Frequently Asked Questions

Please monitor this page for updates on this FAQ. Email your questions to lincs@mail.nih.gov

FAQ for RFA-RM10-004 Advanced Technologies for Detection of Perturbation-Induced Cellular Signatures (U01) and RM10-005 Computational Tool Development and Integrative Data Analysis for LINCS (U01)

1. For the advanced technology FOA (RM10-004), how much of the proposed project should be devoted to data production?
    
2. Will NIH accept grant applications in response to the advanced technology FOA (RM10-004) that focus on tissues or primary cells rather than cell lines? Will grant applications proposing to develop technologies to isolate and/or perturb cells from tissues be accepted?
    
3. Is a statistical or computational approach considered a “technology” for RFA RM10-004?
    
4. For both RM10-004 and RM10-005 are the applications due on February 22 or are can they arrive later if they are post-marked on or before February 22? Can I submit my application electronically through grants.gov?
    
5. What cell lines are being actively used by the U54 centers?

FAQ for RFA-RM-10-003 Large Scale Production of Perturbagen-Induced Cellular Signatures (U54)

1. Is there already an expectation how to distribute resources among 1) technology development / optimization to generate data, 2) data production 3) operational informatics and dissemination 4) data analysis and integration with other data sources; if yes, what would be a desired approximate ratio?
    
2. Additional pilot LINCS funding opportunities may become available in 2011 focusing on new (production ready) data production technologies and informatics. How do these efforts relate to the corresponding components in the current LINCS U54, i.e. is it correct to assume these components are slightly less relevant for this initial RFA?
    
3. In the case of informatics, would it be correct to focus initial efforts on intra-center operational informatics and data dissemination (for example via a web site) mostly for proof of concept, while the later FOA will emphasize integration with other data sources, data standardization, and importantly user-friendly software tools to facilitate browsing, querying and data analysis by a much larger and diverse user community?
    
4. What amount of data are expected to be stored, managed, processed? i.e. what is "Large Scale"?
    
5. Is there a preference for a disease, cell line, patient samples?
    
6. What are the metrics of success?
    
7. Will there be coordination between funded sites on which libraries they will be screening? Seems like that might make sense. If the assays are different, then you would be getting more bang for your buck.
    
8. Will there need to be a special link between these funded sites and PubChem bioassay?
    
9. What metrics are employed to determine that the "data are faithful to human biology" and "useful for the community"? Are these metrics applied during the grant period? Right after the end? Or after some longer period to ensure diffusion of the methods and data into the community?
    
10. The FOA notes that "expected that LINCS pilot production groups will exchange data with each other ..." – how do you envisage this co-operative activity being managed?
     
11. When you talk about data integration - obviously pilots would integrate with well known biomedical resources (NCBI, KEGG, PubChem, etc). But it appears that funded groups are going to be evaluated on how they integrate with each other. From the description it appears that this will be done during the period of the grant. Is that correct? How will such evaluations be made? Does this require that funded groups co-operate with each other? Will this affect things down the road (say competitive renewals)?
     
12. The earliest anticipated start date is 9/30/10, the last day of FY10. The direct costs are limited to $900K in FY10.Please confirm that $900K is for the first year, not one day.
     
13. In the solicitation it states “more than one perturbagen/cell line/readout”.
     
    • Would measuring more than one cell line for more than one perturbagen qualify, or is it necessary to have more than one readout? Would measuring mRNA and measuring miRNA qualify as two readouts? Would using high density array measurement of mRNA followed by PCR qualify as two readouts? Would the measurement of mRNA and determination of fold differences followed by performing dose response data to provide EC50’s and cluster genes according to EC50 qualify as two readouts?
       
14. About application organization: You specified 3 sections to research strategy, should they be in that order? Stage, informatics, then management?
     
15. Does management plan have to be a block of 6 pages, or 2 blocks of 3 pages in 2 places in document?
     
16. What type of public access to details of the data and data descriptors will be expected?
     
17. What is the optimal scientific/disease focus for applications?
     
18. What is the responsibility of the PI for making data and reagents available and accessible to the community?
     
19. What is the intellectual property guidance for this RFA?
     
20. On Multi-PI applications, must each PI contribute 15% effort?

1. For the advanced technology FOA (RM10-004), how much of the proposed project should be devoted to data production? 

This FOA solicits technology development projects, so the focus of the proposed work should be on the technology or methodology development. It is envisioned that some amount of data will be produced in the course of testing and refining the technology. The product of the proposed grant should be a technology or methodology that will enable other researchers to accelerate the rate of data generation and the range of signatures that can be identified and characterized by large scale high-throughput perturbation-induced signature collection efforts like The Library of Integrated Network-Based Cellular Signatures (LINCS).
 

