Population Genomic Screening in Primary Care Pre-Application Webinar FAQ

Consent and Return of Results

Should the SeqC applicants describe how unexpected (secondary) genomic findings will be found and reported? 

Yes, the SeqC should describe their proposed approach to finding and reporting secondary findings. However, the final protocol for this and other aspects of the SeqC’s activities will be agreed upon by the Network during the first year. 

The RFA says that the sequencing center proposal should include a budget for “clinical reporting of secondary findings not included in the screening protocol at the end of the study as consistent with professional society guidelines.” Other parts of the RFA reference expanding to ACMG v3.2 (N=81 genes) at the end of the program. Could you please clarify exactly what should be included in the proposed budget for expanding beyond the 4-7 genes included in the pilot, because analyzing and interpreting for all 81 ACMG genes would be a significant undertaking as compared to returning results for 4-7 genes? 

For budgeting purposes, applicants should assume current professional society guidelines such as the ACMG SF v3.2 list will be followed by the Network, though reporting of some may be delayed until the primary goals of the Network are met. The approach to return secondary finding will be decided during the first year by the network.     

Can the SeqC return results in a spreadsheet with the CGs or must they issue a report?

The SeqC is required to generate clinical reports for PCPs and patients in formats agreed upon by the Steering Committee. 

Will the SeqC, CGs and CC write the informed consent together?

Yes, the informed consent will be written during protocol development and agreed upon by all members of the SC.

Is it likely the services will be offered also in Spanish?

Offering screening in Spanish is a possibility to be discussed by the Network during protocol development. 

Is there a timeline for returning results to participants?

The timeline for return of results to PCPs and patients, once received from the SeqC, will be decided during protocol development. Applicants should propose and justify a timeline they feel meets the aims of this NOFO and document their ability to meet it. 

Does the program need to establish a single Institutional Review Board (sIRB)?

Yes. NIH issued a policy on the use of a sIRB for multi-site research to establish the expectation that it will be used in the ethical review of non-exempt human subjects research protocols that are carried out at more than one site in the United States. For more details see Single IRB for Multi-Site or Cooperative Research.

Is this study a delayed start or a delayed onset human subject study? 

When planning an application that includes human subjects research that will not begin immediately, applicants are able to designate it delayed onset but only if the proposed research cannot be described in detail. Delayed start and delayed onset are different and should be based on the following definitions:
 

• Delayed start: The human subjects research will not begin immediately, but rather later in the funding period. The applicant is able to fully describe their human subjects study in their application and include all required supporting documents with the application (or, for certain documentation, before award during the just-in-time process). 
   
• Delayed onset: The applicant cannot fully define their human subjects study when they apply. They will need initial research results from the funded project to finalize plans for the human subjects study portion later in the funding period. 

It’s important not confuse the two terms. If a delayed start to a human subjects study is planned but applicants wrongly designate it as a delayed onset study, the application will be missing important details which may negatively affect their score or result in a Bar to Award. 

Conversely, if a delayed onset study is planned but applicants do not designate it appropriately, the automated application forms will require completion of a full study record, for which the initial research results will be needed and might not be available.

See Delayed Onset Study in the Grants and Funding Glossary.

See Delayed Onset Study(ies) in the General Application Guide For NIH And Other PHS Agencies

We already have integrated processes and clinical decision support (CDS) for returning results into our system, do we have to create new processes to apply for this opportunity?

Not necessarily. All awardees will be expected to follow agreed-upon Network protocols for returning results, which could include adaptations of existing processes and CDS if agreed to by the Network. In addition, there may be some room for tailoring to individual sites provided they are consistent with the study protocol. Applicants are welcome to leverage their existing processes and infrastructure for collecting the necessary data but must demonstrate that their procedures are consistent with the agreed-upon protocol. 

How will the SeqC communicate results to the CGs?

This may vary from site to site and by the SeqC’s capabilities. Each site will work with the SeqC and arrange the best way to receive the results.

Will VUS be included in the return of results?

Likely not, but this will need to be a Steering Committee discussion and decision. Variants of uncertain significance (VUS) are typically not included in the return as there is usually not enough information about their effects on a person's health. For this reason, the NOFOs focus on pathogenic or likely pathogenic (P/LP) variants.

For patient consent, the NOFO mentions collection for a) genomic and clinical information, b) future research use, and c) broad data sharing. Are patients required to consent to all three elements (a, b, and c) to participate in the screening, or is it possible for them to proceed with testing and receive results even if they choose not to consent to future research or data sharing? 

