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1.  Pathprinting: An integrative approach to understand the functional basis of disease 
Genome Medicine  2013;5(7):68.
New strategies to combat complex human disease require systems approaches to biology that integrate experiments from cell lines, primary tissues and model organisms. We have developed Pathprint, a functional approach that compares gene expression profiles in a set of pathways, networks and transcriptionally regulated targets. It can be applied universally to gene expression profiles across species. Integration of large-scale profiling methods and curation of the public repository overcomes platform, species and batch effects to yield a standard measure of functional distance between experiments. We show that pathprints combine mouse and human blood developmental lineage, and can be used to identify new prognostic indicators in acute myeloid leukemia. The code and resources are available at
PMCID: PMC3971351  PMID: 23890051
2.  The Stem Cell Discovery Engine: an integrated repository and analysis system for cancer stem cell comparisons 
Nucleic Acids Research  2011;40(D1):D984-D991.
Mounting evidence suggests that malignant tumors are initiated and maintained by a subpopulation of cancerous cells with biological properties similar to those of normal stem cells. However, descriptions of stem-like gene and pathway signatures in cancers are inconsistent across experimental systems. Driven by a need to improve our understanding of molecular processes that are common and unique across cancer stem cells (CSCs), we have developed the Stem Cell Discovery Engine (SCDE)—an online database of curated CSC experiments coupled to the Galaxy analytical framework. The SCDE allows users to consistently describe, share and compare CSC data at the gene and pathway level. Our initial focus has been on carefully curating tissue and cancer stem cell-related experiments from blood, intestine and brain to create a high quality resource containing 53 public studies and 1098 assays. The experimental information is captured and stored in the multi-omics Investigation/Study/Assay (ISA-Tab) format and can be queried in the data repository. A linked Galaxy framework provides a comprehensive, flexible environment populated with novel tools for gene list comparisons against molecular signatures in GeneSigDB and MSigDB, curated experiments in the SCDE and pathways in WikiPathways. The SCDE is available at
PMCID: PMC3245064  PMID: 22121217
3.  The Association of Virulence Factors with Genomic Islands 
PLoS ONE  2009;4(12):e8094.
It has been noted that many bacterial virulence factor genes are located within genomic islands (GIs; clusters of genes in a prokaryotic genome of probable horizontal origin). However, such studies have been limited to single genera or isolated observations. We have performed the first large-scale analysis of multiple diverse pathogens to examine this association. We additionally identified genes found predominantly in pathogens, but not non-pathogens, across multiple genera using 631 complete bacterial genomes, and we identified common trends in virulence for genes in GIs. Furthermore, we examined the relationship between GIs and clustered regularly interspaced palindromic repeats (CRISPRs) proposed to confer resistance to phage.
Methodology/Principal Findings
We show quantitatively that GIs disproportionately contain more virulence factors than the rest of a given genome (p<1E-40 using three GI datasets) and that CRISPRs are also over-represented in GIs. Virulence factors in GIs and pathogen-associated virulence factors are enriched for proteins having more “offensive” functions, e.g. active invasion of the host, and are disproportionately components of type III/IV secretion systems or toxins. Numerous hypothetical pathogen-associated genes were identified, meriting further study.
This is the first systematic analysis across diverse genera indicating that virulence factors are disproportionately associated with GIs. “Offensive” virulence factors, as opposed to host-interaction factors, may more often be a recently acquired trait (on an evolutionary time scale detected by GI analysis). Newly identified pathogen-associated genes warrant further study. We discuss the implications of these results, which cement the significant role of GIs in the evolution of many pathogens.
PMCID: PMC2779486  PMID: 19956607
4.  oPOSSUM: integrated tools for analysis of regulatory motif over-representation 
Nucleic Acids Research  2007;35(Web Server issue):W245-W252.
The identification of over-represented transcription factor binding sites from sets of co-expressed genes provides insights into the mechanisms of regulation for diverse biological contexts. oPOSSUM, an internet-based system for such studies of regulation, has been improved and expanded in this new release. New features include a worm-specific version for investigating binding sites conserved between Caenorhabditis elegans and C. briggsae, as well as a yeast-specific version for the analysis of co-expressed sets of Saccharomyces cerevisiae genes. The human and mouse applications feature improvements in ortholog mapping, sequence alignments and the delineation of multiple alternative promoters. oPOSSUM2, introduced for the analysis of over-represented combinations of motifs in human and mouse genes, has been integrated with the original oPOSSUM system. Analysis using user-defined background gene sets is now supported. The transcription factor binding site models have been updated to include new profiles from the JASPAR database. oPOSSUM is available at
PMCID: PMC1933229  PMID: 17576675
5.  oPOSSUM: identification of over-represented transcription factor binding sites in co-expressed genes 
Nucleic Acids Research  2005;33(10):3154-3164.
Targeted transcript profiling studies can identify sets of co-expressed genes; however, identification of the underlying functional mechanism(s) is a significant challenge. Established methods for the analysis of gene annotations, particularly those based on the Gene Ontology, can identify functional linkages between genes. Similar methods for the identification of over-represented transcription factor binding sites (TFBSs) have been successful in yeast, but extension to human genomics has largely proved ineffective. Creation of a system for the efficient identification of common regulatory mechanisms in a subset of co-expressed human genes promises to break a roadblock in functional genomics research. We have developed an integrated system that searches for evidence of co-regulation by one or more transcription factors (TFs). oPOSSUM combines a pre-computed database of conserved TFBSs in human and mouse promoters with statistical methods for identification of sites over-represented in a set of co-expressed genes. The algorithm successfully identified mediating TFs in control sets of tissue-specific genes and in sets of co-expressed genes from three transcript profiling studies. Simulation studies indicate that oPOSSUM produces few false positives using empirically defined thresholds and can tolerate up to 50% noise in a set of co-expressed genes.
PMCID: PMC1142402  PMID: 15933209
6.  Structural characterization of genomes by large scale sequence-structure threading: application of reliability analysis in structural genomics 
BMC Bioinformatics  2004;5:101.
We establish that the occurrence of protein folds among genomes can be accurately described with a Weibull function. Systems which exhibit Weibull character can be interpreted with reliability theory commonly used in engineering analysis. For instance, Weibull distributions are widely used in reliability, maintainability and safety work to model time-to-failure of mechanical devices, mechanisms, building constructions and equipment.
We have found that the Weibull function describes protein fold distribution within and among genomes more accurately than conventional power functions which have been used in a number of structural genomic studies reported to date.
It has also been found that the Weibull reliability parameter β for protein fold distributions varies between genomes and may reflect differences in rates of gene duplication in evolutionary history of organisms.
The results of this work demonstrate that reliability analysis can provide useful insights and testable predictions in the fields of comparative and structural genomics.
PMCID: PMC499543  PMID: 15274750
7.  Toward interoperable bioscience data 
Nature genetics  2012;44(2):121-126.
To make full use of research data, the bioscience community needs to adopt technologies and reward mechanisms that support interoperability and promote the growth of an open ‘data commoning’ culture. Here we describe the prerequisites for data commoning and present an established and growing ecosystem of solutions using the shared ‘Investigation-Study-Assay’ framework to support that vision.
PMCID: PMC3428019  PMID: 22281772

Results 1-7 (7)