2. Will NIH accept grant applications in response to the advanced technology FOA (RM10-004) that focus on tissues or primary cells rather than cell lines? Will grant applications proposing to develop technologies to isolate and/or perturb cells from tissues be accepted?
 

The LINCS program is focused on the generation of perturbation-induced cellular signatures. Typically these efforts are undertaken using cell lines. However, methods designed to perturb and characterize primary cells or isolated cells, would be acceptable as long as they could also be used on cell lines and as long as they meet the other criteria of the RFA (such as higher throughput).

3. Is a statistical or computational approach considered a “technology” for RFA RM10-004?
 

This FOA is designed to support projects which are primarily experimental or laboratory methods rather than computational tools. While it may be necessary to develop companion analysis or computational methods to be used in conjunction with the proposed technologies, applications which are primarily computational in nature should respond to the companion FOA for computational tool development (RFA-RM-10-005).

4. For both RM10-004 and RM10-005 are the applications due on February 22 or are can they arrive later if they are post-marked on or before February 22? Can I submit my application electronically through grants.gov?
 

Because they use the U01 mechanism and are solicited through an RFA, these applications must be submitted as paper applications (you cannot submit electronically) and applications must be received by the Center for Scientific Review (address below) on or before the application receipt date (see section IV.3.A. http://grants.nih.gov/grants/guide/rfa-files/RFA-RM-10-005.html#SectionIV3A for example). If an application is received after that date, the application may be delayed in the review process or not reviewed. Applications must be prepared using the forms found in the PHS 398 instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, and five signed photocopies in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)
 

5. What cell lines are being actively used by the U54 centers?

The cell lines are listed here. Please note that this list will change depending on community input. Not all of perturbations or assays will see all of the HMS cell lines. However, a full matrix of data will be generated for the Broad cell lines.
 

1. Is there already an expectation how to distribute resources among 1) technology development / optimization to generate data, 2) data production 3) operational informatics and dissemination 4) data analysis and integration with other data sources; if yes, what would be a desired approximate ratio?

This depends entirely on what the proposal is going to be, we do expect significant resources both on data generation, analysis, dissemination and integration.
 

2. Additional pilot LINCS funding opportunities may become available in 2011 focusing on new (production ready) data production technologies and informatics. How do these efforts relate to the corresponding components in the current LINCS U54, i.e. is it correct to assume these components are slightly less relevant for this initial RFA?

The potential funding opportunities for 2011 are mentioned in this RFA primarily to provide more context about LINCS and to ensure that the applicants are aware of the potential collaborations that might start later. Your application should anticipate these potential efforts.
 

3. In the case of informatics, would it be correct to focus initial efforts on intra-center operational informatics and data dissemination (for example via a web site) mostly for proof of concept, while the later FOA will emphasize integration with other data sources, data standardization, and importantly user-friendly software tools to facilitate browsing, querying and data analysis by a much larger and diverse user community?
 

Data and standardization efforts will include each center’s data and will be parallel efforts that will begin early within this U54 component. These inter-center informatics efforts will impact intra-center informatics since it will have to adapt to any inter-center standards that are developed. The details of inter-center data query capability will be developed within the scope of this U54 project. Each center should plan to provide a browser/query and access to its own data sets.
 

4. What amount of data are expected to be stored, managed, processed? i.e. what is "Large Scale"?

“Large Scale” means the technology should be developed enough to be applicable (in a standardized, reproducible and high throughput mode) to on the order of thousands of perturbations and to a very broad range of human cell lines or tissues. Regarding choices of assays, they should be “multiparameter” or “multiplexed”. Measuring a single protein, metabolite, phosphorylation site, morphological property or pathway reporter would be unresponsive to the goals of this program. Certain well established methods like mRNA (miRNA) measurements should be mostly “genome-wide” and if you are using imaging assays, they should be high-content. The best way to get feedback would be to submit a Letter of Intent (you can still do this even though the last date is past).
 

5. Is there a preference for a disease, cell line, patient samples?

No, there is no preference except for human cells/samples. You should scientifically justify your choices for human disease and/or biological relevance.
 

6. What are the metrics of success?

The primary metric for this initiative is the production of coherent large-scale datasets. The individual metrics for each applicant should be detailed in the application and will be part of the merit review.

7. Will there be coordination between funded sites on which libraries they will be screening? Seems like that might make sense. If the assays are different, then you would be getting more bang for your buck.

