The discovery of rare genetic variants through Next Generation Sequencing is a very challenging issue in the field of human genetics. We propose a novel region-based statistical approach based on a Bayes Factor (BF) to assess evidence of association between a set of rare variants (RVs) located on the same genomic region and a disease outcome in the context of case-control design. Marginal likelihoods are computed under the null and alternative hypotheses assuming a binomial distribution for the RV count in the region and a beta or mixture of Dirac and beta prior distribution for the probability of RV. We derive the theoretical null distribution of the BF under our prior setting and show that a Bayesian control of the False Discovery Rate (BFDR) can be obtained for genome-wide inference. Informative priors are introduced using prior evidence of association from a Kolmogorov-Smirnov test statistic. We use our simulation program, sim1000G, to generate RV data similar to the 1,000 genomes sequencing project. Our simulation studies showed that the new BF statistic outperforms standard methods (SKAT, SKAT-O, Burden test) in case-control studies with moderate sample sizes and is equivalent to them under large sample size scenarios. Our real data application to a lung cancer case-control study found enrichment for RVs in known and novel cancer genes. It also suggests that using the BF with informative prior improves the overall gene discovery compared to the BF with non-informative prior.
Identifying differentially expressed genes from RNA sequencing data remains a challenging task because of the considerable uncertainties in parameter estimation and the small sample sizes in typical applications. Here we introduce Bayesian Analysis of Differential Expression in RNA-sequencing data (BADER). Due to our choice of data and prior distributions, full posterior inference for BADER can be carried out efficiently. The method appropriately takes uncertainty in gene variance into account, leading to higher power than existing methods in detecting differentially expressed genes. Moreover,…
Background: Single-cell RNA sequencing (scRNA-seq) is a powerful profiling technique at the single-cell resolution. Appropriate analysis of scRNA-seq data can characterize molecular heterogeneity and shed light into the underlying cellular process to better understand development and disease mechanisms. The unique analytic challenge is to appropriately model highly over-dispersed scRNA-seq count data with prevalent dropouts (zero counts), making zero-inflated dimensionality reduction techniques popular for scRNA-seq data analyses. Employing zero-inflated distributions, however, may place extra…
Tumor is heterogeneous - a tumor sample usually consists of a set of subclones with distinct transcriptional profiles and potentially different degrees of aggressiveness and responses to drugs. Understanding tumor heterogeneity is therefore critical to precise cancer prognosis and treatment. In this paper, we introduce BayCount, a Bayesian decomposition method to infer tumor heterogeneity with highly over-dispersed RNA sequencing count data. Using negative binomial factor analysis, BayCount takes into account both the between-sample and gene-specific random effects on raw counts of sequencing …
We perform differential expression analysis of high-throughput sequencing count data under a Bayesian nonparametric framework, removing sophisticated ad-hoc pre-processing steps commonly required in existing algorithms. We propose to use the gamma (beta) negative binomial process, which takes into account different sequencing depths using sample-specific negative binomial probability (dispersion) parameters, to detect differentially expressed genes by comparing the posterior distributions of gene-specific negative binomial dispersion (probability) parameters. These model parameters are inferre…
We present TreeClone, a latent feature allocation model to reconstruct tumor subclones subject to phylogenetic evolution that mimics tumor evolution. Similar to most current methods, we consider data from next-generation sequencing of tumor DNA. Unlike most methods that use information in short reads mapped to single nucleotide variants (SNVs), we consider subclone phylogeny reconstruction using pairs of two proximal SNVs that can be mapped by the same short reads. As part of the Bayesian inference model, we construct a phylogenetic tree prior. The use of the tree structure in the prior greatl…
High throughput technologies have become the practice of choice for comparative studies in biomedical applications. Limited number of sample points due to sequencing cost or access to organisms of interest necessitates the development of efficient sample collections to maximize the power of downstream statistical analyses. We propose a method for sequentially choosing training samples under the Optimal Bayesian Classification framework. Specifically designed for RNA sequencing count data, the proposed method takes advantage of efficient Gibbs sampling procedure with closed-form updates. Our re…
In the case of informative sampling the sampling scheme explicitly or implicitly depends on the response variable. As a result, the sample distribution of response variable can- not be used for making inference about the population. In this research I investigate the problem of informative sampling from the Bayesian perspective. Application of the Bayesian approach permits solving the problems, which arise due to complexity of the models, being used for handling informative sampling. The main objective of the re- search is to combine the elements of the classical sampling theory and Bayesian a…
Rapidly assaying the diversity of a bacterial species present in a sample obtained from a hospital patient or an evironmental source has become possible after recent technological advances in DNA sequencing. For several applications it is important to accurately identify the presence and estimate relative abundances of the target organisms from short sequence reads obtained from a sample. This task is particularly challenging when the set of interest includes very closely related organisms, such as different strains of pathogenic bacteria, which can vary considerably in terms of virulence, res…
