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Register a new userVariance Estimation and Confidence Intervals from High-dimensional Genome-wide Association Studies Through Misspecified Mixed Model Analysis
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Added by
Cecilia Dao
Publication date
2021
fields
Mathematical Statistics
and research's language is
English
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We study variance estimation and associated confidence intervals for parameters characterizing genetic effects from genome-wide association studies (GWAS) misspecified mixed model analysis. Previous studies have shown that, in spite of the model misspecification, certain quantities of genetic interests are estimable, and consistent estimators of these quantities can be obtained using the restricted maximum likelihood (REML) method under a misspecified linear mixed model. However, the asymptotic variance of such a REML estimator is complicated and not ready to be implemented for practical use. In this paper, we develop practical and computationally convenient methods for estimating such asymptotic variances and constructing the associated confidence intervals. Performance of the proposed methods is evaluated empirically based on Monte-Carlo simulations and real-data application.
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We study behavior of the restricted maximum likelihood (REML) estimator under a misspecified linear mixed model (LMM) that has received much attention in recent gnome-wide association studies. The asymptotic analysis establishes consistency of the REML estimator of the variance of the errors in the LMM, and convergence in probability of the REML estimator of the variance of the random effects in the LMM to a certain limit, which is equal to the true variance of the random effects multiplied by the limiting proportion of the nonzero random effects present in the LMM. The aymptotic results also establish convergence rate (in probability) of the REML estimators as well as a result regarding convergence of the asymptotic conditional variance of the REML estimator. The asymptotic results are fully supported by the results of empirical studies, which include extensive simulation studies that compare the performance of the REML estimator (under the misspecified LMM) with other existing methods.
We present an efficient method of calculating exact confidence intervals for the hypergeometric parameter. The method inverts minimum-width acceptance intervals after shifting them to make their endpoints nondecreasing while preserving their level. The resulting set of confidence intervals achieves minimum possible average width, and even in comparison with confidence sets not required to be intervals it attains the minimum possible cardinality most of the time, and always within 1. The method compares favorably with existing methods not only in the size of the intervals but also in the time required to compute them. The available R package hyperMCI implements the proposed method.
The variance of noise plays an important role in many change-point detection procedures and the associated inferences. Most commonly used variance estimators require strong assumptions on the true mean structure or normality of the error distribution, which may not hold in applications. More importantly, the qualities of these estimators have not been discussed systematically in the literature. In this paper, we introduce a framework of equivariant variance estimation for multiple change-point models. In particular, we characterize the set of all equivariant unbiased quadratic variance estimators for a family of change-point model classes, and develop a minimax theory for such estimators.
The issue of honesty in constructing confidence sets arises in nonparametric regression. While optimal rate in nonparametric estimation can be achieved and utilized to construct sharp confidence sets, severe degradation of confidence level often happens after estimating the degree of smoothness. Similarly, for high-dimensional regression, oracle inequalities for sparse estimators could be utilized to construct sharp confidence sets. Yet the degree of sparsity itself is unknown and needs to be estimated, causing the honesty problem. To resolve this issue, we develop a novel method to construct honest confidence sets for sparse high-dimensional linear regression. The key idea in our construction is to separate signals into a strong and a weak group, and then construct confidence sets for each group separately. This is achieved by a projection and shrinkage approach, the latter implemented via Stein estimation and the associated Stein unbiased risk estimate. Our confidence set is honest over the full parameter space without any sparsity constraints, while its diameter adapts to the optimal rate of $n^{-1/4}$ when the true parameter is indeed sparse. Through extensive numerical comparisons, we demonstrate that our method outperforms other competitors with big margins for finite samples, including oracle methods built upon the true sparsity of the underlying model.
Combining data from several case-control genome-wide association (GWA) studies can yield greater efficiency for detecting associations of disease with single nucleotide polymorphisms (SNPs) than separate analyses of the component studies. We compared several procedures to combine GWA study data both in terms of the power to detect a disease-associated SNP while controlling the genome-wide significance level, and in terms of the detection probability ($mathit{DP}$). The $mathit{DP}$ is the probability that a particular disease-associated SNP will be among the $T$ most promising SNPs selected on the basis of low $p$-values. We studied both fixed effects and random effects models in which associations varied across studies. In settings of practical relevance, meta-analytic approaches that focus on a single degree of freedom had higher power and $mathit{DP}$ than global tests such as summing chi-square test-statistics across studies, Fishers combination of $p$-values, and forming a combined list of the best SNPs from within each study.
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