Yes, patients are required to consent to all three elements. NIH expects that informed consent for future research use and broad data sharing will be obtained. If the applicant identifies any reasons that may limit the extent of data sharing, they should describe it in their Data Management and Sharing (DMS) plan. NHGRI will then assess whether an applicant’s DMS plan appropriately considers and describes these factors. See the Frequently Asked Questions for examples of justifiable reasons for limiting sharing of data. Learn more about NHGRI expectations.

The NOFO calls for whole exome sequencing (WES) to be utilized by the SeqC. Given that WES contains far more data than is necessary for returning results on the limited 4-7 conditions specified, how will the data from WES be managed?  Will participants have the option to decline analysis and storage of the remainder of their exome data that is not relevant to the conditions of interest?

No, participants will not have the option to decline analysis and storage of the “unused” data. NHGRI expects that secondary analysis of WES data will occur at some point. The Network will decide when it will be best to return these data as NHGRI has been strongly urged to focus this pilot study on a small number of conditions. In other studies, return of secondary fundings has been done at the end of the study so as not to interfere with the goals of the program. We believe that if explained in the consent, it works well. Also, community engagement can be used to decide on items such as this during the first year of the program.

Will the Seq C reanalyze results after initial screening (but during study period) to identify reclassified variants (e.g. to resolve VUS) and communicating them to CGs?

Likely yes, but this will need to be a Steering Committee discussion and decision during the first year.

Patient Enrollment

While there will be no funding for follow-up (referral) care, may we offer incentives for staying connected (retained) to track outcomes?

Yes, strategies for staying connected and retaining participants will be needed to track outcomes and will be discussed and agreed upon during protocol development.

Is the vision to include uninsured patients?

Yes, as relevant to the applicant’s proposed study. The NOFO requires the inclusion of “Health disparities populations” which refers to racial and ethnic minority groups, people with lower socioeconomic status (SES), underserved rural communities, sexual and gender minority (SGM) groups, and people with disabilities.

Is there a vision for lower age limit for patients?

Yes, “patients” refers collectively to adults ages 18 and older.

Can awarded clinical groups use referrals to increase recruitment or must all subjects be recruited by members listed in the award?

All subjects must be recruited by members listed in the award.

Is this nation-wide recruitment or is recruitment limited to a specific region?

Recruitment is not limited to a specific region, applicants are free to propose whatever scope of recruitment they can directly conduct by the members listed in the award.

The NOFO states that each CG will be responsible for engaging primary care providers (PCPs) to screen, enroll, and follow 5,000 patients who are consented for genomic and clinical information collection, future research use, and broad data sharing.  How involved the PCPs need to be in these activities? Specifically, do they need to directly perform the screening, enrolling, and follow-up, or is it sufficient that these activities occur in the PCP setting with their oversight?

No. PCPs are not expected to directly perform the screening, enrolling, and follow-up. It is acceptable that these activities occur in the PCP setting with their oversight, though they are expected to participate in subsequent management (surveillance, further testing, etc.) of screen positive patients.

Do you consider OB/GYN primary care providers?

Yes, OB/GYN are usually considered PCPs.  However, different sites might consider them differently and not all OB/GYN practitioners actually provide primary care. If sites decide to include OB/GYN as PCPs, they should demonstrate the proposed OB/GYNs actually provide primary care and should consider the impact of their patient populations (typically younger women) on the overall composition of their proposed study population. The NOFOs focus on the general population.

Will clinical groups (CGs) from large health systems be required to engage PCP's from outside their own system?

No, they are not required to engage PCPs outside their system as long as they have enough patients to recruit within their own system to meet the requirements of the NOFO.

Approximately how many PCPs are you looking for per clinical group (CG)?

CGs should plan on having no more than 10 Clinical sites each so that each PCP will have a meaningful experience in managing at least 10-15 positive cases.

Outcomes

Given that more rural clinical enrollment sites/PCPs may be on different EHR systems or lack a traditional EHR, is there an expectation that the PCP sites will allow continued access to medical/clinical records to the study? 

No, there are no specific expectations of PCP sites regarding continued access to medical/clinical records. However, all participants recruited to this study are expected to be patients with existing and accessible EHRs, hard copy medical records, or other means to access their clinical care records for follow up. Applicants should describe how follow up data collection will be achieved using whatever records are available for the duration of the study.

Should the program provide treatment to patients who are determined to have one of the target conditions, or should the program simply refer them to an appropriate specialist outside the program (e.g. through program navigators)?

The program is not designed to provide treatment to those who are determined to have one of the target conditions and such costs will not be supported by the program. Rather the program should offer referral to an appropriate specialist and follow up to see the outcomes of and barriers to those referrals.

Other

If we submit a proposal with multiple PIs, is there a minimum level of effort required?  

No, there is no minimum level of effort required of multiple PIs in an MPI application. However, the individual and total allotted effort should be consistent with the proposed research.