Texas A&M University（德州农工大学）；University of Texas at Austin（德克萨斯大学奥斯汀分校）
Precision medicine aims for personalized prognosis and therapeutics by utilizing recent genome-scale high-throughput profiling techniques, including next-generation sequencing (NGS). However, translating NGS data faces several challenges. First, NGS count data are often overdispersed, requiring appropriate modeling. Second, compared to the number of involved molecules and system complexity, the number of available samples for studying complex disease, such as cancer, is often limited, especially considering disease heterogeneity. The key question is whether we may integrate available data from…
Tumor samples are heterogeneous. They consist of different subclones that are characterized by differences in DNA nucleotide sequences and copy numbers on multiple loci. Heterogeneity can be measured through the identification of the subclonal copy number and sequence at a selected set of loci. Understanding that the accurate identification of variant allele fractions greatly depends on a precise determination of copy numbers, we develop a Bayesian feature allocation model for jointly calling subclonal copy numbers and the corresponding allele sequences for the same loci. The proposed method u…
High-throughput sequencing technology provides unprecedented opportunities to quantitatively explore human gut microbiome and its relation to diseases. Microbiome data are compositional, sparse, noisy, and heterogeneous, which pose serious challenges for statistical modeling. We propose an identifiable Bayesian multinomial matrix factorization model to infer overlapping clusters on both microbes and hosts. The proposed method represents the observed over-dispersed zero-inflated count matrix as Dirichlet-multinomial mixtures on which latent cluster structures are built hierarchically. Under the…
Statistical estimates from survey samples have traditionally been obtained via design-based estimators. In many cases, these estimators tend to work well for quantities such as population totals or means, but can fall short as sample sizes become small. In today's "information age," there is a strong demand for more granular estimates. To meet this demand, using a Bayesian pseudo-likelihood, we propose a computationally efficient unit-level modeling approach for non-Gaussian data collected under informative sampling designs. Specifically, we focus on binary and multinomial data. Our approach i…
In this paper, the panel count data analysis for recurrent events is considered. Such analysis is useful for studying tumor or infection recurrences in both clinical trial and observational studies. A bivariate Gaussian Cox process model is proposed to jointly model the observation process and the recurrent event process. Bayesian nonparametric inference is proposed for simultaneously estimating regression parameters, bivariate frailty effects and baseline intensity functions. Inference is done through Markov chain Monte Carlo, with fully developed computational techniques. Predictive inferenc…
Changepoint analysis (also known as segmentation analysis) aims at analyzing an ordered, one-dimensional vector, in order to find locations where some characteristic of the data changes. Many models and algorithms have been studied under this theme, including models for changes in mean and / or variance, changes in linear regression parameters, etc. In this work, we are interested in an algorithm for the segmentation of long duration acoustic signals; the segmentation is based on the change of the RMS power of the signal. We investigate a Bayesian model with two possible parameterizations, and…
Functional data are often extremely high-dimensional and exhibit strong dependence structures but can often prove valuable for both prediction and inference. The literature on functional data analysis is well developed; however, there has been very little work involving functional data in complex survey settings. Motivated by physical activity monitor data from the National Health and Nutrition Examination Survey (NHANES), we develop a Bayesian model for functional covariates that can properly account for the survey design. Our approach is intended for non-Gaussian data and can be applied in m…
There are many practical difficulties in the calibration of computer models to experimental data. One such complication is the fact that certain combinations of the calibration inputs can cause the code to output data lacking fundamental properties, or even to produce no output at all. In many cases the researchers want or need to exclude the possibility of these "failures" within their analyses. We propose a Bayesian (meta-)model in which the posterior distribution for the calibration parameters naturally excludes regions of the input space corresponding to failed runs. That is, we define a s…
Use of historical data in clinical trial design and analysis has shown various advantages such as reduction of within-study placebo-treated number of subjects and increase of study power. The meta-analytic-predictive (MAP) approach accounts with a hierarchical model for between-trial heterogeneity in order to derive an informative prior from historical (often control) data. In this paper, we introduce the package RBesT (R Bayesian Evidence Synthesis Tools) which implements the MAP approach with normal (known sampling standard deviation), binomial and Poisson endpoints. The hierarchical MAP mod…
Pathogen deep-sequencing is an increasingly routinely used technology in infectious disease surveillance. We present a semi-parametric Bayesian Poisson model to exploit these emerging data for inferring infectious disease transmission flows and the sources of infection at the population level. The framework is computationally scalable in high dimensional flow spaces thanks to Hilbert Space Gaussian process approximations, allows for sampling bias adjustments, and estimation of gender- and age-specific transmission flows at finer resolution than previously possible. We apply the approach to den…