We will strive for the best and most useful types of co-ordination and “cross-validation” within this U54 and potential future projects within the LINCS program. Screening libraries can and will be one of the means of cross-validation.
 

8. Will there need to be a special link between these funded sites and PubChem bioassay?

The location of the final resource and other related issues have not been determined yet. One of the goals of the pilot is to figure out the best way to do integrated data access both to bench scientists and professional data modelers as well as develop standards. So no, you do not have to plan any special links to PubChem or any other specific site in the application.
 

9. What metrics are employed to determine that the "data are faithful to human biology" and "useful for the community"? Are these metrics applied during the grant period? Right after the end? Or after some longer period to ensure diffusion of the methods and data into the community?

You should, in your application scientifically justify that the data you propose to generate will be “faithful to human biology” and “useful to community”. These will be considered during peer-review. These two are not metrics evaluated during the project. The review criteria are listed in the RFA and include the following: Does the proposed approach properly balance the need to produce a well-defined, useful data resource with the exploration of ways to optimize the components of the data production effort over time? Will the approach result in a resource that can eventually be integrated with other data from the community (e.g., genetic, expression, proteomic, etc. data; small molecules; pharmaceutical research)? Are the two major core functions (Data Production/Informatics and Data Integration) properly coordinated? Does the Data Production section describe and adequately justify appropriate goals, timelines, and milestones; are opportunities for obtaining increased efficiency over the period of the award described and justified? Does the database management plan that supports the data production core contain an adequate plan for an annual complete download and rebuild? Is the management plan appropriate to the complexity of the proposed effort? Is the data availability plan adequate? Is there a viable plan for coordinating data standardization? Will the overall plan provide useful information about scalability? How effectively will the chosen perturbagen/cell line/readout capture most of the space of possible cellular responses, and then scale to a complete representation in later efforts? Are the choices of the perturbagens, cell lines or tissues, proposed readouts and related experimental protocols adequately justified and likely to lead to the creation of a valuable public resource that can be used by the whole biomedical research community? Are the proposed plans for sharing the data, the experimental protocols, models and software release plans scientifically meritorious and beneficial to the overall goals of the LINCS program?
 

10. The FOA notes that "expected that LINCS pilot production groups will exchange data with each other ..." – how do you envisage this co-operative activity being managed?

This is a co-operative agreement RFA. One of the criteria for application evaluation is the applicant’s willingness to work together to achieve the overall aims of this RFA and the LINCS program. There are going to be a number of small pilots undertaken during this U54 that will require exchange of data (or provide programmatic access to your internal database), reagents, experimental protocols to ensure reproducibility of experimental data and data integration. Applicants should be prepared to be extremely flexible and demonstrate willingness for such collaborations.
 

11. When you talk about data integration - obviously pilots would integrate with well known biomedical resources (NCBI, KEGG, PubChem, etc). But it appears that funded groups are going to be evaluated on how they integrate with each other. From the description it appears that this will be done during the period of the grant. Is that correct? How will such evaluations be made? Does this require that funded groups co-operate with each other? Will this affect things down the road (say competitive renewals)?

Data integration, as a first step within LINCS, will involve integration between the U54 applicants. For example, it could be integrating mRNA expression data with proteomics data, etc. so that one can query across/together. Developing standards for data and experiment reporting will be a crucial part of this U54 during the funding period. Clearly various annotations available within the well known biomedical resources will be useful, but integration does not involve these other resources per se. LINCS will be a community resource and as such the ability to query in an integrated manner across multiple cell lines/tissues, assays and perturbations will be critical for success. We will have regular meetings and if necessary workshops to explore the best way forward for resolving data integration issues. If such data integration is not demonstrably useful by the end of this pilot phase then such a result has obvious impact on any future phases of LINCS. Another aspect of data integration will be for other scientists to “explore their experiment” within the context of the data generated within this U54; this aspect of integration will be explored using future pilot efforts. Finally, the idea for LINCS is to generate a community resource and so co-operation is essential to success.
 

12. The earliest anticipated start date is 9/30/10, the last day of FY10. The direct costs are limited to $900K in FY10. Please confirm that $900K is for the first year, not one day.

Yes. This is a grant. Once the funding decision is made by NIH you will have a full year to expend it.
 

13. In the solicitation it states “more than one perturbagen/cell line/readout”.

• Would measuring more than one cell line for more than one perturbagen qualify, or is it necessary to have more than one readout? Would measuring mRNA and measuring miRNA qualify as two readouts? Would using high density array measurement of mRNA followed by PCR qualify as two readouts? Would the measurement of mRNA and determination of fold differences followed by performing dose response data to provide EC50’s and cluster genes according to EC50 qualify as two readouts?
   

