RNA-Seq is revolutionizing the way transcript abundances are measured. A key challenge in transcript quantification from RNA-Seq data is the handling of reads that map to multiple genes or isoforms. This issue is particularly important for quantification with de novo transcriptome assemblies in the absence of sequenced genomes, as it is difficult to determine which transcripts are isoforms of the same gene. A second significant issue is the design of RNA-Seq experiments, in terms of the number of reads, read length, and whether reads come from one or both ends of cDNA fragments. We present RSEM, an user-friendly software package for quantifying gene and isoform abundances from single-end or paired-end RNA-Seq data. RSEM outputs abundance estimates, 95% credibility intervals, and visualization files and can also simulate RNA-Seq data. In contrast to other existing tools, the software does not require a reference genome. Thus, in combination with a de novo transcriptome assembler, RSEM enables accurate transcript quantification for species without sequenced genomes. On simulated and real data sets, RSEM has superior or comparable performance to quantification methods that rely on a reference genome. Taking advantage of RSEM's ability to effectively use ambiguously-mapping reads, we show that accurate gene-level abundance estimates are best obtained with large numbers of short single-end reads. On the other hand, estimates of the relative frequencies of isoforms within single genes may be improved through the use of paired-end reads, depending on the number of possible splice forms for each gene. RSEM is an accurate and user-friendly software tool for quantifying transcript abundances from RNA-Seq data. As it does not rely on the existence of a reference genome, it is particularly useful for quantification with de novo transcriptome assemblies. In addition, RSEM has enabled valuable guidance for cost-efficient design of quantification experiments with RNA-Seq, which is currently relatively expensive.

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RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome

THE DESIGN AND ANALYSIS OF EXPERIMENTS. By Oscar Kempthorne. New York, John Wiley and Sons, Inc., 1952. 631 pp. $8.50. This book by a teacher of statistics (as well as a consultant for \"experimenters\") is a comprehensive study of the philosophical background for the statistical design of experiment. It is necessary to have some facility with algebraic notation and manipulation to be able to use the volume intelligently. The problems are presented from the theoretical point of view, without such practical examples as would be helpful for those not acquainted with mathematics. The mathematical justification for the techniques is given. As a somewhat advanced treatment of the design and analysis of experiments, this volume will be interesting and helpful for many who approach statistics theoretically as well as practically. With emphasis on the \"why,\" and with description given broadly, the author relates the subject matter to the general theory of statistics and to the general problem of experimental inference. MARGARET J. ROBERTSON

The Design and Analysis of Experiments

Machine Learning is the study of methods for programming computers to learn. Computers are applied to a wide range of tasks, and for most of these it is relatively easy for programmers to design and implement the necessary software. However, there are many tasks for which this is difficult or impossible. These can be divided into four general categories. First, there are problems for which there exist no human experts. For example, in modern automated manufacturing facilities, there is a need to predict machine failures before they occur by analyzing sensor readings. Because the machines are new, there are no human experts who can be interviewed by a programmer to provide the knowledge necessary to build a computer system. A machine learning system can study recorded data and subsequent machine failures and learn prediction rules. Second, there are problems where human experts exist, but where they are unable to explain their expertise. This is the case in many perceptual tasks, such as speech recognition, hand-writing recognition, and natural language understanding. Virtually all humans exhibit expert-level abilities on these tasks, but none of them can describe the detailed steps that they follow as they perform them. Fortunately, humans can provide machines with examples of the inputs and correct outputs for these tasks, so machine learning algorithms can learn to map the inputs to the outputs. Third, there are problems where phenomena are changing rapidly. In finance, for example, people would like to predict the future behavior of the stock market, of consumer purchases, or of exchange rates. These behaviors change frequently, so that even if a programmer could construct a good predictive computer program, it would need to be rewritten frequently. A learning program can relieve the programmer of this burden by constantly modifying and tuning a set of learned prediction rules. Fourth, there are applications that need to be customized for each computer user separately. Consider, for example, a program to filter unwanted electronic mail messages. Different users will need different filters. It is unreasonable to expect each user to program his or her own rules, and it is infeasible to provide every user with a software engineer to keep the rules up-to-date. A machine learning system can learn which mail messages the user rejects and maintain the filtering rules automatically. Machine learning addresses many of the same research questions as the fields of statistics, data mining, and psychology, but with differences of emphasis. Statistics focuses on understanding the phenomena that have generated the data, often with the goal of testing different hypotheses about those phenomena. Data mining seeks to find patterns in the data that are understandable by people. Psychological studies of human learning aspire to understand the mechanisms underlying the various learning behaviors exhibited by people (concept learning, skill acquisition, strategy change, etc.).

Machine learning

Recent advances in high-throughput cDNA sequencing (RNA-seq) can reveal new genes and splice variants and quantify expression genome-wide in a single assay. The volume and complexity of data from RNA-seq experiments necessitate scalable, fast and mathematically principled analysis software. TopHat and Cufflinks are free, open-source software tools for gene discovery and comprehensive expression analysis of high-throughput mRNA sequencing (RNA-seq) data. Together, they allow biologists to identify new genes and new splice variants of known ones, as well as compare gene and transcript expression under two or more conditions. This protocol describes in detail how to use TopHat and Cufflinks to perform such analyses. It also covers several accessory tools and utilities that aid in managing data, including CummeRbund, a tool for visualizing RNA-seq analysis results. Although the procedure assumes basic informatics skills, these tools assume little to no background with RNA-seq analysis and are meant for novices and experts alike. The protocol begins with raw sequencing reads and produces a transcriptome assembly, lists of differentially expressed and regulated genes and transcripts, and publication-quality visualizations of analysis results. The protocol's execution time depends on the volume of transcriptome sequencing data and available computing resources but takes less than 1 d of computer time for typical experiments and ∼1 h of hands-on time.