Measurement of operator quality performance has been challenging in the construction fabrication industry. Among various causes, the learning effect is a significant factor, which needs to be incorporated in achieving a reliable operator quality performance analysis. This research aims to enhance a previously developed operator quality performance measurement approach by incorporating the learning effect (i.e., work experience). To achieve this goal, the Plateau learning model is selected to quantitatively represent the relationship between quality performance and work experience through a bet…
Early Prediction of Student Performance Using Bayesian Updating with Informative Priors Across Cohorts
Hector Research Institute of Education Sciences and Psychology, University of Tübingen（蒂宾根大学教育科学与心理学赫克托研究所）；Department of Statistics, TU Dortmund University（多特蒙德工业大学统计系）
We discuss Bayesian inference for parameters selected using the data. First, we provide a critical analysis of the existing positions in the literature regarding the correct Bayesian approach under selection. Second, we propose two types of non-informative priors for selection models. These priors may be employed to produce a posterior distribution in the absence of prior information as well as to provide well-calibrated frequentist inference for the selected parameter. We test the proposed priors empirically in several scenarios.
Priors in which a large number of parameters are specified to be independent are dangerous; they make it hard to learn from data. I present a couple of examples from the literature and work through a bit of large sample theory to show what happens.
The use of the conditional autoregressive framework proposed by Besag, York, and Mollié (1991; BYM) is ubiquitous in Bayesian disease mapping and spatial epidemiology. While it is understood that Bayesian inference is based on a combination of the information contained in the data and the information contributed by the model, quantifying the contribution of the model relative to the information in the data is often non-trivial. Here, we provide a measure of the contribution of the BYM framework by first considering the simple Poisson-gamma setting in which quantifying the prior's contribution …
Using a collection of simulated an real benchmarks, we compare Bayesian and frequentist regularization approaches under a low informative constraint when the number of variables is almost equal to the number of observations on simulated and real datasets. This comparison includes new global noninformative approaches for Bayesian variable selection built on Zellner's g-priors that are similar to Liang et al. (2008). The interest of those calibration-free proposals is discussed. The numerical experiments we present highlight the appeal of Bayesian regularization methods, when compared with non-B…
Cambridge Cancer Genomics（剑桥癌症基因组学公司）；The University of Cambridge（剑桥大学）
The emerging field of precision oncology relies on the accurate pinpointing of alterations in the molecular profile of a tumor to provide personalized targeted treatments. Current methodologies in the field commonly include the application of next generation sequencing technologies to a tumor sample, followed by the identification of mutations in the DNA known as somatic variants. The differentiation of these variants from sequencing error poses a classic classification problem, which has traditionally been approached with Bayesian statistics, and more recently with supervised machine learning…
The normal-normal hierarchical model (NNHM) constitutes a simple and widely used framework for meta-analysis. In the common case of only few studies contributing to the meta-analysis, standard approaches to inference tend to perform poorly, and Bayesian meta-analysis has been suggested as a potential solution. The Bayesian approach, however, requires the sensible specification of prior distributions. While non-informative priors are commonly used for the overall mean effect, the use of weakly informative priors has been suggested for the heterogeneity parameter, in particular in the setting of…
Additive Bayesian networks are types of graphical models that extend the usual Bayesian generalized linear model to multiple dependent variables through the factorisation of the joint probability distribution of the underlying variables. When fitting an ABN model, the choice of the prior of the parameters is of crucial importance. If an inadequate prior - like a too weakly informative one - is used, data separation and data sparsity lead to issues in the model selection process. In this work a simulation study between two weakly and a strongly informative priors is presented. As weakly informa…
Motivated by the analysis of the distribution of university grades, which is usually asymmetric, we discuss two informative priors for the shape parameter of the skew-normal distribution, showing that they lead to closed-form full-conditional posterior distributions, particularly useful in MCMC computation. Gibbs sampling algorithms are discussed for the joint vector of parameters, given independent prior distributions for the location and scale parameters. Simulation studies are performed to assess the performance of Gibbs samplers and to compare the choice of informative priors against a non…
The aim of this work is to study the problem of prior elicitation for the Mallows model with Spearman's distance, a popular distance-based model for rankings or permutation data. Previous Bayesian inference for such model has been limited to the use of the uniform prior over the space of permutations. We present a novel strategy to elicit subjective prior beliefs on the location parameter of the model, discussing the interpretation of hyper-parameters and the implication of prior choices for the posterior analysis.
