NIH Common Fund Library of Integrated Network-based Cellular Signatures LINCS

1. NIH Common FundLibrary of Integrated Network-based Cellular SignaturesLINCS Applicant Information Webinar for RFA-RM13-013 September 6, 2013 3:00 – 4:30 PM EDT

2. LINCS: Applicant Information Webinar • RFA-RM-13-013: Perturbation-Induced Data and Signature Generation Centers (U54) • Today’s Webinar: • LINCS program goals and background • Overview of new FOA • Questions

3. LINCS: Library of Integrated Network-based Cellular Signatures Human cell types Phenotypicassays Perturbations • LINCS aims to inform a network-based understanding of biological systems in health and disease that can facilitate drug and biomarker development. • LINCS is: • Developing a library of molecular and cellular signatures that describe how different cell types respond to a variety of perturbations. • Addressing challenges in high-throughput data generation, data integration, annotation, and analysis. • Actively exploring collaborations with new biomedical research communities. • RNAi • small molecules • gene expression • protein level • metabolites http://lincsproject.org

4. LINCS Program (2014 – 2020) • LINCS goals • informing a network-based understanding of cellular functions and response • expand the scope and richness of cellular responses to be measured. • support the addition of a broader and more informative range of human cell types, perturbations, and measurements. • LINCS Program Structure • 3-5 Data and Signature Generating Centers (RFA-RM13-013) to be funded in FY14 • One Data Coordination and Integration Center (TBA) to be funded in FY15 • 6 year program with Mid-Course Review (~July 2017)

5. RFA-RM13-013LINCS Data and Signature Generating Centers • Will fund 3-5 DSGC awards • Direct costs are limited to a maximum of $1.7M in each year for up to 6 years • Part of a collaborative LINCS program • DSGC structure: • Data Generation (40% effort) • Data Analysis and Signature Identification (40% effort) • Community Interactions Outreach • Administrative • (20% effort)

6. DSGC: Data Generation • Data and Signature production at scale, within first year of award (tens of thousands of data points per year) • Proposal should be aware of existing perturbation response data in the public domain • Cell Types: human cells (cell lines, primary tissue, iPS cells and their differentiated derivatives) • Perturbagens: • Pilot: small molecules, growth factors, and genetic (knockdown or up-regulation by gene overexpression) • These will continue but applicants may propose other perturbations • Assays: • Should be medium to high throughput • Provide measures of wide interest to biomedical researchers • Should be flexible and amenable to multiple cell types • Should be replicable with high level of QC/QA under SOPs

7. DSGC: Data Generation • Include a strategy for most informative data and signature generation • Maximize usefulness of new data in relation to existing resources • Laboratory Technology Development. • Some technology development in first 3 years ($200K DC per year) • Should focus primarily on the further development or refinement of the assays proposed in this application • Minor refinements of new technologies that are sufficiently advanced (but not being proposed to be used within the DSGC) are also permissible • Establish suitable milestones and identify the approaches that would enable improvements in the technology

8. DSGC: Data Analysis and Signature Generation • Each DSGC should devote roughly equal effort to data generation and data analysis • Goal: to build meaningful, generalizable signatures with sufficient predictive power and/or broad applicability from the LINCS assays • Computational research that would lead to improved signatures is an important scientific goal • LINCS aims to create a single user interface via the separate DCICfor all of the LINCS resources for all biomedical researchers, including computational biologists

9. DSGC: Data Analysis and Signature Generation • LINCS will have a distributed data resource and infrastructure to support queries • Each DSGC will build an appropriate database and an underlying infrastructure to support queries and other analytical requirements on their datasets • Support a robust pipeline to handle large-scale data generation and cleanup and to generate and validate signatures • Each DSGC will develop novel approaches to visualize, browse, and query the data and signatures for all data and signature types the DSGC proposes

10. DSGC: Data Analysis and Signature Generation • Unified access to DSGC resources will be developed by a future DCIC, to be solicited in a separate FOA. • An essential feature of accessibility to all of LINCS data and resources is adequate annotation and documentation. • Metadata annotation for both data and software resources is crucial. • Should aim to facilitate innovative methods to support data provenance.

11. LINCS: Community Interaction and Outreach • Access to Bench Scientists in collaboration with the DCIC and other DSGCs. • Access to Computational Scientists to support development, validation, and implementation of new analytical, visualization, and integration approaches. • Creative solutions to providing access the large data sets and resource are encouraged.

12. LINCS: Community Interaction and Outreach To facilitate the incorporation of related data types from external sources into LINCS, each DSGC will: • Take the scientific lead in identifying relevant external data (and signatures, as appropriate) from the larger community; • Identify high quality, relevant non-LINCS data sets that might be incorporated into LINCS; • Work with the DCIC and the outside community to facilitate identification and inclusion of such resources into LINCS.

13. LINCS: Community Interaction and Outreach • Community Interaction Projects: each DSGC should support scientific collaborations with external researchers (10% of the entire DSGC budget) • Support specific and challenging research collaborations in conjunction with researchers in specific communities [identify some communities that will be receptive, and a few where it might be a challenge] • The resulting data and signatures will be made publicly available to the research community.

14. LINCS: program administration • Cooperative agreement, with substantial collaboration between LINCS grantees and involvement of program staff. • DSGCs are expected to work on common projects, on cell lines and/or perturbations shared across multiple DSGCs • Support and adopt common methods for annotation of resources and ways to make such resources available • Participate in LINCS working groups, committees, and meetings.

15. LINCS: Midcourse Review • Will be in 2017, via an external group of scientists convened by NIH. • Assess the productivity of the center to date, • its collaborations within the LINCS consortium; • the use and adoption of its data by the greater research community. • DSGC opportunity: propose refinements to their proposed activities (based on tech dev) for the remainder of the project period.  • The NIH will determine funding levels for each center past 2017 based, in part, on the results of the mid-course review.

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17. NIH Common Fund • Supports cross-cutting programs that are expected to have exceptionally high impact. • Develops bold, innovative, and often risky approaches to address problems that may seem intractable or to seize new opportunities that offer the potential for rapid progress. • NIH LINCS Program Co-Chairs: • Alan Michelson, PhD (NHLBI) • Mark Guyer, PhD (NHGRI) • NIH LINCS Coordinators • Ajay Pillai, PhD (NHGRI) • Jennie Larkin, PhD (NHLBI)

18. LINCS Pilot Phase (2010 – 2013) • Pilot goals: • Develop a limited yet coherent data, and signature resource that could be used by the general research community. • Identify key issues in data annotation, integration, and analysis. • Pilot activities: • Two data and signature generating U54 awards • Development of new high-throughput assays to detect perturbation-induced cellular responses • Novel computational methods for integrative data analysis • Active collaborations and working groups http://lincsproject.org