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Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks

The modern science of networks has brought significant advances to our understanding of complex systems. One of the most relevant features of graphs representing real systems is community structure, or clustering, i. e. the organization of vertices in clusters, with many edges joining vertices of the same cluster and comparatively few edges joining vertices of different clusters. Such clusters, or communities, can be considered as fairly independent compartments of a graph, playing a similar role like, e. g., the tissues or the organs in the human body. Detecting communities is of great importance in sociology, biology and computer science, disciplines where systems are often represented as graphs. This problem is very hard and not yet satisfactorily solved, despite the huge effort of a large interdisciplinary community of scientists working on it over the past few years. We will attempt a thorough exposition of the topic, from the definition of the main elements of the problem, to the presentation of most methods developed, with a special focus on techniques designed by statistical physicists, from the discussion of crucial issues like the significance of clustering and how methods should be tested and compared against each other, to the description of applications to real networks.

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Community detection in graphs

Randomized experiments, or A/B tests, are the standard approach for evaluating the causal effects of new product features, i.e., treatments. The validity of these tests rests on the "stable unit treatment value assumption" (SUTVA), which implies that the treatment only affects the behavior of treated users, and does not affect the behavior of their connections. Violations of SUTVA, common in features that exhibit network effects, result in inaccurate estimates of the causal effect of treatment. In this paper, we leverage a new experimental design for testing whether SUTVA holds, without making any assumptions on how treatment effects may spill over between the treatment and the control group. To achieve this, we simultaneously run both a completely randomized and a cluster-based randomized experiment, and then we compare the difference of the resulting estimates. We present a statistical test for measuring the significance of this difference and offer theoretical bounds on the Type I error rate. We provide practical guidelines for implementing our methodology on large-scale experimentation platforms. Importantly, the proposed methodology can be applied to settings in which a network is not necessarily observed but, if available, can be used in the analysis. Finally, we deploy this design to LinkedIn's experimentation platform and apply it to two online experiments, highlighting the presence of network effects and bias in standard A/B testing approaches in a real-world setting.

Detecting Network Effects: Randomizing Over Randomized Experiments

In response to scientific needs for more diverse and structured explanations of statistical data, researchers have discovered how to model individual data points as belonging to multiple groups. Handbook of Mixed Membership Models and Their Applications shows you how to use these flexible modeling tools to uncover hidden patterns in modern high-dimensional multivariate data. It explores the use of the models in various application settings, including survey data, population genetics, text analysis, image processing and annotation, and molecular biology. Through examples using real data sets, youll discover how to characterize complex multivariate data in: Studies involving genetic databases Patterns in the progression of diseases and disabilities Combinations of topics covered by text documents Political ideology or electorate voting patterns Heterogeneous relationships in networks, and much more The handbook spans more than 20 years of the editors and contributors statistical work in the field. Top researchers compare partial and mixed membership models, explain how to interpret mixed membership, delve into factor analysis, and describe nonparametric mixed membership models. They also present extensions of the mixed membership model for text analysis, sequence and rank data, and network data as well as semi-supervised mixed membership models.

Handbook of Mixed Membership Models and Their Applications

Recent work in text analysis commonly describes topics in terms of their most frequent words, but the exclusivity of words to topics is equally important for communicating content. We introduce Hierarchical Poisson Convolution (HPC), a model which infers regularized estimates of the differential use of words across topics as well as their frequency within topics. HPC uses known hierarchical structure on human-labeled topics to make focused comparisons of differential usage within each branch of the hierarchy of labels. We then infer a summary for each topic in terms of words that are both frequent and exclusive. We develop a parallelized Hamiltonian Monte Carlo sampler that allows for fast and scalable computation.

Summarizing topical content with word frequency and exclusivity

Non-parametric approaches for analyzing network data based on exchangeable graph models (ExGM) have recently gained interest. The key object that defines an ExGM is often referred to as a graphon. This non-parametric perspective on network modeling poses challenging questions on how to make inference on the graphon underlying observed network data. In this paper, we propose a computationally efficient procedure to estimate a graphon from a set of observed networks generated from it. This procedure is based on a stochastic blockmodel approximation (SBA) of the graphon. We show that, by approximating the graphon with a stochastic block model, the graphon can be consistently estimated, that is, the estimation error vanishes as the size of the graph approaches infinity.

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Stochastic blockmodel approximation of a graphon: Theory and consistent estimation

Modeling relational data is an important problem for modern data analysis and machine learning. In this paper we propose a Bayesian model that uses a hierarchy of probabilistic assumptions about the way objects interact with one another in order to learn latent groups, their typical interaction patterns, and the degree of membership of objects to groups. Our model explains the data using a small set of parameters that can be reliably estimated with an efficient inference algorithm. In our approach, the set of probabilistic assumptions may be tailored to a specific application domain in order to incorporate intuitions and/or semantics of interest. We demonstrate our methods on simulated data and we successfully apply our model to a data set of protein-to-protein interactions.

Edoardo M. Airoldi

Papers

Detecting Network Effects: Randomizing Over Randomized Experiments

Handbook of Mixed Membership Models and Their Applications

Summarizing topical content with word frequency and exclusivity

Stochastic blockmodel approximation of a graphon: Theory and consistent estimation

A latent mixed membership model for relational data