Genetic data are frequently categorical and have complex dependence structures that are not always well understood. For this reason, clustering and classification based on genetic data, while highly relevant, are challenging statistical problems. Here we consider a highly versatile U-statistics based approach built on dissimilarities between pairs of data points for nonparametric clustering. In this work we propose statistical tests to assess group homogeneity taking into account the multiple testing issues, and a clustering algorithm based on dissimilarities within and between groups that highly speeds up the homogeneity test. We also propose a test to verify classification significance of a sample in one of two groups. A Monte Carlo simulation study is presented to evaluate power of the classification test, considering different group sizes and degree of separation. Size and power of the homogeneity test are also analyzed through simulations that compare it to competing methods. Finally, the methodology is applied to three different genetic datasets: global human genetic diversity, breast tumor gene expression and Dengue virus serotypes. These applications showcase this statistical framework's ability to answer diverse biological questions while adapting to the specificities of the different datatypes.
This paper studies the problem of statistical inference for genetic relatedness between binary traits based on individual-level genome-wide association data. Specifically, under the high-dimensional logistic regression models, we define parameters characterizing the cross-trait genetic correlation, the genetic covariance and the trait-specific genetic variance. A novel weighted debiasing method is developed for the logistic Lasso estimator and computationally efficient debiased estimators are proposed. The rates of convergence for these estimators are studied and their asymptotic normality is …
In genetic association studies, detecting disease-genotype associations is a primary goal. For most diseases, the underlying genetic model is unknown, and we study seven robust test statistics for monotone association. For a given test statistic, there are many ways to calculate a p-value, but in genetic association studies, calculations have predominantly been based on asymptotic approximations or on simulated permutations. We show that when the number of permutations tends to infinity, the permutation p-value approaches the exact conditional enumeration p-value, and further that calculating …
The tau statistic $τ$ uses geolocation and, usually, symptom onset time to assess global spatiotemporal clustering from epidemiological data. We test different factors that could affect graphical hypothesis tests of clustering or bias clustering range estimates based on the statistic, by comparison with a baseline analysis of an open access measles dataset. From re-analysing this data we find that the spatial bootstrap sampling method used to construct the confidence interval for the tau estimate and confidence interval (CI) type can bias clustering range estimates. We suggest that the bias-co…
Purdue University（普渡大学）；University of Maryland, Baltimore County（马里兰大学巴尔的摩郡分校）；University of Missouri（密苏里大学）
Statistical power is a measure of the replicability of a categorical hypothesis test. Formally, it is the probability of detecting an effect, if there is a true effect present in the population. Hence, optimizing statistical power as a function of some parameters of a hypothesis test is desirable. However, for most hypothesis tests, the explicit functional form of statistical power for individual model parameters is unknown; but calculating power for a given set of values of those parameters is possible using simulated experiments. These simulated experiments are usually computationally expens…
Clustering methods are a valuable tool for the identification of patterns in high dimensional data with applications in many scientific problems. However, quantifying uncertainty in clustering is a challenging problem, particularly when dealing with High Dimension Low Sample Size (HDLSS) data. We develop here a U-statistics based clustering approach that assesses statistical significance in clustering and is specifically tailored to HDLSS scenarios. These non-parametric methods rely on very few assumptions about the data, and thus can be applied to a wide range of datasets for which the euclid…
Mendelian randomization (MR) is a method of exploiting genetic variation to unbiasedly estimate a causal effect in presence of unmeasured confounding. MR is being widely used in epidemiology and other related areas of population science. In this paper, we study statistical inference in the increasingly popular two-sample summary-data MR design. We show a linear model for the observed associations approximately holds in a wide variety of settings when all the genetic variants satisfy the exclusion restriction assumption, or in genetic terms, when there is no pleiotropy. In this scenario, we der…
Neural networks (NN) play a central role in modern Artificial intelligence (AI) technology and has been successfully used in areas such as natural language processing and image recognition. While majority of NN applications focus on prediction and classification, there are increasing interests in studying statistical inference of neural networks. The study of NN statistical inference can enhance our understanding of NN statistical proprieties. Moreover, it can facilitate the NN-based hypothesis testing that can be applied to hypothesis-driven clinical and biomedical research. In this paper, we…
Many practical studies rely on hypothesis testing procedures applied to data sets with missing information. An important part of the analysis is to determine the impact of the missing data on the performance of the test, and this can be done by properly quantifying the relative (to complete data) amount of available information. The problem is directly motivated by applications to studies, such as linkage analyses and haplotype-based association projects, designed to identify genetic contributions to complex diseases. In the genetic studies the relative information measures are needed for the …
