Frequently Asked Questions for the Electronic Medical Records and Genomics (eMERGE) Network, Phase III RFAs

RFA-HG-14-025: The Electronic Medical Records and Genomics (eMERGE) Network, Phase III - Study Investigators (U01)

RFA-HG-14-026: The Electronic Medical Records and Genomics (eMERGE) Network, Phase III - Coordinating Center (U01)

RFA-HG-14-027: The Electronic Medical Records and Genomics (eMERGE) Network, Phase III - Central Genome Sequencing and Genotyping Facility (U01)

Are projects using research cohort data linked to hospital billing data eligible for this RFA?

The goal of eMERGE is to use electronic medical records (EMRs) linked to existing biorepository to conduct genomic discovery and clinical implementation research. Hospital billing data without the full spectrum of EMR phenotypic and clinical data would not assist in fulfilling goals of the Network and would not be eligible.

What are the expected roles of the Coordinating Center (CC) and Central Genomic Sequencing/Genotyping Facility(-ies) (CSG) in analysis of the genome sequencing data, including but not limited to imputation and quality control (QC) in eMERGE III?

As described in the RFAs, eMERGE III investigators at the study sites, CC, and CSG will work collaboratively although particular entities may be asked to lead some specific aspects of the Network's activities. For sequencing data quality assurance, management, and analyses, investigators at the CC and CSG are expected to work very closely with each other. The CC RFA "Research Plan" requires that all applicants describe their suggested strategies for working with the CSG. The specific emphases for the CC and CSG are described in Section IV. 2., under "Research Strategy."

In brief, the CSG will provide high-quality BAM and VCF files to the CC (and other eMERGE sites as desired) including component tasks leading to the production of such files such as alignment, variant calling, quality control/quality testing, analysis completion, and validation. The CSG will also participate collaboratively with other eMERGE-funded sites and NHGRI in annotation of variants and identification of potential pathogenic or functional variants in genes critical to health and disease. The CC will be responsible for conducting comprehensive quality assurance on delivered BAM and VCF files; storing, hosting, managing, and distributing to eMERGE investigators and to public repositories such as dbGaP the large amount of sequencing and phenotyping data; harmonizing data across studies; and leading (in close collaboration with the other eMERGE-funded sites and NHGRI) the cross-study analyses. The CC is expected to be primary site for hosting the datasets generated by the CSG and the primary point of contact for responding to inquiries and for distributing the data within and outside eMERGE according to policies agreed upon by the Steering Committee and NHGRI.

The exact division of responsibilities for data analysis is nearly impossible to define in advance given the rapidly evolving nature of this field and the variety of capabilities that may ultimately reside in the selected awardees. Applicants for both the CC and CSG should describe the components of analysis they are capable of undertaking and their willingness to participate collaboratively and share responsibilities as deemed appropriate by the Steering Committee and NHGRI.

Are food-related costs an allowable expense to be included in the grantee budget?

Food for programmatic meetings is permissible - this should be based on the consistent application of the grantee's own policies for research grant meetings with food, and in accordance with the cost principles applicable to the grantee. Please see the excerpt from the Guide Notice below (NOT-OD-12-041: New NIH Policy on Efficient Spending Related to Grants Supporting Conferences and Meetings):

Research Grants and Other Mechanisms that are not Awarded Specifically to Support Conferences: The policy does not apply to research grants and other mechanism that are not awarded specifically to support conferences. Any meetings conducted under these programs are considered an ancillary effort under the grant and cooperative agreement and are not subject to the new policy. In these cases, the allowability of food-related costs is governed by the respective cost principles and the terms of award which include references to the NIH Grants Policy Statement.

Is an applicant eligible for RFA-HG-14-025 if it will be able to achieve one, two, or three, but not all eMERGE III goals?

No, all applicants must meet all requirements identified in the RFA for consideration.

Should it be sufficient to bring genome-wide genotyping data from platforms testing around 200k-250k with imputation?

No, testing around 200k-250k SNPs with imputation is not sufficient. The platform must test for ?500k SNPs.

For RFA-HG-14-025, to meet the requirement of 3,000 GWAS samples and 2,000 samples to be sequenced in eMERGE III, can there be overlap between these two sets?

Yes, some or all of the 2,000 to be sequenced can be drawn from the 3,000 GWAS samples.

How are we going to define the ~100 clinically relevant genes?

For planning purposes, eMERGE III is proposed to start with a targeted panel (roughly 100 genes), and as technologies advance to move to targeted analysis using exome sequencing and then to full genome analysis. The final genomic technology used for eMERGE III will be determined by the SC. Genes likely to be considered by the SC will include those recommended by expert groups, such as the ACMG Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing PDF file [acmg.net] referred to in RFA-HG-14-027. Applicants should propose and justify a list of genes that they feel to be most scientifically meritorious. The final list of genes will be decided by the SC.

Is the central sequencing/genotyping center(s) responsible for DNA Isolation?

The biorepositories are expected to provide purified DNA to the sequencing/genotyping center(s). However, the sequencing/genotyping center(s) may be required to provide DNA isolation services in situations where the biorepositories' sample processing are not adequate to satisfy the requirements for sequencing by the sequencing/genotyping center(s). Applicants in their respond to RFA-HG-14-027 should anticipate 5-10% of samples being submitted for sequencing will require re-isolation.