Unit-level models for survey data offer many advantages over their area-level counterparts, such as potential for more precise estimates and a natural benchmarking property. However two main challenges occur in this context: accounting for an informative survey design and handling non-Gaussian data types. The pseudo-likelihood approach is one solution to the former, and conjugate multivariate distribution theory offers a solution to the latter. By combining these approaches, we attain a unit-level model for count data that accounts for informative sampling designs and includes fully Bayesian m…
The United States Bureau of Labor Statistics collects data using survey instruments under informative sampling designs that assign probabilities of inclusion to be correlated with the response. The bureau extensively uses Bayesian hierarchical models and posterior sampling to impute missing items in respondent-level data and to infer population parameters. Posterior sampling for survey data collected based on informative designs are computationally expensive and do not support production schedules of the bureau. Motivated by this problem, we propose a new method to scale Bayesian computations …
Computational convenience has led to widespread use of Bayesian inference with vague or flat priors to analyze state-space models in ecology. Vague priors are claimed to be objective and to let the data speak. Neither of these claims is valid. Statisticians have criticized the use of vague priors from philosophical to computational to pragmatic reasons. Ecologists, however, dismiss such criticisms as empty philosophical wonderings with no practical implications. We illustrate that use of vague priors in population viability analysis and occupancy models can have significant impact on the analy…
We investigate Bayesian predictive inference for finite population quantities when there are unequal probabilities of selection. Only limited information about the sample design is available; i.e., only the first-order selection probabilities corresponding to the sample units are known. Our methodology, unlike that of Chambers, Dorfman and Wang (1998), can be used to make inference for finite population quantities and provides measures of precision and intervals. Moreover, our methodology, using Markov chain Monte Carlo methods, avoids the necessity of using asymptotic closed form approximatio…
Mixed modeling of extreme values and random effects is relatively unexplored topic. Computational difficulties in using the maximum likelihood method for mixed models and the fact that maximum likelihood method uses available data and does not use the prior information motivate us to use Bayesian method. Our simulation studies indicate that random effects modeling produces more reliable estimates when heterogeneity is present. The application of the proposed model to the climate data and return values of some economic indexes reveals the same pattern as the simulation results and confirms the …
Next-generation sequencing (NGS) to profile temporal changes in living systems is gaining more attention for deriving better insights into the underlying biological mechanisms compared to traditional static sequencing experiments. Nonetheless, the majority of existing statistical tools for analyzing NGS data lack the capability of exploiting the richer information embedded in temporal data. Several recent tools have been developed to analyze such data but they typically impose strict model assumptions, such as smoothness on gene expression dynamic changes. To capture a broader range of gene ex…
We develop statistically based methods to detect single nucleotide DNA mutations in next generation sequencing data. Sequencing generates counts of the number of times each base was observed at hundreds of thousands to billions of genome positions in each sample. Using these counts to detect mutations is challenging because mutations may have very low prevalence and sequencing error rates vary dramatically by genome position. The discreteness of sequencing data also creates a difficult multiple testing problem: current false discovery rate methods are designed for continuous data, and work poo…
We study the accuracy of Bayesian supervised method used to cluster individuals into genetically homogeneous groups on the basis of dominant or codominant molecular markers. We provide a formula relating an error criterion the number of loci used and the number of clusters. This formula is exact and holds for arbitrary number of clusters and markers. Our work suggests that dominant markers studies can achieve an accuracy similar to that of codominant markers studies if the number of markers used in the former is about 1.7 times larger than in the latter.
