variance ◽  
Meta Analyses

Abstract BackgroundThe use of meta-analysis to aggregate the results of multiple studies has increased dramatically over the last 40 years. For homogeneous meta-analysis, the Mantel-Haenszel technique has typically been utilized. In such meta-analyses, the effect size across the contributing studies of the meta-analysis differ only by statistical error. If homogeneity cannot be assumed or established, the most popular technique developed to date is the inverse-variance DerSimonian & Laird (DL) technique [1]. However, both of these techniques are based on large sample, asymptotic assumptions. At best, they are approximations especially when the number of cases observed in any cell of the corresponding contingency tables is small.ResultsThis research develops an exact, non-parametric test for evaluating statistical significance and a related method for estimating effect size in the meta-analysis of k 2 x 2 tables for any level of heterogeneity as an alternative to the asymptotic techniques. Monte Carlo simulations show that even for large values of heterogeneity, the Enhanced Bernoulli Technique (EBT) is far superior at maintaining the pre-specified level of Type I Error than the DL technique. A fully tested implementation in the R statistical language is freely available from the author. In addition, a second related exact test for estimating the Effect Size was developed and is also freely available.ConclusionsThis research has developed two exact tests for the meta-analysis of dichotomous, categorical data. The EBT technique was strongly superior to the DL technique in maintaining a pre-specified level of Type I Error even at extremely high levels of heterogeneity. As shown, the DL technique demonstrated many large violations of this level. Given the various biases towards finding statistical significance prevalent in epidemiology today, a strong focus on maintaining a pre-specified level of Type I Error would seem critical.

Evaluation of the Normality Assumption in Meta-Analyses

2019 ◽  
Vol 189 (3) ◽  
pp. 235-242 ◽  
Author(s):  
Chia-Chun Wang ◽  
Wen-Chung Lee
Keyword(s):  
Random Effects ◽  
Type I Error ◽  
Meta Analysis ◽  
Error Rates ◽  
Type I ◽  
Simulation Studies ◽  
Type I Error Rates ◽  
Normality Assumption ◽  
Normality Test ◽  
Meta Analyses

Abstract Random-effects meta-analysis is one of the mainstream methods for research synthesis. The heterogeneity in meta-analyses is usually assumed to follow a normal distribution. This is actually a strong assumption, but one that often receives little attention and is used without justification. Although methods for assessing the normality assumption are readily available, they cannot be used directly because the included studies have different within-study standard errors. Here we present a standardization framework for evaluation of the normality assumption and examine its performance in random-effects meta-analyses with simulation studies and real examples. We use both a formal statistical test and a quantile-quantile plot for visualization. Simulation studies show that our normality test has well-controlled type I error rates and reasonable power. We also illustrate the real-world significance of examining the normality assumption with examples. Investigating the normality assumption can provide valuable information for further analysis or clinical application. We recommend routine examination of the normality assumption with the proposed framework in future meta-analyses.

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