Does the Network have an official name yet?

No, the Network doesn’t have an official name or logo yet. This will be decided by the Network during the first year.

Do I understand correctly that each applicant for the CG will come up with their own plan for community engagement, recruitment strategies and the research trial, and the genomes to be tested, BUT the selected groups will all discuss in a network and in consensus have the same protocols and genes and research trials etc.?

Yes, this is correct.

Is this a one-shot application opportunity or will there be the possibility to reapply?

This is a one-shot opportunity. There is no possibility to reapply.

Will the NIH prioritize single site applicants or are they welcoming collaborative/ regional projects?

NIH will not prioritize single site applicants and will welcome collaborative projects as long as they meet the goals of the NOFO.

Is the application by institution or laboratory group?

Any applicant, whether institution, laboratory group, or other organization that meets the criteria described in “Section III - Eligibility Information” can apply to the NOFOs.

Will FDA review/approval of return of results to participants be required? In other words, will the project need an IDE w/ the FDA?  

Most likely no, but if a study proposes to use a genomic test that is not FDA-cleared or approved, the investigator of the study must consider FDA's IDE regulation before proceeding with enrollment. In the context of genomics research, the purpose of the IDE process is to demonstrate that a test has plausible analytical validity and to protect the interests of study participants who might receive test results that could affect their clinical care. There are also some situations when clinical genomics research is exempt from the IDE regulation, or "IDE exempt". See FDA-IDE Points to Consider (PDF).

Will the slides and the recorded video be available?

Yes, they will be available on the webinar page.

Will certificate of attendance be available after the webinar?

No, we will not issue certificates of attendance.

Should an applicant submit a proposal for all three centers?

No, an applicant is not required nor expected to submit an application for all 3 components of the program. The applicant should decide which to apply to.

Would a plan focused on cascade screening be considered responsive to this NOFO?

No, the program is intended to conduct genomic screening in primary care of any patient regardless of their family history, health status, or other conditions. Cascade screening, as defined by NCI, will likely be a recommendation to Primary Care Providers (PCPs) and patients once a pathogenic/likely pathogenic variant is found in a screened patient, but relatives of patients found to have a pathogenic/likely pathogenic variant through this study will not be screened or included in this study unless they happen to be part of the general population of patients offered screening within a CG’s participating primary care practice.

Should we request a specific study section when submitting?

No, this is an NOFO and will be reviewed by a dedicated panel of experts selected and coordinated by the Review Branch at NHGRI.

“Health disparities populations” - how should we define "people with disabilities"? Similarly, is there a specific definition we should use for "people with lower SES"?

“Health disparities populations” refers to racial and ethnic minority groups, people with lower socioeconomic status (SES), underserved rural communities, sexual and gender minority (SGM) groups, and people with disabilities. For more details see Minority Health and Health Disparities Definitions.

Is it appropriate for applicants to name advisory group members?

No. If an advisory group or groups are envisioned, their proposed roles and expertise should be described. However, potential members should not be named in the application.

Can one institution apply for both the Coordinating Center (CC) and the Clinical Groups (CGs)? Can the Contact PI for the CC application also be a co-Investigator on the CG application?

Yes, one institution may submit applications to both the CC and CG opportunities. These must be distinct applications. The proposed PI on one may be a co-Investigator on the other, provided there is no overlap in duties or funding and no over commitment for that individual. It is not recommended for a PI on one application to be an MPI on another.

Are each of the NOFOs expected to be a single institution? In other words, could multiple institutions partner to serve as the Coordinating Center (CC) or partner to be on a single Clinical Group (CG) application?

Yes, organizations may partner on an application to be the CC or on a single CG application.

Are U01s eligible for transfer if an investigator moves from one institution to another during the course of the grant period?

Yes, transfer is possible if certain requirements are met, including but not limited to the NOFO institutional eligibility requirements, but the original recipient institution (the actual “awardee”) must agree to the transfer. For more information see Change of Recipient Organization.

Must an introduction be included for the application?

An introduction is not required; applicants should follow application instructions.

Clinical Groups (CGs)

Is the expectation to include clinic leadership and or the clinicians recruiting as co-investigators or if it would be acceptable to have them included in a provider advisory board to inform workflows as well as patient engagement and recruitment strategies?

It’s up to the applicants to propose and justify how to include clinic leadership and recruiting clinicians, while ensuring they are meeting the goals of the RFA.

What is the expected size of the clinical groups? Is it advantageous to be a single large site or partner with geographically distinct sites for a single CG application?

There is no expectation about the size or distribution of the clinical groups. The applicants should consider the advantages and disadvantages of a single large site versus geographically distinct sites for a single CG application and justify their choice based on the goals of the NOFO.

