Yes. Information on the current protocol can be found in the UDN Manual of Operations at: https://undiagnosed.hms.harvard.edu/udn-manual-of-operations/.

The “Funds Available and Anticipated Number of Awards” is in total costs while the “Award Budget” is in direct costs. Your application budget should not exceed the “Award Budget” in direct costs.

The direct costs are excluding the consortium F&A costs requested by a subcontract following this Guide Notice: https://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-040.html.

The PD/PI on a Clinical Site application may have any role on a different UDN Phase II application other than PD/PI (or co-PI on a multi-PI application). Funding multiple UDN Phase II awards at the same institution would require that potential conflicts and overlaps be resolved before awards are made.

The PD/PI (or co-PI on a multi-PI application) of any other UDN Phase II application may not be the PD/PI (or co-PI on a multi-PI application) of a Clinical Site application. However, other individuals located at the same institution may be the PD/PI on a Clinical Site application. Funding multiple UDN Phase II awards at the same institution would require that potential conflicts and overlaps be resolved before awards are made.

PD/PIs on a multi-PI application must as a team be well-established in clinical research.

Letters of support should clearly document commitments (including but not limited to staff or monetary commitments) to meet the requirements of the FOA during the period of award. Institutional commitment and willingness to sustain the program beyond NIH Common Fund support should also be indicated, however, a specific monetary commitment level is not required. Additionally, the Sustainability Plan proposed in the Other Attachments section should include the investigators’ plan for sustainability as NIH Common Fund funding ramps down.

Yes, the slides from the Applicant Information Webinar are available at: https://commonfund.nih.gov/Diseases/grants/webinar.

Currently, the NIH does not have any formal plans for support of UDN resources after Common Fund support ends. How to transition the UDN to a sustainable national resource will be addressed at the sustainability workshop that is anticipated to take place in FY20.

The Sustainability Plan proposed should be relevant to maintaining the critical functions of the UDN component applied for. Ideas regarding sustainability for the network may be included, but are not required.

The single (or central IRB as referred to in Phase I of the UDN) IRB for Phase II of the UDN will be at the NIH. There will be no cost to the UDN sites to use this IRB.

Please refer to the Clinical Site FOA for requirements. The UDN is a network and as such each FOA plays a role. Reviewing the objectives of the 5 FOAs may help clarify their roles. For example, the Model Organisms Screening Center will provide Drosophila and zebrafish models, the Sequencing Core will provide exome and genome sequencing, and the Metabolomics Core will provide metabolomics analyses to the UDN. Clinical Sites do not need to budget for the services provided by the UDN Core Laboratories in their Clinical Site application.

Yes. Information on the current protocol can be found in the UDN Manual of Operations at: https://undiagnosed.hms.harvard.edu/udn-manual-of-operations/.

The “Funds Available and Anticipated Number of Awards” is in total costs while the “Award Budget” is in direct costs. Your application budget should not exceed the “Award Budget” in direct costs.

The direct costs are excluding the consortium F&A costs requested by a subcontract following this Guide Notice: https://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-040.html.

The PD/PI on a Coordinating Center application may have any role on a different UDN Phase II application other than PD/PI (or co-PI on a multi-PI application). Funding multiple UDN Phase II awards at the same institution would require that potential conflicts be resolved before awards are made.

The PD/PI (or co-PI on a multi-PI application) of any other UDN Phase II application may not be the PD/PI (or co-PI on a multi-PI application) of a Coordinating Center application. However, other individuals located at the same institution may be the PD/PI on a Coordinating Center application. Funding multiple UDN Phase II awards at the same institution would require that potential conflicts be resolved before awards are made.

At least one PD/PI on a multi-PI application must be well-established in clinical research.

Letters of support should clearly document commitments (including but not limited to staff or monetary commitments) to meet the requirements of the FOA during the period of award. Institutional commitment and willingness to sustain the program beyond NIH Common Fund support should also be indicated, however, a specific monetary commitment level is not required. Additionally, the Sustainability Plan proposed in the Other Attachments section should include the investigators plan for sustainability as NIH Common Fund funding ramps down.

