eMERGE Genomics Risk Assessment and Management Network

On June 13, 2019, NHGRI held a pre-application interactive Q&A webinar for the eMERGE Genomic Risk Assessment and Management Network funding opportunities.

Frequently asked questions from prospective applicants are provided below.

Do the proposed disease-specific genomic risk assessment and management plans need to be proven via randomized clinical trials or are interventions with other levels of evidence allowed?

Randomized clinical trial evidence is not required; other resources including expert panels and guidelines will be considered. Applicants should clearly describe the evidence available for the genomic risk assessment and management plans they propose and justify their choice of plans. 

How will the outcome measures of genomic risk assessment and management be selected?

Investigators should propose the outcomes they think are most suitable for the condition being addressed by the genomic risk assessment and management plan. Outcomes suggested by awardees will be compiled during the first year after award by the Coordinating Center. The final list of outcomes will be reviewed and agreed upon by the Steering Committee.

If patients have already had genetic testing, can they still be included in the 2,500-person cohort? 

The individual can be included as long as the results have not been returned to the patient or clinicians treating the patient. The goal is to capture the impact of genomic risk information on patients’ outcomes, which must be done prospectively through reporting and monitoring of these patients.

Can pediatric patients be included in this program?

Yes, they may, as long as it is possible to implement the genomic risk assessment and management plans across all of the sites and the proposed risk assessment and management plans in pediatric patients meet other criteria as explained in the RFA for generalizability, clinical importance, feasibility, potential impact, and cost. The inherent challenges with providing genomic risk information to pediatric patients and obtaining timely outcomes in them over a four-year follow-up period should be addressed when proposing genomic risk assessment and management plans for pediatric patients.

Is the goal to recruit patients with high PRS?

No, the goal is NOT to recruit patients with high PRS. The goal is to recruit a reasonably diverse and generalizable sample of persons across the spectrum of risk within a clinical care system and then calculate their genomic and clinical risk estimates to determine their risk for the 15 conditions selected by the Steering Committee. Assuming these conditions are largely independent, binomial probabilities can be used to estimate that ~25% of the population will be at the top 2% of risk for at least one of 15 conditions. But, the goal is NOT to preferentially recruit people with high-risk.

Is it possible to recruit families?

Yes.

Where can applicants find the race/ethnic breakdown of all eMERGE participants?

The eMERGE website provides a breakdown of the self-identified race/ethnic background of all eMERGE participants.

Does NHGRI anticipate limiting return of secondary findings as described by the American College of Medical Genetics and Genomics (ACMG)?

No, applicants should expect to return all results that the Network determines actionable based on the Network’s collective expertise.

Should applicants include a detailed analytic plan with power calculations?

Yes, applicants should describe what approach will be used to validate the genomic risk assessment and outcomes. Applicants can explain their design in detail and some elements may fit into the clinical trial section.

Can sites focus recruitment on patients with a medical or family history that increases risk for one of the targeted phenotypes?

Yes, they may, if such a strategy is needed to provide a reasonably diverse and generalizable sample of persons across the spectrum of risk and can be achieved within the budgetary constraints of the RFA. Applicants should explain how such a strategy could be achieved across the entire Network and why it is a reasonable strategy to propose.

Is it possible to have two groups of patients: some of whom would receive genomic predictors and others who would have these data held back as a control?

NHGRI is not expecting to include a control group of recruited and consented participants. Applicants can consider proposing a comparator group with relevant available data if that can be achieved within the budgetary constraints of the RFA.

The RFA indicates that the Clinical Site will be expected to return secondary findings not included in the reported PRS. What are secondary findings within the context of this RFA?

Secondary findings are genetic test results that are not part of the primary purpose for performing the selected genomic risk assessments.

Will sites be required to implement all 15 genomic risk assessments?

Yes, all 15 genomic risk assessments are expected to be implemented for all patients.

Why does this program meet the NIH definition of a clinical trial?

In 2015, NIH broadened its definition of clinical trials to include non-randomized implementation of interventions such as genetic testing where results are reported back to participants. These definitions are described int NOT-OD-15-015 and other useful materials are available at the NIH Office of Extramural Research website. Please note that the eMERGE Genomic Risk Assessment and Management Network is not intended to be a traditional randomized controlled clinical trial. The goal of this Network is to implement genomic medicine risk assessment into a cohort of 20,000 individuals and measure the impact this has on clinical outcomes. Applicants should respond to this defined purpose as outlined in the RFAs, regardless of differing perspectives on what may or not constitute a clinical trial.

What is the impact on investigators as a result of classifying this program as a clinical trial?

This expanded definition and the policies accompanying it were implemented to ensure that the public investment in clinical trials research is shared among a larger audience. Applicants should familiarize themselves with requirements for NIH defined clinical trials when submitting a response to RFA-HG-19-013, RFA-HG-19-014 or RFA-HG-19-015.

NIH requires appropriate data and safety monitoring for clinical trials. Are eMERGE applicants expected to include plans for a Data Safety Monitoring Board (DSMB) at their institutions?