Existing high-dimensional statistical methods are largely established for analyzing individual-level data. In this work, we study estimation and inference for high-dimensional linear models where we only observe "proxy data", which include the marginal statistics and sample covariance matrix that are computed based on different sets of individuals. We develop a rate optimal method for estimation and inference for the regression coefficient vector and its linear functionals based on the proxy data. Moreover, we show the intrinsic limitations in the proxy-data based inference: the minimax optima…
Identifying the risk factors for mental illnesses is of significant public health importance. Diagnosis, stigma associated with mental illnesses, comorbidity, and complex etiologies, among others, make it very challenging to study mental disorders. Genetic studies of mental illnesses date back at least a century ago, beginning with descriptive studies based on Mendelian laws of inheritance. A variety of study designs including twin studies, family studies, linkage analysis, and more recently, genomewide association studies have been employed to study the genetics of mental illnesses, or comple…
Genome-wide association studies (GWAS) have been widely used to examine the association between single nucleotide polymorphisms (SNPs) and complex traits, where both the sample size n and the number of SNPs p can be very large. Recently, cross-trait polygenic risk score (PRS) method has gained extremely popular for assessing genetic correlation of complex traits based on GWAS summary statistics (e.g., SNP effect size). However, empirical evidence has shown a common bias phenomenon that even highly significant cross-trait PRS can only account for a very small amount of genetic variance (R^2 oft…
Stirling numbers of the first kind are used in the derivation of several population genetics statistics, which in turn are useful for testing evolutionary hypotheses directly from DNA sequences. Here, we explore the cumulative distribution function of these Stirling numbers, which enables a single direct estimate of the sum, using representations in terms of the incomplete beta function. This estimator enables an improved method for calculating an asymptotic estimate for one useful statistic, Fu's $F_s$. By reducing the calculation from a sum of terms involving Stirling numbers to a single est…
We consider the problems of hypothesis testing and model comparison under a flexible Bayesian linear regression model whose formulation is closely connected with the linear mixed effect model and the parametric models for SNP set analysis in genetic association studies. We derive a class of analytic approximate Bayes factors and illustrate their connections with a variety of frequentist test statistics, including the Wald statistic and the variance component score statistic. Taking advantage of Bayesian model averaging and hierarchical modeling, we demonstrate some distinct advantages and flex…
With the rapid growth of modern technology, many large-scale biomedical studies have been/are being/will be conducted to collect massive datasets with large volumes of multi-modality imaging, genetic, neurocognitive, and clinical information from increasingly large cohorts. Simultaneously extracting and integrating rich and diverse heterogeneous information in neuroimaging and/or genomics from these big datasets could transform our understanding of how genetic variants impact brain structure and function, cognitive function, and brain-related disease risk across the lifespan. Such understandin…
The widely used genetic pleiotropic analysis of multiple phenotypes are often designed for examining the relationship between common variants and a few phenotypes. They are not suited for both high dimensional phenotypes and high dimensional genotype (next-generation sequencing) data. To overcome these limitations, we develop sparse structural equation models (SEMs) as a general framework for a new paradigm of genetic analysis of multiple phenotypes. To incorporate both common and rare variants into the analysis, we extend the traditional multivariate SEMs to sparse functional SEMs. To deal wi…
While studies show that autism is highly heritable, the nature of the genetic basis of this disorder remains illusive. Based on the idea that highly correlated genes are functionally interrelated and more likely to affect risk, we develop a novel statistical tool to find more potentially autism risk genes by combining the genetic association scores with gene co-expression in specific brain regions and periods of development. The gene dependence network is estimated using a novel partial neighborhood selection (PNS) algorithm, where node specific properties are incorporated into network estimat…
Investigating the pleiotropic effects of genetic variants can increase statistical power, provide important information to achieve deep understanding of the complex genetic structures of disease, and offer powerful tools for designing effective treatments with fewer side effects. However, the current multiple phenotype association analysis paradigm lacks breadth (number of phenotypes and genetic variants jointly analyzed at the same time) and depth (hierarchical structure of phenotype and genotypes). A key issue for high dimensional pleiotropic analysis is to effectively extract informative in…
The prediction of phenotypic traits using high-density genomic data has many applications such as the selection of plants and animals of commercial interest; and it is expected to play an increasing role in medical diagnostics. Statistical models used for this task are usually tested using cross-validation, which implicitly assumes that new individuals (whose phenotypes we would like to predict) originate from the same population the genomic prediction model is trained on. In this paper we propose an approach based on clustering and resampling to investigate the effect of increasing genetic di…