How many samples will have been obtained in a CLIA-certified manner such that a new specimen is not required for clinical confirmation/reporting?

There is no way to find the exact number until the final awards will be made.

Should applicants in their response to RFA-HG-14-027 budget for 2,000 samples that will be CLIA-validated as mentioned in RFA-HG-14-025?

Yes, while the sample number for CLIA validation in RFA-HG-14-025 is only an approximation, applicants may use this estimate when developing their budget submission for their RFA-HG-14-027 response.

If sequencing is conducted in a non-CLIA environment, are variants then confirmed in a CLIA environment? If so, which variants will be confirmed and who will select them?

Yes, actionable clinical variants should be confirmed in a CLIA environment before clinical use. The eMERGE Steering Committee will decide which variants need to be confirmed, based largely on those proposed for return of results and use in clinical care.

Since eMERGE III aims to identify rare variants with presumed major impact on function of a to-be-decided-upon number of clinically relevant genes, does that mean eMERGE focuses on rare diseases with high penetrance?

No, the goal of eMERGE III is to study rare variants in clinically relevant genes, whether related to rare or common diseases.

In studying rare variants, will applicants be expected to offer study populations of a specific phenotype?

No, applicants may select phenotypes according to their interests and expertise and the character of their study populations.

Besides identifying rare variants, can we also investigate common variants relevant to our patient community?

Yes, you can propose to study both rare and common variants that may be related to your selected phenotypes.

For phenotyping methodology development and clinical decision support demonstration, are there predefined priority clinical phenotypes?

No, not at this time. Phenotyping priority may be determined by the eMERGE III SC after awards are made.

The RFA-HG-14-027 indicates "CLIA-approved sequencing is not required, but a plan for CLIA variant validation for clinical use must be provided." Since some sites may not be able to provide all samples collected in a CLIA-compatible way, except for their validation samples, should applicants in their response to RFA-HG-14-027 budget a certain amount of funds for non-CLIA-approved sequencing?

Yes, applicants may wish to raise this issue and budget an estimated amount of funds for a non-CLIA sequencing of some samples.

Can applicants submit a two-institution joint application with full budget for each of the two institutions?

No, a two-institution joint application should remain within the budget cap by dividing the total between the two institutions.

For applications demonstrating approaches to electronic phenotyping for late-onset or atypical forms of genes/disease, should applicants start with specific phenotypes to identify genes or by selecting genes to find atypical phenotypes?

Applicants are free to propose either one or both of these approaches that are suitable for their study participants and they prefer to use to meet the scientific goals of the FOA.

If we already have exome- or whole-genome sequence data, are we expected to use our sequence data for eMERGE experiments or are we expected to use the sequence data generated by the central facility exclusively?

Applicants should propose any combination of these data (their data, central facility data, or some combination) they prefer to meet the scientific goals of the FOA.

If you propose to use your exome- or whole-genome sequence data for clinical implementations, your data should be generated in a CLIA environment. Variants that the eMERGE SC decides to use for clinical care should be included in your sequence data or additional sequencing will be needed. The eMERGE SC will decide if your genotypes need to be re-validated by the central facility(-ies) in a CLIA environment. To use your existing sequence data for eMERGE discovery analyses, the data quality will be evaluated by the network and a decision on re-sequencing, if needed, will be made by the eMERGE III SC. Note that exome- or whole-genome sequencing data should be submitted to the CC and dbGaP prior to award if these data are committed for use by the network.

How many new sites will be included in eMERGE III?

Applicants from existing and new sites will have an equal opportunity for this competition. We do not know the number of existing and new sites until awards will be made.

If an eMERGE site has already recruited and consented participants and another site in the Network has not yet completed recruitment, then the site with recruited and consented participants might be at a disadvantage. Will sequencing be staggered?

Yes, some phasing of sequencing will be needed as it is unlikely that all 25,000 samples can be sequenced simultaneously. Plans and priorities for phasing the sequencing will be discussed among the eMERGE III sites and recommended by the Steering Committee. The CGS will set up its timeline according to these priorities.

If it is more efficient, can an applicant propose to recruit new participants for return of results (RoR) rather than re-consent their existing biobank subjects?

Yes, if recruiting new participants would be more efficient than re-consenting existing biobank subjects. However, as stated in RFA HG-14-025, applicants who have samples that already have data and have been consented for RoR at the time of submission will be given preference.

How much time will be given to recruit participants?

No time limit has yet been set on recruitment, but applicants are encouraged to propose a realistic timeline for recruitment and other study tasks that will meet the goals of the RFA within the eMERGE III funding period.

We currently have samples that have mutations of interests that were collected for research studies but were not processed for RoR. Is there a mechanism that is available to validate these samples and prepare them for RoR?

Yes, the Central Sequencing and Genotyping Facilit(-ies) will have the capacity to CLIA validate samples.

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For more information, please contact:

Rongling Li, M.D., Ph.D.
Phone: (301) 594-6524
E-mail: lir2@mail.nih.gov

Last updated: September 22, 2014