Corey Flynn

Bio: Corey Flynn is an academic researcher from Broad Institute. The author has contributed to research in topics: Serialization & File format. The author has an hindex of 5, co-authored 5 publications receiving 1508 citations.

A Next Generation Connectivity Map: L1000 Platform And The First 1,000,000 Profiles

Abstract: We previously piloted the concept of a Connectivity Map (CMap), whereby genes, drugs and disease states are connected by virtue of common gene-expression signatures. Here, we report more than a 1,000-fold scale-up of the CMap as part of the NIH LINCS Consortium, made possible by a new, low-cost, high throughput reduced representation expression profiling method that we term L1000. We show that L1000 is highly reproducible, comparable to RNA sequencing, and suitable for computational inference of the expression levels of 81% of non-measured transcripts. We further show that the expanded CMap can be used to discover mechanism of action of small molecules, functionally annotate genetic variants of disease genes, and inform clinical trials. The 1.3 million L1000 profiles described here, as well as tools for their analysis, are available at https://clue.io.

LINCS Canvas Browser: interactive web app to query, browse and interrogate LINCS L1000 gene expression signatures

Abstract: For the Library of Integrated Network-based Cellular Signatures (LINCS) project many gene expression signatures using the L1000 technology have been produced. The L1000 technology is a costeffective method to profile gene expression in large scale. LINCS Canvas Browser (LCB) is an interactive HTML5 web-based software application that facilitates querying, browsing and interrogating many of the currently available LINCS L1000 data. LCB implements two compacted layered canvases, one to visualize clustered L1000 expression data, and the other to display enrichment analysis results using 30 different gene set libraries. Clicking on an experimental condition highlights gene-sets enriched for the differentially expressed genes from the selected experiment. A search interface allows users to input gene lists and query them against over 100 000 conditions to find the top matching experiments. The tool integrates many resources for an unprecedented potential for new discoveries in systems biology and systems pharmacology. The LCB application is available at http://www.maayanlab.net/LINCS/LCB. Customized versions will be made part of the http:// lincscloud.org and http://lincs.hms.harvard.edu websites.

The GCTx format and cmap{Py, R, M, J} packages: resources for optimized storage and integrated traversal of annotated dense matrices.

Abstract: Motivation Facilitated by technological improvements, pharmacologic and genetic perturbational datasets have grown in recent years to include millions of experiments Sharing and publicly distributing these diverse data creates many opportunities for discovery, but in recent years the unprecedented size of data generated and its complex associated metadata have also created data storage and integration challenges Results We present the GCTx file format and a suite of open-source packages for the efficient storage, serialization and analysis of dense two-dimensional matrices We have extensively used the format in the Connectivity Map to assemble and share massive datasets currently comprising 13 million experiments, and we anticipate that the format's generalizability, paired with code libraries that we provide, will lower barriers for integrated cross-assay analysis and algorithm development Availability and implementation Software packages (available in Python, R, Matlab and Java) are freely available at https://githubcom/cmap Additional instructions, tutorials and datasets are available at clueio/code Supplementary information Supplementary data are available at Bioinformatics online

The GCTx format and cmap{Py, R, M} packages: resources for the optimized storage and integrated traversal of dense matrices of data and annotations

Abstract: Motivation: Computational analysis of datasets generated by treating cells with pharmacological and genetic perturbagens has proven useful for the discovery of functional relationships. Facilitated by technological improvements, perturbational datasets have grown in recent years to include millions of experiments. While initial studies, such as our work on Connectivity Map, used gene expression readouts, recent studies from the NIH LINCS consortium have expanded to a more diverse set of molecular readouts, including proteomic and cell morphological signatures. Sharing these diverse data creates many opportunities for research and discovery, but the unprecedented size of data generated and the complex metadata associated with experiments have also created fundamental technical challenges regarding data storage and cross-assay integration. Results: We present the GCTx file format and a suite of open-source packages for the efficient storage, serialization, and analysis of dense two-dimensional matrices. The utility of this format is not just theoretical; we have extensively used the format in the Connectivity Map to assemble and share massive data sets comprising 1.7 million experiments. We anticipate that the generalizability of the GCTx format, paired with code libraries that we provide, will stimulate wider adoption and lower barriers for integrated cross-assay analysis and algorithm development. Availability: Software packages (available in Matlab, Python, and R) are freely available at https://github.com/cmap

Proteogenomics connects somatic mutations to signalling in breast cancer

Abstract: Somatic mutations have been extensively characterized in breast cancer, but the effects of these genetic alterations on the proteomic landscape remain poorly understood. Here we describe quantitative mass-spectrometry-based proteomic and phosphoproteomic analyses of 105 genomically annotated breast cancers, of which 77 provided high-quality data. Integrated analyses provided insights into the somatic cancer genome including the consequences of chromosomal loss, such as the 5q deletion characteristic of basal-like breast cancer. Interrogation of the 5q trans-effects against the Library of Integrated Network-based Cellular Signatures, connected loss of CETN3 and SKP1 to elevated expression of epidermal growth factor receptor (EGFR), and SKP1 loss also to increased SRC tyrosine kinase. Global proteomic data confirmed a stromal-enriched group of proteins in addition to basal and luminal clusters, and pathway analysis of the phosphoproteome identified a G-protein-coupled receptor cluster that was not readily identified at the mRNA level. In addition to ERBB2, other amplicon-associated highly phosphorylated kinases were identified, including CDK12, PAK1, PTK2, RIPK2 and TLK2. We demonstrate that proteogenomic analysis of breast cancer elucidates the functional consequences of somatic mutations, narrows candidate nominations for driver genes within large deletions and amplified regions, and identifies therapeutic targets.

The harmonizome: a collection of processed datasets gathered to serve and mine knowledge about genes and proteins.

Abstract: Genomics, epigenomics, transcriptomics, proteomics and metabolomics efforts rapidly generate a plethora of data on the activity and levels of biomolecules within mammalian cells. At the same time, curation projects that organize knowledge from the biomedical literature into online databases are expanding. Hence, there is a wealth of information about genes, proteins and their associations, with an urgent need for data integration to achieve better knowledge extraction and data reuse. For this purpose, we developed the Harmonizome: a collection of processed datasets gathered to serve and mine knowledge about genes and proteins from over 70 major online resources. We extracted, abstracted and organized data into ∼72 million functional associations between genes/proteins and their attributes. Such attributes could be physical relationships with other biomolecules, expression in cell lines and tissues, genetic associations with knockout mouse or human phenotypes, or changes in expression after drug treatment. We stored these associations in a relational database along with rich metadata for the genes/proteins, their attributes and the original resources. The freely available Harmonizome web portal provides a graphical user interface, a web service and a mobile app for querying, browsing and downloading all of the collected data. To demonstrate the utility of the Harmonizome, we computed and visualized gene-gene and attribute-attribute similarity networks, and through unsupervised clustering, identified many unexpected relationships by combining pairs of datasets such as the association between kinase perturbations and disease signatures. We also applied supervised machine learning methods to predict novel substrates for kinases, endogenous ligands for G-protein coupled receptors, mouse phenotypes for knockout genes, and classified unannotated transmembrane proteins for likelihood of being ion channels. The Harmonizome is a comprehensive resource of knowledge about genes and proteins, and as such, it enables researchers to discover novel relationships between biological entities, as well as form novel data-driven hypotheses for experimental validation.Database URL: http://amp.pharm.mssm.edu/Harmonizome.