No, applicants are not expected to plan or budget for a DSMB. As described in the eMERGE RFAs, an External Scientific Panel (ESP) and Steering Committee will evaluate the progress of the eMERGE Genomic Risk Assessment and Management Network. The ESP's role will include central data and safety monitoring of eMERGE patients on behalf of the eMERGE consortium. Twice-yearly meetings of the ESP will be supported through RFA-HG-19-015 (eMERGE Coordinating Center) and will include data and safety monitoring.

Are applications with multiple Principal Investigators permitted?

Yes, for institutions/organizations proposing multiple PDs/PIs, visit the NHGRI Multiple Program Director/Principal Investigator website for further information.

Are foreign institutions eligible to apply?

No.

Are foreign components allowed under this RFA?

Yes, foreign components as defined in the NIH Grants Policy Statement are permitted as part of applications from domestic institutions.

What are the main differences between RFA-HG-19-013 and RFA-HG-19-014?

The main difference is the sociodemographic composition of the populations from which patients are recruited for the Network to ensure acceptable levels of study power. RFA-HG-19-013 requires a minimum of 35% of patients to come from racial or ethnic minority populations, underserved populations, or populations who experience poorer medical outcomes, while RFA-HG-19-014 requires a minimum of 75% of such patients. The available funds for RFA-HG-19-014 are also higher than for RFA-HG-19-013 due to the expected increased costs of recruiting, following, and providing medical services in underserved populations.

Can follow-up genetic testing be used as part of a genomic risk management plan?

Yes, pharmacogenomic or other genetic testing can be included as part of the risk management plan if, for example, specific follow-up testing is indicated for persons identified in etwork-wide testing as being at risk. As an illustration, a patient at high risk of coronary disease might be identified by the genomic risk assessment. Pharmacogenetic testing for lipid-lowering therapy might then be indicated (if not already included in the initial genomic testing). If the genetic testing is expected to be performed across the Network, this testing would be expected to be managed and paid through the Coordinating Center to ensure standardization and reduce the cost of this testing.

Where can I find out more about the eMERGE Network?

The eMERGE Network has established a Projects website website that includes past Steering Committee Notes & ESP packets, lessons learned, the current data use agreement, studies available in dbGaP, and publications. Additional information can also be found on the Resources tab on the main website.

How will the genomic risk assessment be calculated?

The Steering Committee will need to establish a process and analysis pipeline that receives and combines the genetic and clinical covariates to calculate a genomic risk estimate. The CC will be responsible for coordinating this effort and ensuring a consistent calculation among all the sites. The Clinical Site will be responsible for integrating the result into the EMR and the electronic Clinical Decision Support (eCDS).

When is prospective recruitment expected to begin and end?

Prospective recruitment will begin toward the end of Year 1 and continue into Year 4

Is the plan to have a central consent form which will be used by all clinical sites?

Yes, there will be a central consent form that might need slight modification based on local IRB requirements. The sites are expected to have a single IRB submission as instructed in the RFA.

The RFA indicates that 15 genomic risk assessments will be incorporated into the EMR and returned to patients. When and how will these 15 conditions be selected?

During the first year, the Steering Committee will select 15 conditions that will have genomic risk assessment and management plans developed and implemented across the Network.

Why is FDA approval required for the genotyping technology?

The FDA approval is required due to the clinical implementation component of the program. The one-year protocol development period is insufficient for developing and validating a custom array; the eMERGE Network will need an array that is essentially off the shelf and CLIA and FDA approved for clinical use.

FDA has approved some panels, but they sometimes require confirmatory testing for results that are returned to patients. Has this been addressed?

No, the Steering Committee will need to address this once the genotyping panel is selected.

Are sub-projects allowed or is this meant to be a Network-wide single project where opportunities to do sub-projects are discouraged? Applicants are encouraged to submit ideas for sub-projects. But, it is important to recognize that resources are limited and the primary purpose of this RFA is to understand the impact of genomic risk assessments on the 20,000-patients and their clinicians.

What kind of research is envisioned for the small two-year ethical, legal, and social implications (ELSI) research study?

The ELSI study should be designed to provide foundational and novel research findings that can inform the development and implementation of the PRS protocol proposed by the Clinical Site or Enhanced Diversity Clinical Site. The proposed ELSI research may utilize a variety of methodologies including empirical, legal and/or normative approaches as appropriate for the research question. The proposed ELSI study must be specific to the unique ELSI research questions raised by the calculation, return, understanding, use, and utility of polygenic risk scores in the diverse populations enrolled in eMERGE. In addition, the ELSI research study should be integrated into the larger eMERGE protocol such that the ELSI research informs the subsequent implementation of PRS.

How much detail is required about the ELSI study?
Applicants are encouraged to include a clear statement of the unique ELSI questions related to PRS, a brief description of the methodologies that will be used to study those questions, relevant ELSI expertise on the project team, and a concise description of how the ELSI research will be integrated into and inform the overall study design.

Is an ELSI research study required to apply to RFA-HG-19-013 or RFA-HG-19-014?
While an ELSI research study is not required to apply to either the eMERGE Clinical Sites or Enhanced Diversity Clinical Sites RFAs, inclusion of an ELSI research study is welcomed.

eMERGE lesson learned

eMERGE resources

You can email us at emergerfa@nih.gov