Bayesian analysis is increasingly popular for use in social science and other application areas where the data are observations from an informative sample. An informative sampling design leads to inclusion probabilities that are correlated with the response variable of interest. Model inference performed on the observed sample taken from the population will be biased for the population generative model under informative sampling since the balance of information in the sample data is different from that for the population. Typical approaches to account for an informative sampling design under B…
Microorganisms play a critical role in host health. The advancement of high-throughput sequencing technology provides opportunities for a deeper understanding of microbial interactions. However, due to the limitations of 16S ribosomal RNA sequencing, microbiome data are zero-inflated, and a quantitative comparison of microbial abundances cannot be made across subjects. By leveraging a recent microbiome profiling technique that quantifies 16S ribosomal RNA microbial counts, we propose a novel Bayesian graphical model that incorporates microorganisms' evolutionary history through a phylogenetic …
Bayesian estimation is increasingly popular for performing model based inference to support policymaking. These data are often collected from surveys under informative sampling designs where subject inclusion probabilities are designed to be correlated with the response variable of interest. Sampling weights constructed from marginal inclusion probabilities are typically used to form an exponentiated pseudo likelihood that adjusts the population likelihood for estimation on the sample due to ease-of-estimation. We propose an alternative adjustment based on a Bayes rule construction that simult…
In recent years, Bayesian statistics methods in neuroscience have been showing important advances. In particular, detection of brain signals for studying the complexity of the brain is an active area of research. Functional magnetic resonance imagining (fMRI) is an important tool to determine which parts of the brain are activated by different types of physical behavior. According to recent results there is evidence that the values of the connectivity brain signal parameters are close to zero and due to the nature of time series fMRI data with high frequency behavior, Bayesian dynamic models f…
When random effects are correlated with sample design variables, the usual approach of employing individual survey weights (constructed to be inversely proportional to the unit survey inclusion probabilities) to form a pseudo-likelihood no longer produces asymptotically unbiased inference. We construct a weight-exponentiated formulation for the random effects distribution that achieves unbiased inference for generating hyperparameters of the random effects. We contrast our approach with frequentist methods that rely on numerical integration to reveal that only the Bayesian method achieves both…
Survey data are often collected under multistage sampling designs where units are binned to clusters that are sampled in a first stage. The unit-indexed population variables of interest are typically dependent within cluster. We propose a Fully Bayesian method that constructs an exact likelihood for the observed sample to incorporate unit-level marginal sampling weights for performing unbiased inference for population parameters while simultaneously accounting for the dependence induced by sampling clusters of units to produce correct uncertainty quantification. Our approach parameterizes clus…
We propose a probabilistic model for interpreting gene expression levels that are observed through single-cell RNA sequencing. In the model, each cell has a low-dimensional latent representation. Additional latent variables account for technical effects that may erroneously set some observations of gene expression levels to zero. Conditional distributions are specified by neural networks, giving the proposed model enough flexibility to fit the data well. We use variational inference and stochastic optimization to approximate the posterior distribution. The inference procedure scales to over on…
We study the problem of distributed multi-robot coverage over an unknown, nonuniform sensory field. Modeling the sensory field as a realization of a Gaussian Process and using Bayesian techniques, we devise a policy which aims to balance the tradeoff between learning the sensory function and covering the environment. We propose an adaptive coverage algorithm called Deterministic Sequencing of Learning and Coverage (DSLC) that schedules learning and coverage epochs such that its emphasis gradually shifts from exploration to exploitation while never fully ceasing to learn. Using a novel definiti…
We propose a probabilistic model for interpreting gene expression levels that are observed through single-cell RNA sequencing. In the model, each cell has a low-dimensional latent representation. Additional latent variables account for technical effects that may erroneously set some observations of gene expression levels to zero. Conditional distributions are specified by neural networks, giving the proposed model enough flexibility to fit the data well. We use variational inference and stochastic optimization to approximate the posterior distribution. The inference procedure scales to over on…
