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Frequently Asked Questions for Clinical Sequencing Evidence-Generating Research (CSER2) RFAs

CSER2 Webinar Information

YouTube video Watch the CSER2 Pre-Application Informational Webinar | View Slides PDF file

Date: Wednesday, June 15, 2016
Time: 3:00 p.m. - 4:00 p.m. Eastern

The intent of the pre-application webinar is to provide an overview of the CSER2 FOAs and to address questions pertinent to preparing applications.

Prospective applicants are encouraged to submit their questions or comments regarding the RFA to before Monday, June 13.  Afterwards, slides of the Webinar will be posted on the same website.

Prospective applicants with inquiries concerning the FOAs who are unable to participate in the Webinar are encouraged to view the summary of questions and answers after the webinar.  For any additional questions, contact the Scientific/Research contacts listed in RFA-HG-16-010,RFA-HG-16-011, and RFA-HG-16-012.


3:00 p.m. Overview of CSER2 RFAs (NIH staff)

Lucia Hindorff, NHGRI
Dave Kaufman, NHGRI
Charlisse Caga-Anan, NCI
Regina James, NIMHD

3:15 p.m. FAQ site and sample questions (Lucia Hindorff)
3:20 p.m. Questions & answers (All)
4:00 p.m. Webinar adjourned

Questions about the Goals of the RFAs

1. Where can I find more information about the CSER2 funding opportunities? (RFA-HG-16-010, RFA HG-16-011, RFA HG-16-012)

Potential applicants should consult the appropriate Funding Opportunity Announcements (FOAs):

  • RFA-HG-16-010: Clinical Sequencing Evidence-Generating Research (CSER2) - Clinical Sites (U01)
  • RFA-HG-16-011: Clinical Sequencing Evidence-Generating Research (CSER2) - Clinical Sites with Enhanced Diversity (U01)
  • RFA-HG-16-012: Clinical Sequencing Evidence-Generating Research (CSER2) - Coordinating Center (U24)
2. How many diseases/patient groups/geographic regions should my application include? (RFA-HG-16-010, RFA HG-16-011)

The RFAs refer to patient diversity and breadth of clinical conditions and healthcare settings throughout (for example, see Objectives of this Research Program). As stated, "Central to this focus is research that will assess and improve the current processes of recruitment, testing, and follow-up of patients from diverse racial and ethnic groups, as well as those from the range of as-yet understudied clinical healthcare settings where genomic medicine might be put into practice." The RFAs also state in Section IV.2, Research Strategy, "Applicants should justify the proposed clinical condition(s) that they plan to study and describe the relevance to each CSER2 aim. Applicants are neither required nor discouraged from including multiple clinical conditions in their application."

The optimal balance of diseases, patient groups, or geographic regions must thus be considered in light of the scientific questions to be addressed in each application, the unique strengths of each investigative team, as well as practical constraints (e.g., budget). Applicants are advised to address participant diversity and breadth of clinical conditions and healthcare settings sufficiently to meet project- and RFA-specific goals while avoiding the spreading of resources too thinly.

3. Are cancer-only applications responsive and if so, do they need to include a germline component? (RFA-HG-16-010, RFA HG-16-011)

Cancer-only applications are responsive as long as they address the aims of the CSER2 RFA. Applicants are strongly encouraged ? Applicants are also encouraged to investigate ELSI issues related specifically to the management of germline sequencing results.

4. Would a study that explores the utility of clinical genome sequencing in risk assessment and prevention be responsive? (RFA-HG-16-010, RFA HG-16-011)

Yes, such a study may be responsive. All applicants will need to justify the proposed clinical condition(s) to be studied, including disease-free individuals if applicable, and describe the relevance to each CSER2 aim.

5. If my proposed study design includes a randomized trial, does the sample size of 1,100 apply to the total number of participants, or just to the sequenced participants? (RFA-HG-16-010, RFA HG-16-011)

The RFAs state in the section "Objectives of this Research Program section":  "Each CSER2 Clinical Site is anticipated to include and analyze at least 1,100 patients over the entire term of the award, with the potential for larger sample sizes per site as funding and scientific priorities permit." This minimum sample size of 1,100 per Clinical Site applies across study arms or components, so for a randomized trial, a minimum sample size of 1,100 in the trial would meet the minimal requirement, even if not all of the participants were sequenced.

