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Register a new userCombined Hypothesis Testing on Graphs with Applications to Gene Set Enrichment Analysis
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Ming Yuan
Publication date
2016
fields
Mathematical Statistics
and research's language is
English
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Motivated by gene set enrichment analysis, we investigate the problem of combined hypothesis testing on a graph. We introduce a general framework to effectively use the structural information of the underlying graph when testing multivariate means. A new testing procedure is proposed within this framework. We show that the test is optimal in that it can consistently detect departure from the collective null at a rate that no other test could improve, for almost all graphs. We also provide general performance bounds for the proposed test under any specific graph, and illustrate their utility through several common types of graphs. Numerical experiments are presented to further demonstrate the merits of our approach.
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Motivation: Gene set testing is typically performed in a supervised context to quantify the association between groups of genes and a clinical phenotype. In many cases, however, a gene set-based interpretation of genomic data is desired in the absence of a phenotype variable. Although methods exist for unsupervised gene set testing, they predominantly compute enrichment relative to clusters of the genomic variables with performance strongly dependent on the clustering algorithm and number of clusters. Results: We propose a novel method, spectral gene set enrichment (SGSE), for unsupervised competitive testing of the association between gene sets and empirical data sources. SGSE first computes the statistical association between gene sets and principal components (PCs) using our principal component gene set enrichment (PCGSE) method. The overall statistical association between each gene set and the spectral structure of the data is then computed by combining the PC-level p-values using the weighted Z-method with weights set to the PC variance scaled by Tracey-Widom test p-values. Using simulated data, we show that the SGSE algorithm can accurately recover spectral features from noisy data. To illustrate the utility of our method on real data, we demonstrate the superior performance of the SGSE method relative to standard cluster-based techniques for testing the association between MSigDB gene sets and the variance structure of microarray gene expression data. Availability: http://cran.r-project.org/web/packages/PCGSE/index.html Contact: [email protected] or [email protected]
We present a general framework for hypothesis testing on distributions of sets of individual examples. Sets may represent many common data sources such as groups of observations in time series, collections of words in text or a batch of images of a given phenomenon. This observation pattern, however, differs from the common assumptions required for hypothesis testing: each set differs in size, may have differing levels of noise, and also may incorporate nuisance variability, irrelevant for the analysis of the phenomenon of interest; all features that bias test decisions if not accounted for. In this paper, we propose to interpret sets as independent samples from a collection of latent probability distributions, and introduce kernel two-sample and independence tests in this latent space of distributions. We prove the consistency of tests and observe them to outperform in a wide range of synthetic experiments. Finally, we showcase their use in practice with experiments of healthcare and climate data, where previously heuristics were needed for feature extraction and testing.
We develop a unified approach to hypothesis testing for various types of widely used functional linear models, such as scalar-on-function, function-on-function and function-on-scalar models. In addition, the proposed test applies to models of mixed types, such as models with both functional and scalar predictors. In contrast with most existing methods that rest on the large-sample distributions of test statistics, the proposed method leverages the technique of bootstrapping max statistics and exploits the variance decay property that is an inherent feature of functional data, to improve the empirical power of tests especially when the sample size is limited and the signal is relatively weak. Theoretical guarantees on the validity and consistency of the proposed test are provided uniformly for a class of test statistics.
Motivation: Although principal component analysis (PCA) is widely used for the dimensional reduction of biomedical data, interpretation of PCA results remains daunting. Most existing methods attempt to explain each principal component (PC) in terms of a small number of variables by generating approximate PCs with few non-zero loadings. Although useful when just a few variables dominate the population PCs, these methods are often inadequate for characterizing the PCs of high-dimensional genomic data. For genomic data, reproducible and biologically meaningful PC interpretation requires methods based on the combined signal of functionally related sets of genes. While gene set testing methods have been widely used in supervised settings to quantify the association of groups of genes with clinical outcomes, these methods have seen only limited application for testing the enrichment of gene sets relative to sample PCs. Results: We describe a novel approach, principal component gene set enrichment (PCGSE), for computing the statistical association between gene sets and the PCs of genomic data. The PCGSE method performs a two-stage competitive gene set test using the correlation between each gene and each PC as the gene-level test statistic with flexible choice of both the gene set test statistic and the method used to compute the null distribution of the gene set statistic. Using simulated data with simulated gene sets and real gene expression data with curated gene sets, we demonstrate that biologically meaningful and computationally efficient results can be obtained from a simple parametric version of the PCGSE method that performs a correlation-adjusted two-sample t-test between the gene-level test statistics for gene set members and genes not in the set. Availability: http://cran.r-project.org/web/packages/PCGSE/index.html Contact: [email protected] or [email protected]
A central goal in designing clinical trials is to find the test that maximizes power (or equivalently minimizes required sample size) for finding a true research hypothesis subject to the constraint of type I error. When there is more than one test, such as in clinical trials with multiple endpoints, the issues of optimal design and optimal policies become more complex. In this paper we address the question of how such optimal tests should be defined and how they can be found. We review different notions of power and how they relate to study goals, and also consider the requirements of type I error control and the nature of the policies. This leads us to formulate the optimal policy problem as an explicit optimization problem with objective and constraints which describe its specific desiderata. We describe a complete solution for deriving optimal policies for two hypotheses, which have desired monotonicity properties, and are computationally simple. For some of the optimization formulations this yields optimal policies that are identical to existing policies, such as Hommels procedure or the procedure of Bittman et al. (2009), while for others it yields completely novel and more powerful policies than existing ones. We demonstrate the nature of our novel policies and their improved power extensively in simulation and on the APEX study (Cohen et al., 2016).
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