These are detailed and specific questions that are hard to answer without further context. In general the answer will be a ‘yes’ for most of these questions. First, please send us a Letter of Intent (with sufficient scientific details) and we would be better placed to provide feedback on responsiveness. Second, keep in mind that the overall aim of LINCS (and this U54 specifically) is to create a public resource that would be broadly useful for a very wide range of biology and medicine. So the questions to ask primarily are “how generalizable would the results from my proposal be?,” “would the data I generate, if merged/integrated with other large scale/broadly usable datasets, likely to teach one more than the sum of the parts?,” “are my experiments likely to only be usable for a specific disease?” In the application it would make sense to address: how broadly applicable is your application, how adaptable to other measures/perturbagens? Whether you do them all is less important than showing it can be done with different pertubagens and how it could be expandable. To be repetitive, we are open to a broad range of signatures (transcriptional, cell phenotypic, proteomic, etc.) as long as the approach can be justified in terms of providing direct and general insights into the feasibility and utility of a large catalog of cellular signatures.
 

14. Question about application organization: You specified 3 sections to research strategy, should they be in that order? Stage, informatics, then management?

The general answer would be yes, it helps us look at them together, it helps the reviewers, if everybody keeps it in the same order. There is no strict requirement. If you have reasons for presenting differently, that is your decision.
 

15. Does management plan have to be a block of 6 pages, or 2 blocks of 3 pages in 2 places in document?

Please keep them together.
 

16. What type of public access to details of the data and data descriptors will be expected?

The LINCS initiative comprises several components, including that described in the U54 RFA, and those to be described in forthcoming RFAs in the areas of analytic computational tools for LINCS data and technologies to generate LINCS data (i.e., data on the cellular signatures of responses of particular cells to particular perturbagens). Shortly after the “Notice(s) of Grant Award” are made under the U54 RFA, the successful applicant(s) will be required to make public details about the nature of data that will be produced in the project. Data values will not be released, but awardees should provide information on the types of cells and perturbagens they will be using, as well as information describing the data they will be collecting, including data and metadata type and format, and terminologies and ontologies used in annotating the data. This information should be sufficient for applicants to the Computational Tool Development FOA to understand the types of data that will be collected by the U54s, so they may propose innovative analytic computational approaches. The U54 data descriptions will allow those applying for support under the forthcoming RFAs to propose projects that will articulate well with this first LINCS component.
 

17. What is the optimal scientific/disease focus for applications?

The focus of the LINCS program and data generation within this U54 RFA is to create a “long-lived resource that can be used broadly by the community”. This means the applications have to scientifically justify the choices of cell lines, perturbagens, assays etc. and demonstrate that the proposal is likely to generate data that will be useful for a range of human diseases and/or biology. It is unlikely that applications focused on a specific disease area or narrow area of biology would serve the broad use envisioned by this initiative.
 

18. What is the responsibility of the PI for making data and reagents available and accessible to the community?

As the RFA states the applicant is responsible to “[e]nsure that all data, experimental protocols, and data on the perturbagens used will be deposited in an open access database according to the timeline agreed upon by the LINCS Steering Committee and the LINCS Project Team, and that resources developed as a part of this project (e.g., information about assays and chemical probes) are made publicly available according to LINCS policies. The LINCS Steering Committee and Project Team recommendation will be consistent with the ongoing genomic scale data sharing policies being developed by NIH.”
 

19. What is the intellectual property guidance for this RFA?

As the RFA states, “The applications are expected to include written statements from the officials responsible for intellectual property issues at all of the applicant institutions (including subcontractors) to the effect that the institution supports and agrees to abide by the software dissemination plans put forth in the application,” and “Approved Users and Investigators supported under this FOA, and their institutions, should acknowledge the program’s IP Policy, the goal of which is to ensure the greatest possible public benefit from the development of this LINCS application.”
 

20. On Multi-PI applications, must each PI contribute 15% effort?

This program requires a substantial commitment from the senior leadership of each award. As stated in the FOA, “Due to the complex nature of the anticipated effort, including managing data production, informatics/analysis, and collaborations, PIs must invest a minimum of 15% of their time and effort to this award.” The NIH considers that a 15% time commitment from the PD/PIs ought to be a minimal level of commitment to the program. When deciding on roles within the team, particularly within the leadership team of the project, applicants should consider the experience and level of commitment possible for each member. The review panel will seriously consider the qualifications and commitment of the PD/PIs and the senior leadership team in the application. For such a substantial endeavor, the applicants should also include a management and leadership plan.