6. Does retrospectively collected data count toward the sample size of 1,100? (RFA-HG-16-010, RFA HG-16-011)

The RFAs state in the section "Objectives of this Research Program":  "Each CSER2 Clinical Site is anticipated to include and analyze at least 1,100 patients over the entire term of the award, with the potential for larger sample sizes per site as funding and scientific priorities permit." Use of retrospective or existing data to meet this minimum sample size is allowed; applicants are advised to note the following section from the Research Strategy section of the RFA:

Use of existing data or data to be generated by external efforts. Reliance of CSER2 efforts on such data should be clearly documented, including:

  • Population characteristics and quality and completeness metrics for phenotype or sequence data
  • Integration of data with CSER2 aims
  • Timeframe and scope of data availability, including IRB approval or any necessary data sharing agreements
  • Ability to commit data to cross-Consortium efforts
  • The possibility of recontacting patients from whom existing data were generated and/or obtaining additional data from them if needed
7. Our investigative team finds it challenging to simultaneously meet the goals of enhancing participant diversity and breadth of clinical conditions and healthcare settings and piloting the data integration aim. Specifically, recruiting patients in under-resourced settings while expecting data sharing and integration from these settings will be difficult.  Do you have any guidance for us? (RFA-HG-16-010, RFA HG-16-011)

The CSER2 aim related to "identifying and addressing real-world barriers to integrating genomic, clinical, and healthcare utilization data within an existing healthcare system to build a shared evidence base for clinical decision-making" is intended as a pilot effort.  Investigative teams should propose their best ideas that can be addressed within the bounds of their proposed research settings.  The scope and approaches taken by each investigative team may thus differ from one another.  Indeed, the extent to which these aspects differ among investigative teams underscores the "real-world" context of this aim and is seen as an opportunity to identify common challenges and opportunities that are applicable across settings.  As one example, an application that proposes collaboration among multiple sites may pilot the data integration aim in one of those sites and still be broadly responsive to this CSER2 aim. Specific questions should be directed to the scientific contacts listed in the RFAs. 

8. Regarding the data integration aim, what is the appropriate scale for a healthcare system, e.g., would a single site community health center be considered appropriate? (RFA-HG-16-010, RFA HG-16-011)

An application proposing a single site community health center would be responsive as long as the plans for integration of multiple data sources to facilitate clinical decision-making, as described in the RFA, are clearly described.

9. For the aim on interactions among patients, family members, practitioners and clinical laboratories, does the reference to clinical laboratories refer to routine diagnostic testing as opposed to clinical sequencing laboratories? (RFA-HG-16-010, RFA HG-16-011)

The aim was envisioned with clinical sequencing laboratories in mind given the emphasis of the RFA on the clinical utility of clinical sequencing. There may be overlap between the two types of laboratories, however. Applications proposing research that includes laboratories that perform routine diagnostic testing may be responsive if the goals of the RFA are otherwise met.

10. In clinical domains where exome sequencing is already moving into clinical use, is it responsive to compare alternative sequencing approaches to exome sequencing, or is it necessary to compare sequencing to non-sequencing modalities?  Is there a preferred approach between whole exome and whole genome sequencing?  (RFA-HG-16-010, RFA HG-16-011)

All CSER2 applications should include one or more DNA-based genome sequencing approach(es), as defined in the Definitions section, and an alternative modality that may or may not be DNA sequence-based. The specific choice of genome sequencing and alternate modalities should be explained and justified in the application.

11. Is RNA-seq an allowable genomic analysis approach if it is done along with a DNA-based approach? (RFA-HG-16-010, RFA HG-16-011)

Generally, yes.  All CSER2 applications should include one or more DNA-based genome sequencing approach(es), as defined in the Definitions section, and an alternate genomic testing modality that may or may not be DNA sequence-based.

12. Are costs for genomic sequencing done at commercial laboratories allowable? (RFA-HG-16-010, RFA HG-16-011)

Yes, commercial sequencing performed as part of CSER2 can be included in the proposed budget. Applicants should be aware of the instructions in Section IV., Application and Submission Information, on "Genome Sequencing" and "R&R or Modular Budget" that provide guidance on information to be included for all sequencing laboratories, whether commercial or non-commercial.

