2,360 research outputs found

    Microarrays, Empirical Bayes and the Two-Groups Model

    Get PDF
    The classic frequentist theory of hypothesis testing developed by Neyman, Pearson and Fisher has a claim to being the twentieth century's most influential piece of applied mathematics. Something new is happening in the twenty-first century: high-throughput devices, such as microarrays, routinely require simultaneous hypothesis tests for thousands of individual cases, not at all what the classical theory had in mind. In these situations empirical Bayes information begins to force itself upon frequentists and Bayesians alike. The two-groups model is a simple Bayesian construction that facilitates empirical Bayes analysis. This article concerns the interplay of Bayesian and frequentist ideas in the two-groups setting, with particular attention focused on Benjamini and Hochberg's False Discovery Rate method. Topics include the choice and meaning of the null hypothesis in large-scale testing situations, power considerations, the limitations of permutation methods, significance testing for groups of cases (such as pathways in microarray studies), correlation effects, multiple confidence intervals and Bayesian competitors to the two-groups model.Comment: This paper commented in: [arXiv:0808.0582], [arXiv:0808.0593], [arXiv:0808.0597], [arXiv:0808.0599]. Rejoinder in [arXiv:0808.0603]. Published in at http://dx.doi.org/10.1214/07-STS236 the Statistical Science (http://www.imstat.org/sts/) by the Institute of Mathematical Statistics (http://www.imstat.org

    Statistical Methods for Two Problems in Cancer Research: Analysis of RNA-seq Data from Archival Samples and Characterization of Onset of Multiple Primary Cancers

    Get PDF
    My dissertation is focused on quantitative methodology development and application for two important topics in translational and clinical cancer research. The first topic was motivated by the challenge of applying transcriptome sequencing (RNA-seq) to formalin-fixation and paraffin-embedding (FFPE) tumor samples for reliable diagnostic development. We designed a biospecimen study to directly compare gene expression results from different protocols to prepare libraries for RNA-seq from human breast cancer tissues, with randomization to fresh-frozen (FF) or FFPE conditions. To comprehensively evaluate the FFPE RNA-seq data quality for expression profiling, we developed multiple computational methods for assessment, such as the uniformity and continuity of coverage, the variance and correlation of overall gene expression, patterns of measuring coding sequence expression, phenotypic patterns of gene expression, and measurements from representative multi-gene signatures. Our results showed that the principle determinant of variance from these protocols was use of exon capture probes, followed by the conditions of preservation (FF versus FFPE), then phenotypic differences between breast cancers. We also successfully identified one protocol, with RNase H-based ribosomal RNA (rRNA) depletion, exhibited least variability of gene expression measurements, strongest correlation between FF and FFPE samples, and was generally representative of the transcriptome. In the second topic, we focused on TP53 penetrance estimation for multiple primary cancers (MPC). The study was motivated by the high proportion of MPC patients observed in Li-Fraumeni syndrome (LFS) families, but no MPC risk estimates so far have been provided for a better clinical management of LFS. To this end, we proposed a Bayesian recurrent event model based on a non-homogeneous Poisson process in order to estimate a set of penetrance for MPC related to LFS. Toward the associated inference, we employed the familywise likelihood that allows for utilizing genetic information inherited through the family. The ascertainment bias, which is inevitable in rare disease studies, was also properly adjusted by inverse probability weighting scheme. We applied the proposed method to the LFS data, a family cohort collected through pediatric sarcoma patients at MD Anderson Cancer Center from 1944 to 1982. Both internal and external validation studies show that the proposed model provides reliable penetrance estimates for MPC in LFS, which, to the best of our knowledge, have never been reported in the LFS literatures yet. The research I conducted during my PhD study will be useful to translational scientists who want to obtain accurate gene expression by applying RNA-seq technology to FFPE tumor tissue samples. This research will also be helpful to genetic counselors or genetic epidemiologists who need high-resolution penetrance estimates for primary cancer risk assessment

    On New Approaches for Variable Selection under Single Index Model and DNA Methylation Status Calling

    Get PDF
    This thesis consists of two main components: a regularization based variable selection method for the single index model and a novel classification based method for DNA methylation status calling for bisulphite-sequencing data

