Disease signatures are robust across tissues and experiments

Meta-analyses combining gene expression microarray experiments offer new insights into the molecular pathophysiology of disease not evident from individual experiments. Although the established technical reproducibility of microarrays serves as a basis for meta-analysis, pathophysiological reproducibility across experiments is not well established. In this study, we carried out a large-scale analysis of disease-associated experiments obtained from NCBI GEO, and evaluated their concordance across a broad range of diseases and tissue types. On evaluating 429 experiments, representing 238 diseases and 122 tissues from 8435 microarrays, we find evidence for a general, pathophysiological concordance between experiments measuring the same disease condition. Furthermore, we find that the molecular signature of disease across tissues is overall more prominent than the signature of tissue expression across diseases. The results offer new insight into the quality of public microarray data using pathophysiological metrics, and support new directions in meta-analysis that include characterization of the commonalities of disease irrespective of tissue, as well as the creation of multi-tissue systems models of disease pathology using public data

Comparison of automated and human assignment of MeSH terms on publicly-available molecular datasets

AbstractPublicly available molecular datasets can be used for independent verification or investigative repurposing, but depends on the presence, consistency and quality of descriptive annotations. Annotation and indexing of molecular datasets using well-defined controlled vocabularies or ontologies enables accurate and systematic data discovery, yet the majority of molecular datasets available through public data repositories lack such annotations. A number of automated annotation methods have been developed; however few systematic evaluations of the quality of annotations supplied by application of these methods have been performed using annotations from standing public data repositories. Here, we compared manually-assigned Medical Subject Heading (MeSH) annotations associated with experiments by data submitters in the PRoteomics IDEntification (PRIDE) proteomics data repository to automated MeSH annotations derived through the National Center for Biomedical Ontology Annotator and National Library of Medicine MetaMap programs. These programs were applied to free-text annotations for experiments in PRIDE. As many submitted datasets were referenced in publications, we used the manually curated MeSH annotations of those linked publications in MEDLINE as “gold standard”. Annotator and MetaMap exhibited recall performance 3-fold greater than that of the manual annotations. We connected PRIDE experiments in a network topology according to shared MeSH annotations and found 373 distinct clusters, many of which were found to be biologically coherent by network analysis. The results of this study suggest that both Annotator and MetaMap are capable of annotating public molecular datasets with a quality comparable, and often exceeding, that of the actual data submitters, highlighting a continuous need to improve and apply automated methods to molecular datasets in public data repositories to maximize their value and utility

Translational bioinformatics in the cloud: an affordable alternative

With the continued exponential expansion of publicly available genomic data and access to low-cost, high-throughput molecular technologies for profiling patient populations, computational technologies and informatics are becoming vital considerations in genomic medicine. Although cloud computing technology is being heralded as a key enabling technology for the future of genomic research, available case studies are limited to applications in the domain of high-throughput sequence data analysis. The goal of this study was to evaluate the computational and economic characteristics of cloud computing in performing a large-scale data integration and analysis representative of research problems in genomic medicine. We find that the cloud-based analysis compares favorably in both performance and cost in comparison to a local computational cluster, suggesting that cloud computing technologies might be a viable resource for facilitating large-scale translational research in genomic medicine

Natural Language Processing of Clinical Notes on Chronic Diseases: Systematic Review

Novel approaches that complement and go beyond evidence-based medicine are required in the domain of chronic diseases, given the growing incidence of such conditions on the worldwide population. A promising avenue is the secondary use of electronic health records (EHRs), where patient data are analyzed to conduct clinical and translational research. Methods based on machine learning to process EHRs are resulting in improved understanding of patient clinical trajectories and chronic disease risk prediction, creating a unique opportunity to derive previously unknown clinical insights. However, a wealth of clinical histories remains locked behind clinical narratives in free-form text. Consequently, unlocking the full potential of EHR data is contingent on the development of natural language processing (NLP) methods to automatically transform clinical text into structured clinical data that can guide clinical decisions and potentially delay or prevent disease onset

Genome-Wide Significant Loci: How Important Are They? Systems Genetics to Understand Heritability of Coronary Artery Disease and Other Common Complex Disorders

AbstractGenome-wide association studies (GWAS) have been extensively used to study common complex diseases such as coronary artery disease (CAD), revealing 153 suggestive CAD loci, of which at least 46 have been validated as having genome-wide significance. However, these loci collectively explain <10% of the genetic variance in CAD. Thus, we must address the key question of what factors constitute the remaining 90% of CAD heritability. We review possible limitations of GWAS, and contextually consider some candidate CAD loci identified by this method. Looking ahead, we propose systems genetics as a complementary approach to unlocking the CAD heritability and etiology. Systems genetics builds network models of relevant molecular processes by combining genetic and genomic datasets to ultimately identify key “drivers” of disease. By leveraging systems-based genetic approaches, we can help reveal the full genetic basis of common complex disorders, enabling novel diagnostic and therapeutic opportunities

An integrative method for scoring candidate genes from association studies: application to warfarin dosing

BackgroundA key challenge in pharmacogenomics is the identification of genes whose variants contribute to drug response phenotypes, which can include severe adverse effects. Pharmacogenomics GWAS attempt to elucidate genotypes predictive of drug response. However, the size of these studies has severely limited their power and potential application. We propose a novel knowledge integration and SNP aggregation approach for identifying genes impacting drug response. Our SNP aggregation method characterizes the degree to which uncommon alleles of a gene are associated with drug response. We first use pre-existing knowledge sources to rank pharmacogenes by their likelihood to affect drug response. We then define a summary score for each gene based on allele frequencies and train linear and logistic regression classifiers to predict drug response phenotypes.ResultsWe applied our method to a published warfarin GWAS data set comprising 181 individuals. We find that our method can increase the power of the GWAS to identify both VKORC1 and CYP2C9 as warfarin pharmacogenes, where the original analysis had only identified VKORC1. Additionally, we find that our method can be used to discriminate between low-dose (AUROC=0.886) and high-dose (AUROC=0.764) responders.ConclusionsOur method offers a new route for candidate pharmacogene discovery from pharmacogenomics GWAS, and serves as a foundation for future work in methods for predictive pharmacogenomics

STORMSeq: An Open-Source, User-Friendly Pipeline for Processing Personal Genomics Data in the Cloud

The increasing public availability of personal complete genome sequencing data has ushered in an era of democratized genomics. However, read mapping and variant calling software is constantly improving and individuals with personal genomic data may prefer to customize and update their variant calls. Here, we describe STORMSeq (Scalable Tools for Open-Source Read Mapping), a graphical interface cloud computing solution that does not require a parallel computing environment or extensive technical experience. This customizable and modular system performs read mapping, read cleaning, and variant calling and annotation. At present, STORMSeq costs approximately $2 and 5–10 hours to process a full exome sequence and$30 and 3–8 days to process a whole genome sequence. We provide this open-access and open-source resource as a user-friendly interface in Amazon EC2