Yes, the slides from the Applicant Information Webinar are available at: https://commonfund.nih.gov/Diseases/grants/webinar.

Currently, the NIH does not have any formal plans for support of UDN resources after Common Fund support ends. How to transition the UDN to a sustainable national resource will be addressed at the sustainability workshop that is anticipated to take place in FY20.

The Sustainability Plan proposed should be relevant to maintaining the critical functions of the UDN component applied for. Ideas regarding sustainability for the network may be included, but are not required.

The single (or central IRB as referred to in Phase I of the UDN) IRB for Phase II of the UDN will be at the NIH. There will be no cost to the UDN sites to use this IRB.

Yes. Information on the current protocol can be found in the UDN Manual of Operations at: https://undiagnosed.hms.harvard.edu/udn-manual-of-operations/.

The “Funds Available and Anticipated Number of Awards” is in total costs while the “Award Budget” is in direct costs. Your application budget should not exceed the “Award Budget” in direct costs.

The direct costs are excluding the consortium F&A costs requested by a subcontract following this Guide Notice: https://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-040.html.

No, this is a typo. The correct application budget is $350K direct costs in FY21. See Notice NOT-RM-17-037.

The PD/PI on a Model Organisms Screening Center application may have any role on a different UDN Phase II application other than PD/PI (or co-PI on a multi-PI application). Funding multiple UDN Phase II awards at the same institution would require that potential conflicts and overlaps be resolved before awards are made.

The PD/PI (or co-PI on a multi-PI application) of any other UDN Phase II application may not be the PD/PI (or co-PI on a multi-PI application) of a Model Organisms Screening Center application. However, other individuals located at the same institution may be the PD/PI on a Model Organisms Screening Center application. Funding multiple UDN Phase II awards at the same institution would require that potential conflicts and overlaps be resolved before awards are made.

Letters of support should clearly document commitments (including but not limited to staff or monetary commitments) to meet the requirements of the FOA during the period of award. Institutional commitment and willingness to sustain the program beyond NIH Common Fund support should also be indicated, however, a specific monetary commitment level is not required. Additionally, the Sustainability Plan proposed in the Other Attachments section should include the investigators plan for sustainability as NIH Common Fund funding ramps down.

The NIH hopes to award the Model Organisms Screening Center application that can best assist the UDN in the diagnosis of UDN participants (i.e., the proband and family members) network-wide. We encourage innovative strategies (for example, involving resourceful combinations of model organisms, cell-based assays and/or bioinformatics tools and existing genomics resources) that can rapidly and efficiently assist the UDN in evaluating the clinical impact of participant gene variants. In addition, the most competitive applications will propose a screening pipeline and analysis plan that can accommodate the diversity of UDN participant mutations and clinical phenotypes likely to be encountered by the Network. To accomplish these ambitious goals, we hope to recruit an outstanding, highly qualified team of investigators who are poised to work in a high throughput and interactive/collaborative team environment with the UDN.

We expect that there will be ongoing and close communication/collaboration between the Model Organisms Screening Center and the UDN Clinical Sites, Metabolomics Core, Sequencing Core and Coordinating Center, in screening, selecting and prioritizing putative disease-causing gene variants (~200 per year) for analysis by the Model Organisms Screening Center. Although the Clinical Sites typically submit candidate variants on a rolling basis to the Model Organism Screening Center for initial screening, the UDN Steering Committee (comprised of the PDs/PIs from the above mentioned Centers, Cores and Clinical Sites along with the NIH Project Scientist) will provide oversight in the final selection and prioritization of variants for analysis by the Center, and will adjudicate the allocation of Center resources across Sites if needed.

It will depend, of course, on the number of candidate gene variants that are identified for a participant after whole genome/exome sequencing and initial bioinformatics investigation by the Sequencing Core and Clinical Sites. From past experience in diagnosing participants enrolled in the Network, we anticipate that some participants will have multiple variants submitted for analysis.

