Diffusion Component Analysis: Unraveling Functional Topology in Biological Networks

Complex biological systems have been successfully modeled by biochemical and genetic interaction networks, typically gathered from high-throughput (HTP) data. These networks can be used to infer functional relationships between genes or proteins. Using the intuition that the topological role of a gene in a network relates to its biological function, local or diffusion based "guilt-by-association" and graph-theoretic methods have had success in inferring gene functions. Here we seek to improve function prediction by integrating diffusion-based methods with a novel dimensionality reduction technique to overcome the incomplete and noisy nature of network data. In this paper, we introduce diffusion component analysis (DCA), a framework that plugs in a diffusion model and learns a low-dimensional vector representation of each node to encode the topological properties of a network. As a proof of concept, we demonstrate DCA's substantial improvement over state-of-the-art diffusion-based approaches in predicting protein function from molecular interaction networks. Moreover, our DCA framework can integrate multiple networks from heterogeneous sources, consisting of genomic information, biochemical experiments and other resources, to even further improve function prediction. Yet another layer of performance gain is achieved by integrating the DCA framework with support vector machines that take our node vector representations as features. Overall, our DCA framework provides a novel representation of nodes in a network that can be used as a plug-in architecture to other machine learning algorithms to decipher topological properties of and obtain novel insights into interactomes.Comment: RECOMB 201

Enabling Privacy-Preserving GWAS in Heterogeneous Human Populations

The projected increase of genotyping in the clinic and the rise of large genomic databases has led to the possibility of using patient medical data to perform genomewide association studies (GWAS) on a larger scale and at a lower cost than ever before. Due to privacy concerns, however, access to this data is limited to a few trusted individuals, greatly reducing its impact on biomedical research. Privacy preserving methods have been suggested as a way of allowing more people access to this precious data while protecting patients. In particular, there has been growing interest in applying the concept of differential privacy to GWAS results. Unfortunately, previous approaches for performing differentially private GWAS are based on rather simple statistics that have some major limitations. In particular, they do not correct for population stratification, a major issue when dealing with the genetically diverse populations present in modern GWAS. To address this concern we introduce a novel computational framework for performing GWAS that tailors ideas from differential privacy to protect private phenotype information, while at the same time correcting for population stratification. This framework allows us to produce privacy preserving GWAS results based on two of the most commonly used GWAS statistics: EIGENSTRAT and linear mixed model (LMM) based statistics. We test our differentially private statistics, PrivSTRAT and PrivLMM, on both simulated and real GWAS datasets and find that they are able to protect privacy while returning meaningful GWAS results.Comment: To be presented at RECOMB 201

Entropy-scaling search of massive biological data

Many datasets exhibit a well-defined structure that can be exploited to design faster search tools, but it is not always clear when such acceleration is possible. Here, we introduce a framework for similarity search based on characterizing a dataset's entropy and fractal dimension. We prove that searching scales in time with metric entropy (number of covering hyperspheres), if the fractal dimension of the dataset is low, and scales in space with the sum of metric entropy and information-theoretic entropy (randomness of the data). Using these ideas, we present accelerated versions of standard tools, with no loss in specificity and little loss in sensitivity, for use in three domains---high-throughput drug screening (Ammolite, 150x speedup), metagenomics (MICA, 3.5x speedup of DIAMOND [3,700x BLASTX]), and protein structure search (esFragBag, 10x speedup of FragBag). Our framework can be used to achieve "compressive omics," and the general theory can be readily applied to data science problems outside of biology.Comment: Including supplement: 41 pages, 6 figures, 4 tables, 1 bo

HapTree-X: An Integrative Bayesian Framework for Haplotype Reconstruction from Transcriptome and Genome Sequencing Data

By running standard genotype calling tools, it is possible to accurately identify the number of wild type and mutant alleles for each single-nucleotide polymorphism (SNP) site. However, in the case of two heterozygous SNP sites, genotype calling tools cannot determine whether mutant alleles from different SNP loci are on the same chromosome or on different homologous chromosomes (i.e. compound heterozygote)

One Size Doesn't Fit All: Measuring Individual Privacy in Aggregate Genomic Data

Even in the aggregate, genomic data can reveal sensitive information about individuals. We present a new model-based measure, PrivMAF, that provides provable privacy guarantees for aggregate data (namely minor allele frequencies) obtained from genomic studies. Unlike many previous measures that have been designed to measure the total privacy lost by all participants in a study, PrivMAF gives an individual privacy measure for each participant in the study, not just an average measure. These individual measures can then be combined to measure the worst case privacy loss in the study. Our measure also allows us to quantify the privacy gains achieved by perturbing the data, either by adding noise or binning. Our findings demonstrate that both perturbation approaches offer significant privacy gains. Moreover, we see that these privacy gains can be achieved while minimizing perturbation (and thus maximizing the utility) relative to stricter notions of privacy, such as differential privacy. We test PrivMAF using genotype data from the Welcome Trust Case Control Consortium, providing a more nuanced understanding of the privacy risks involved in an actual genome-wide association studies. Interestingly, our analysis demonstrates that the privacy implications of releasing MAFs from a study can differ greatly from individual to individual. An implementation of our method is available at http://privmaf.csail.mit.edu.Wellcome Trust (London, England) (Award 076113

Metabolic Network Analysis Demystified

15th Annual International Conference, RECOMB 2011, Vancouver, BC, Canada, March 28-31, 2011. ProceedingsMetabolic networks are a representation of current knowledge about the metabolic reactions available to a given organism. These networks can be placed into various mathematical frameworks, of which the constraintbased framework [1] has received the most attention over the past 15 years. This results in a predictive model of metabolism. Metabolic models can yield predictions of two types: quantitative, such as the growth rate of an organism under given experimental conditions [2], and qualitative, such as the viability of a mutant [3] or minimal media required for growth [4]. Qualitative predictions, on which we focus, tend to be more robust and reliable than quantitative ones, while remaining experimentally testable and biologically relevant

Structure-based whole-genome realignment reveals many novel noncoding RNAs

Recent genome-wide computational screens that search for conservation of RNA secondary structure in whole-genome alignments (WGAs) have predicted thousands of structural noncoding RNAs (ncRNAs). The sensitivity of such approaches, however, is limited, due to their reliance on sequence-based whole-genome aligners, which regularly misalign structural ncRNAs. This suggests that many more structural ncRNAs may remain undetected. Structure-based alignment, which could increase the sensitivity, has been prohibitive for genome-wide screens due to its extreme computational costs. Breaking this barrier, we present the pipeline REAPR (RE-Alignment for Prediction of structural ncRNA), which efficiently realigns whole genomes based on RNA sequence and structure, thus allowing us to boost the performance of de novo ncRNA predictors, such as RNAz. Key to the pipeline's efficiency is the development of a novel banding technique for multiple RNA alignment. REAPR significantly outperforms the widely used predictors RNAz and EvoFold in genome-wide screens; in direct comparison to the most recent RNAz screen on D. melanogaster, REAPR predicts twice as many high-confidence ncRNA candidates. Moreover, modENCODE RNA-seq experiments confirm a substantial number of its predictions as transcripts. REAPR's advancement of de novo structural characterization of ncRNAs complements the identification of transcripts from rapidly accumulating RNA-seq data.National Institutes of Health (U.S.) (Grant RO1GM081871