Will each CG propose its own research trial but the network will decide in concert in year 1?

Yes, the CGs should propose their own research trials based on the specifications of the NOFO and during the first year the Network will agree collectively on the implementation approaches to be tested as well as the specific variants to be screened based on the conditions proposed by the successful applicants.

Are all CGs sequencing the same conditions? And following the same protocol for return of results?

Yes, the goal is for all clinical sites to sequence the same conditions and follow the same protocol for return of results. There may be some room for tailoring to individual sites provided they are consistent with the study protocol. The network will discuss case by case should a clinical site require a different approach to return results to PCPs and Patients.

Is the scope of the NOFO to test methods for uptake of screening, or testing the validity of new tests? Similarly, what are the outcomes being assessed?

The scope of the NOFO is to assess uptake of the population-based genomic screening and more. Please see the research topics section of the NOFO. Examples of topics that could be addressed in implementing a population genomic screening program include but are not limited to those listed mentioned there. Outcomes to be assessed will be determined by the Steering Committee during protocol development.

Among the “extra” 4-7 conditions, will all sites be expected to offer the same overall panel of conditions, or could that be influenced at CG level (or even clinical site level) based on results of community engagement?

Yes, all sites are expected to offer the same overall panel of conditions.

In the Instructions in the CG NOFO, 3 Specific Aims are already given. Are those the SA's that all CG applicants must include in their proposal?

Yes, applicants must address these aims but are free to state or restate them in any ways that best fit their proposed study. Applicants should make clear how their aims meet the NOFO aims and are free to propose additional aims if they are able to do so within the budget and timeframe of the NOFO.

Are there specific requirements for what clinical outcomes we should assess over 24 months?

No, there are no specific requirements. Suggestions are available in the research topics section of the NOFO but applicants should propose and justify outcomes that would best fit their proposed study.

Is there an expectation that the Research Strategy of the application propose an RCT that specifically evaluates the effectiveness of implementation strategies to recruit patients for genetic testing, ascertain samples, and follows patients for follow-up? If so, how will the network of funded sites determine the final procedures?

No, there is no specific expectation for an RCT as long as the proposed population screening test is offered to everyone regardless of health status and other conditions, without preferentially selecting for or excluding anyone who might be at risk. Final procedures will be determined by Steering Committee deliberation and vote in the first (protocol development) year.

Do clinical groups need to budget for the WES that will be done at the SeqC?

No, CGs should not budget for WES costs.

Should CGs budget for AnVIL computing for analyses?

Yes, applicants should budget for any analyses they propose to participate in, including (if desired) analyses performed by the CC in which they will be actively involved.

Can CG applicants propose to work with a different sequencing laboratory, perhaps one with which they have a prior relationship, instead of using the Sequencing Center (SeqC)?

No, for reasons of standardization, logistics, and costs all CGs will be expected to work with the SeqC. Sequencing for this program will be limited to the specific tests for the specific variants agreed upon by the Network and will have to be standardized and harmonized for reporting to the participating CGs. This will also facilitate making the data accessible to the broader scientific community to comply with NIH data standards. For these reasons, only sequencing conducted by the Network SeqC will be supported and included in the study data. Any laboratory that can meet these requirements would be welcome to apply to RFA-HG-24-023 , Population Genomic Screening in Primary Care SeqC.

Do all the CGs have to do the same additional conditions and measure outcomes in the same way?

Yes. The Steering Committee will decide the 4-7 conditions that will be implemented across the Network. A single Network-wide protocol will also be established during the first year by the Network’s Steering Committee that will identify and collect outcomes important to patients, PCPs, and other stakeholders for successful uptake of screening and referral to follow-up care. NHGRI recognizes that while a single protocol for implementing population genomic screening in primary care will be agreed upon and followed by this Network, some adaptation to local systems and practices may be necessary. Documentation and assessment of these adaptations will also address useful scientific questions.

Are CGs allowed to recommend more than four additional conditions for consideration in the population screening program?

Yes, CGs may choose to suggest more conditions but they must fit all the information needed by reviewers to evaluate them within the limited space permitted in the application. The Network will agree collectively on the specific tests for the specific variants to be screened based on the conditions proposed by the successful applicants. For budgeting purposes, CG applicants should assume only 3 additional conditions to be screened and followed up to ensure comparable staffing and funding across sites.

The NOFO states that the protocol development will take place in year 1; are the CGs then required to propose a plan in the research strategy?

Yes, CG applicants are expected to propose a plan for carrying out the study as described in the “Research Strategy” section of “Section IV. Application and Submission Information” in the population screening NOFOs. Successful applicants will then work with the other funded sites during the first year to finalize a protocol that works at all sites.