We propose a new methodology for selecting and ranking covariates associated with a variable of interest in a context of high-dimensional data under dependence but few observations. The methodology successively intertwines the clustering of covariates, decorrelation of covariates using Factor Latent Analysis, selection using aggregation of adapted methods and finally ranking. Simulations study shows the interest of the decorrelation inside the different clusters of covariates. We first apply our method to transcriptomic data of 37 patients with advanced non-small-cell lung cancer who have rece…
The recent explosion of genetic and high dimensional biobank and 'omic' data has provided researchers with the opportunity to investigate the shared genetic origin (pleiotropy) of hundreds to thousands of related phenotypes. However, existing methods for multi-phenotype genome-wide association studies (GWAS) do not model pleiotropy, are only applicable to a small number of phenotypes, or provide no way to perform inference. To add further complication, raw genetic and phenotype data are rarely observed, meaning analyses must be performed on GWAS summary statistics whose statistical properties …
A Weighted U Statistic for Genetic Association Analyses of Sequencing Data
Michigan State University（密歇根州立大学）；University of North Texas Health Science Center（北德克萨斯大学健康科学中心）；University of Arkansas for Medical Sciences（阿肯色大学医学科学大学）；University of Michigan（密歇根大学）；Mayo Clinic（梅奥诊所）
PPGMMGA is a Projection Pursuit (PP) algorithm aimed at detecting and visualizing clustering structures in multivariate data. The algorithm uses the negentropy as PP index obtained by fitting Gaussian Mixture Models (GMMs) for density estimation, and then optimized using Genetic Algorithms (GAs). Since the PPGMMGA algorithm is a dimension reduction technique specifically introduced for visualization purposes, cluster memberships are not explicitly provided. In this paper a modal clustering approach is proposed for estimating clusters of projected data points. In particular, a modal EM algorith…
In this manuscript, we study the statistical properties of convex clustering. We establish that convex clustering is closely related to single linkage hierarchical clustering and $k$-means clustering. In addition, we derive the range of tuning parameter for convex clustering that yields a non-trivial solution. We also provide an unbiased estimate of the degrees of freedom, and provide a finite sample bound for the prediction error for convex clustering. We compare convex clustering to some traditional clustering methods in simulation studies.
The greed package implements the general and flexible framework of arXiv:2002.11577 for model-based clustering in the R language. Based on the direct maximization of the exact Integrated Classification Likelihood with respect to the partition, it allows jointly performing clustering and selection of the number of groups. This combinatorial problem is handled through an efficient hybrid genetic algorithm, while a final hierarchical step allows accessing coarser partitions and extract an ordering of the clusters. This methodology is applicable in a wide variety of latent variable models and, hen…
Graphical modelling has a long history in statistics as a tool for the analysis of multivariate data, starting from Wright's path analysis and Gibbs' applications to statistical physics at the beginning of the last century. In its modern form, it was pioneered by Lauritzen and Wermuth and Pearl in the 1980s, and has since found applications in fields as diverse as bioinformatics, customer satisfaction surveys and weather forecasts. Genetics and systems biology are unique among these fields in the dimension of the data sets they study, which often contain several hundreds of variables and only …
We approach the problem of combining top-ranking association statistics or P-value from a new perspective which leads to a remarkably simple and powerful method. Statistical methods, such as the Rank Truncated Product (RTP), have been developed for combining top-ranking associations and this general strategy proved to be useful in applications for detecting combined effects of multiple disease components. To increase power, these methods aggregate signals across top ranking SNPs, while adjusting for their total number assessed in a study. Analytic expressions for combined top statistics or P-v…
Motivated by genetic association studies of SNPs with genotype uncertainty, we propose a generalization of the Kruskal-Wallis test that incorporates group uncertainty when comparing k samples. The extended test statistic is based on probability-weighted rank-sums and follows an asymptotic chi-square distribution with k-1 degrees of freedom under the null hypothesis. Simulation studies confirm the validity and robustness of the proposed test in finite samples. Application to a genome-wide association study of type 1 diabetic complications further demonstrates the utilities of this generalized K…
Univ. of North Carolina at Chapel Hill（北卡罗来纳大学教堂山分校）
Cluster analysis methods seek to partition a data set into homogeneous subgroups. It is useful in a wide variety of applications, including document processing and modern genetics. Conventional clustering methods are unsupervised, meaning that there is no outcome variable nor is anything known about the relationship between the observations in the data set. In many situations, however, information about the clusters is available in addition to the values of the features. For example, the cluster labels of some observations may be known, or certain observations may be known to belong to the sam…