Yes, the UDN anticipates considerable communication and collaboration between the Model Organisms Screening Center and the Clinical Sites and Sequencing Cores in evaluating the putative pathogenicity of UDN gene variants. Clinical and sequencing data will be shared to the fullest extent possible without violating the privacy of UDN participants.

No. The Center will be responsible for developing and implementing an efficient, cost-effective and tailored screening pipeline and analysis plan for evaluating specific gene variants in the most relevant and informative model system(s) and assays. Although the Center may decide that a subset of gene variants warrant analysis in multiple model systems in order to assess the physiological consequence, this is neither a requirement of the FOA nor necessarily the best approach for analyzing all variants. The Center should strive to maximize the value and cost-effectiveness of available resources and funds. Therefore, a thoughtful and well-developed plan for screening and analyzing specific gene variants will be essential to the success of the project.

No. Although a central objective of the announcement includes creating a model organisms screening resource for the UDN, the FOA does not prescribe a specific analysis plan for the ~200 gene variants each year. We hope that the Center will devise the most successful, innovative and efficient strategies using available resources and funds to investigate the causality of gene variants in human disease. The primary screening platform could involve a combination of bioinformatics and utilization of publicly-available genomics databases and resources, leveraging information available through existing collaborations and/or wet-lab approaches (analysis in model organisms or cell-based assays). For example, innovative bioinformatics/computational tools or other available genomics information potentially could be used to identify promising candidates for phenotypic analysis in model organisms while triaging other variants judged unlikely to be disease-causing. The goal is to develop a screening pipeline and analysis plan that has the greatest potential to provide valuable and novel information to the UDN and assist the Clinical Centers in the diagnoses of UDN participants.

Yes. The Model Organisms Screening Center is intended to serve as a resource for the UDN with the capacity to analyze UDN gene variants in at least two small animal models. Both Drosophila and zebrafish models are required at a minimum because of their tractable genetics, phenotyping and throughput capabilities, as well as a successful track record of using these models in Phase I of the UDN. However, it is not expected that every variant submitted to the Center will require analysis in Drosophila or zebrafish (see FAQs # 12 and 13 above).

Yes. In addition to the required Drosophila and zebrafish Cores, up to three additional Resource Cores are allowed (a maximum of five Resource Cores) in a Model Organisms Screening Center application. The UDN recognizes that other model organisms (e.g., Xenopus, c. elegans, mouse, etc.) and cell-based models offer unique and distinct advantages for understanding gene function in human disease. Moreover, with the rapid development and validation of new genome editing strategies and phenotyping capabilities in the field, a number of organisms in addition to fly and zebrafish are viewed as attractive models for UDN gene function studies. For these reasons, the FOA does not exclude any model organisms in the announcement as long as the throughput and timeline requirements can be met, and invites investigators using a spectrum of models to form partnerships and submit proposals.

No. The Model Organisms Screening Center is tasked with conducting the initial screen and analysis of candidate UDN gene variants and is not expected to provide definitive functional or pathogenic characterization of all variants. Some variants may require additional and/or more comprehensive analysis beyond the scope of the Model Organisms Screening Center in order to understand their role in human disease. However, the Center may conduct more comprehensive characterization of a subset of the most promising variants in collaboration with the other UDN Sites/Cores and with the approval of the UDN Steering Committee. For example, additional funds may be available through the UDN Coordinating Center to support collaborations among UDN Sites/Cores/Centers for such gene function studies.

Yes, the slides from the Applicant Information Webinar are available at: https://commonfund.nih.gov/Diseases/grants/webinar.

Currently, the NIH does not have any formal plans for support of UDN resources after Common Fund support ends. How to transition the UDN to a sustainable national resource will be addressed at the sustainability workshop that is anticipated to take place in FY20.

The Sustainability Plan proposed should be relevant to maintaining the critical functions of the UDN component applied for. Ideas regarding sustainability for the network may be included, but are not required.

The single (or central IRB as referred to in Phase I of the UDN) IRB for Phase II of the UDN will be at the NIH. There will be no cost to the UDN sites to use this IRB.