13. In the PHS 398 Research Plan, Cross-Consortium efforts section, the RFA states "Plans for how their research team will interact with other CSER2 sites in the development and design of research and consultation methods, procedures, policies and strategies to be applied in this program." Should applicants provide examples of specific projects in collaboration with other applicants who are submitting to the RFA and/or provide letters of support on the possibility of cross-consortium collaboration? Or should applicants address consortium collaboration more generally, independent of specific projects? (RFA-HG-16-010, RFA HG-16-011)

In the spirit of a collaborative CSER2 consortium, applicants should describe general ways of working with other sites to accomplish common CSER2 aims.  Ideas for collaborative activities should be described at a level that does not rely on specific groups being funded, or on letters of support being provided.  For example, CSER Working Groups were convened based on common areas of interest among sites, and ideas for CSER2 WG's to convene and/or topics those WG's could cover would be welcome.  Another way to think about responding to this part of the RFA is to propose ideas that will give a sense of how the site will contribute to cross-consortium collaborations, independently of what other sites are funded (e.g., how will the site contribute to or lead CSER2 collaborations, share data and ideas with other sites, retain flexibility to incorporate ideas from other sites, etc.).

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Questions about Application Format

14. How do I determine whether to submit a "new" or "renewal" application? (RFA-HG-16-010, RFA HG-16-011, RFA HG-16-012)
  • An investigator awarded a CSER grant under RFA-HG-10-017, RFA-HG-12-008, or RFA-HG-12-009 should submit a competing renewal.
  • An investigator funded as key personnel or multiple-PI under RFA-HG-10-017, RFA-HG-12-008, or RFA-HG-12-009 and who plans to submit a separate CSER2 application as the PI or as a multi-PI, with a different investigative team and/or different scientific goals from the previous CSER grant, should submit a new application. 
15. How should we document the involvement of stakeholders as part of the Stakeholder Engagement Plan described in the RFA?  Would they need to be included as part of an advisory board?  (RFA-HG-16-010, RFA HG-16-011, RFA HG-16-012)

The rationale for a Stakeholder Engagement Plan (SEP) is described in several sections of the CSER2 RFAs (see Objectives of this Research Program, External Input to the Network, and Research Strategy sections).  In preparing CSER2 applications, applicants should consider all phases of the study where stakeholder input would be valuable and where possible, propose defined plans to engage them.  Applicants should propose site-specific SEPs that are relevant to the scientific questions and participants at that site, but also to describe how they envision engaging stakeholders more broadly across CSER2 to meet the collaborative CSER2 goals. Each applicant has the flexibility to propose the approach that he/she thinks is best, including, but not limited to, designating formal roles (e.g., co-investigators, consultants).. Applicants should be aware that naming an individual or organization in a formal role, or obtaining letters of support,  causes a potential peer review conflict with that individual/organization. In order to minimize potential conflicts during the review process, unless formal roles are already in place at the time of application, applicants are encouraged to outline the type of expertise they would put on such a panel rather than name specific people or organizations who could serve on these panels.

16. Can you provide an example of a Stakeholder Engagement Plan? (RFA-HG-16-010, RFA HG-16-011, RFA HG-16-012)

The Patient-Centered Outcomes Research Institute (PCORI) has a wealth of information about the value of stakeholder engagement, including an engagement rubric [] PDF fileillustrating how input from stakeholders can be incorporated throughout the entire research process.  Sample engagement plans that meet PCORI-specific requirements [] PDF fileare also available.  CSER2 applicants should recognize that the requirements for PCORI applicants are generally more rigorous and do not correspond exactly to the CSER2 RFA expectations, underscoring differences in missions among the Institutes; therefore these resources should be regarded as providing information broadly relevant to stakeholder engagement rather than specific requirements for CSER2 applications.  Each applicant should propose a plan that makes sense for his/her approach and scientific questions and describe how these site-specific efforts may contribute to Consortium-wide stakeholder engagement.

17. We are aware that NIH requires appropriate data and safety monitoring for clinical trials.  Are CSER2 applicants expected include plans for a Data Safety Monitoring Board (DSMB) at their institutions?