    Methods for Epigenetic Analyses from Long-Read Sequencing Data

    Get PDF
    Epigenetics, particularly the study of DNA methylation, is a cornerstone field for our understanding of human development and disease. DNA methylation has been included in the "hallmarks of cancer" due to its important function as a biomarker and its contribution to carcinogenesis and cancer cell plasticity. Long-read sequencing technologies, such as the Oxford Nanopore Technologies platform, have evolved the study of structural variations, while at the same time allowing direct measurement of DNA methylation on the same reads. With this, new avenues of analysis have opened up, such as long-range allele-specific methylation analysis, methylation analysis on structural variations, or relating nearby epigenetic modalities on the same read to another. Basecalling and methylation calling of Nanopore reads is a computationally expensive task which requires complex machine learning architectures. Read-level methylation calls require different approaches to data management and analysis than ones developed for methylation frequencies measured from short-read technologies or array data. The 2-dimensional nature of read and genome associated DNA methylation calls, including methylation caller uncertainties, are much more storage costly than 1-dimensional methylation frequencies. Methods for storage, retrieval, and analysis of such data therefore require careful consideration. Downstream analysis tasks, such as methylation segmentation or differential methylation calling, have the potential of benefiting from read information and allow uncertainty propagation. These avenues had not been considered in existing tools. In my work, I explored the potential of long-read DNA methylation analysis and tackled some of the challenges of data management and downstream analysis using state of the art software architecture and machine learning methods. I defined a storage standard for reference anchored and read assigned DNA methylation calls, including methylation calling uncertainties and read annotations such as haplotype or sample information. This storage container is defined as a schema for the hierarchical data format version 5, includes an index for rapid access to genomic coordinates, and is optimized for parallel computing with even load balancing. It further includes a python API for creation, modification, and data access, including convenience functions for the extraction of important quality statistics via a command line interface. Furthermore, I developed software solutions for the segmentation and differential methylation testing of DNA methylation calls from Nanopore sequencing. This implementation takes advantage of the performance benefits provided by my high performance storage container. It includes a Bayesian methylome segmentation algorithm which allows for the consensus instance segmentation of multiple sample and/or haplotype assigned DNA methylation profiles, while considering methylation calling uncertainties. Based on this segmentation, the software can then perform differential methylation testing and provides a large number of options for statistical testing and multiple testing correction. I benchmarked all tools on both simulated and publicly available real data, and show the performance benefits compared to previously existing and concurrently developed solutions. Next, I applied the methods to a cancer study on a chromothriptic cancer sample from a patient with Sonic Hedgehog Medulloblastoma. I here report regulatory genomic regions differentially methylated before and after treatment, allele-specific methylation in the tumor, as well as methylation on chromothriptic structures. Finally, I developed specialized methylation callers for the combined DNA methylation profiling of CpG, GpC, and context-free adenine methylation. These callers can be used to measure chromatin accessibility in a NOMe-seq like setup, showing the potential of long-read sequencing for the profiling of transcription factor co-binding. In conclusion, this thesis presents and subsequently benchmarks new algorithmic and infrastructural solutions for the analysis of DNA methylation data from long-read sequencing

    Advances in Data Mining Knowledge Discovery and Applications

    Get PDF
    Advances in Data Mining Knowledge Discovery and Applications aims to help data miners, researchers, scholars, and PhD students who wish to apply data mining techniques. The primary contribution of this book is highlighting frontier fields and implementations of the knowledge discovery and data mining. It seems to be same things are repeated again. But in general, same approach and techniques may help us in different fields and expertise areas. This book presents knowledge discovery and data mining applications in two different sections. As known that, data mining covers areas of statistics, machine learning, data management and databases, pattern recognition, artificial intelligence, and other areas. In this book, most of the areas are covered with different data mining applications. The eighteen chapters have been classified in two parts: Knowledge Discovery and Data Mining Applications

    Smartphone User Privacy Preserving through Crowdsourcing

    Get PDF
    In current Android architecture, users have to decide whether an app is safe to use or not. Expert users can make savvy decisions to avoid unnecessary private data breach. However, the majority of regular users are not technically capable or do not care to consider privacy implications to make safe decisions. To assist the technically incapable crowd, we propose a permission control framework based on crowdsourcing. At its core, our framework runs new apps under probation mode without granting their permission requests up-front. It provides recommendations on whether to accept or not the permission requests based on decisions from peer expert users. To seek expert users, we propose an expertise rating algorithm using a transitional Bayesian inference model. The recommendation is based on aggregated expert responses and their confidence level. As a complete framework design of the system, this thesis also includes a solution for Android app risks estimation based on behaviour analysis. To eliminate the negative impact from dishonest app owners, we also proposed a bot user detection to make it harder to utilize false recommendations through bot users to impact the overall recommendations. This work also covers a multi-view permission notification design to customize the app safety notification interface based on users\u27 need and an app recommendation method to suggest safe and usable alternative apps to users
    corecore