No, applicants are not expected to plan or budget for a local DSMB. As described in the CSER2 RFAs, an External Scientific Panel (ESP) will evaluate the progress of the CSER2 program, providing recommendations to the network about the progress and scientific direction of all components of the program. The ESP's role will include central data and safety monitoring of CSER2 patients, typically performed by a Data Safety Monitoring Board (DSMB), on behalf of the CSER2 consortium. Twice-yearly meetings of the ESP are already supported by RFA HG-16-012 (CSER2 Coordinating Center) and will include data and safety monitoring. For any funded CSER2 grants not meeting the definition of a clinical trial requiring data and safety monitoring, the ESP will function in the advisory role described above.

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Questions about Eligibility and Funding

18. For an investigator who currently meets the requirements for a New Investigator (NI), would a Program Director/Principal Investigator role in a CSER2 application disqualify him/her for NI status for a future application (RFA-HG-16-010, RFA HG-16-011, RFA HG-16-012) ?

NIH guidance on NI's can be found at:  An investigator with current NI status would lose that NI status if he/she is named as a PD/PI (either overall or as a PD/PI on a multi-PI application) on a funded CSER2 award.  Being named senior key personnel on a funded CSER2 award would not lead to a loss of NI status. 

19. Are cancer related applications allowed for this PAR?

As noted in the background section of the PAR "Projects should be broadly applicable to clinical genome sequencing as a field, rather than being applicable only to a specific disease. "  This means that cancer-related applications should address research questions that generalize to diseases other than cancer.  Applications that focus solely on somatic sequencing of tumors are less likely to be applicable to diseases other than cancer.

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Questions about PAR-16-209 (Investigator-Initiated Clinical Sequencing Research (R01)

20. If an institution is submitting applications to CSER2 (RFA-HG-16-010, -011, -012), may different investigators from that institution submit applications to PAR-16-209?

Section III.3, Additional Information on Eligibility, states "Awards will not be made to the same PDs/PIs in any of the CSER2 FOAs (RFA HG-16-010, HG-16-011, or HG-16-012) and this FOA. Investigators are allowed to apply for both the CSER2 FOAs and this PAR, but should be cautioned that they will not be eligible to be funded for both." Investigators from the same institution are welcome to submit applications for both CSER2 and the PAR, and would be eligible for funding under both mechanisms provided the PIs are not the same.  Technically applications can be submitted with overlapping PIs to both the PAR and the CSER2 RFAs; however, NHGRI will not fund the same PIs for both, even if both applications scored well. 

21. Are PIs for NHGRI consortia other than CSER (e.g. eMERGE, CMG, IGNITE) eligible for this PAR?

This eligibility restriction applies only to this PAR and the CSER2 RFAs. It does not apply to other NHGRI or NIH consortia or programs.  PIs for other consortia may apply for, and be funded under this PAR.  However, as noted in the "Review and Selection Process" section of the PAR, one of the program priorities that will be considered in making funding decisions for this PAR is "Expansion of the community of genomic medicine researchers to new investigators, experienced investigators who are new to this field, and investigators from demographic groups or institutions that are generally underrepresented in genomic medicine."  This will be taken into account along with the other items listed (merit based by peer review, availability of funds, additional program priorities, etc).

22. Can you provide more detail on program priorities for this PAR?

We describe items that will be considered when making funding "Review and Selection Process" section of the application.

  • Scientific and technical merit of the proposed project as determined by scientific peer review.
  • Availability of funds.
  • Relevance of the proposed project to program priorities including:
    • Broad applicability to clinical genomic sequencing as a field
    • Contribution to the reduction of health disparities
    • Inclusion of population groups traditionally underrepresented in genomic research
    • Expansion of the community of genomic medicine researchers to new investigators, experienced investigators who are new to this field, and investigators from demographic groups or institutions that are generally underrepresented in genomic medicine.
    • Expansion of the scope of research questions to those suited to be studied by individual investigators, rather than a consortium approach.
    • Awards under this FOA will not be made to PD(s)/PI(s) funded in the CSER consortium through the CSER2 FOAs.
    • Programmatic balance among diseases to be studied, approaches to be implemented, and research questions being addressed.
  • Compliance with data and resource sharing policies.
  • Appropriateness of costs for proposed sequencing or other technologies in the application.

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Last Updated: July 25, 2016

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YouTube video CSER2 Pre-Application Informational Webinar