Based on the allocated funds, we anticipate funding one Model Organisms Screening Center. However, we would consider funding more than one.

Yes. Information on the current protocol can be found in the UDN Manual of Operations at: https://undiagnosed.hms.harvard.edu/udn-manual-of-operations/.

The “Funds Available and Anticipated Number of Awards” is in total costs while the “Award Budget” is in direct costs. Your application budget should not exceed the “Award Budget” in direct costs.

The direct costs are excluding the consortium F&A costs requested by a subcontract following this Guide Notice: https://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-040.html .

The PD/PI on a Sequencing Core application may have any role on a different UDN Phase II application other than PD/PI (or co-PI on a multi-PI application). Funding multiple UDN Phase II awards at the same institution would require that potential conflicts and overlaps be resolved before awards are made.

The PD/PI (or co-PI on a multi-PI application) of any other UDN Phase II application may not be the PD/PI (or co-PI on a multi-PI application) of a Sequencing Core application. However, other individuals located at the same institution may be the PD/PI on a Sequencing Core application. Funding multiple UDN Phase II awards at the same institution would require that potential conflicts and overlaps be resolved before awards are made.

At least one PD/PI on a multi-PI application must be well-established in sequencing.

Letters of support should clearly document commitments (including but not limited to staff or monetary commitments) meet the requirements of the FOA during the period of award. Institutional commitment and willingness to sustain the program beyond NIH Common Fund support should also be indicated, however, a specific monetary commitment level is not required. Additionally, the Sustainability Plan proposed in the Other Attachments section should include the investigators’ plan for sustainability as NIH Common Fund funding ramps down.

The two-week turnaround time begins with the start of DNA sample preparation for sequencing including but not limited to library preparation, enrichment, capture, and cluster generation for exome sequencing, but excluding DNA extraction. The process is complete when raw (unassembled) sequence data has been returned to either the UDN Coordinating Center and/or a UDN Clinical Site.

Applicants for the UDN DNA Sequencing Core may offer to provide DNA extraction services to the UDN Clinical Sites as part of their proposal, but DNA extraction is not required.

Re-analysis starts with the original raw data and the entire analysis and interpretation pipeline is rerun. This is recommended with a significant pipeline change.

Re-interpretation is the review of variants in the context of new data in the literature, both new disease gene associations and changes in variant interpretation.

The budget for additional research sequencing approaches must fit within the direct costs of the application budget.

Yes, the slides from the Applicant Information Webinar are available at: https://commonfund.nih.gov/Diseases/grants/webinar.

Currently, the NIH does not have any formal plans for support of UDN resources after Common Fund support ends. How to transition the UDN to a sustainable national resource will be addressed at the sustainability workshop that is anticipated to take place in FY20.

The Sustainability Plan proposed should be relevant to maintaining the critical functions of the UDN component applied for. Ideas regarding sustainability for the network may be included, but are not required.

The single (or central IRB as referred to in Phase I of the UDN) IRB for Phase II of the UDN will be at the NIH. There will be no cost to the UDN sites to use this IRB.

Under “Eligible applicants” – For-profit organizations are eligible applicants. Commercial sequencing is allowed as long as the Sequencing Core, as a whole, can provide the final CLIA clinical variant report with Sanger validation. The applicant must provide a description of Sanger variant validation and the facilities and instrumentation to be utilized (see Research Strategy section, Genomic Sequence Plan).

Yes. Information on the current protocol can be found in the UDN Manual of Operations at: https://undiagnosed.hms.harvard.edu/udn-manual-of-operations/.

The “Funds Available and Anticipated Number of Awards” is in total costs while the “Award Budget” is in direct costs. Your application budget should not exceed the “Award Budget” in direct costs.

The direct costs are excluding the consortium F&A costs requested by a subcontract following this Guide Notice: https://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-040.html.

The PD/PI on a Sequencing Core application may have any role on a different UDN Phase II application other than PD/PI (or co-PI on a multi-PI application). Funding multiple UDN Phase II awards at the same institution would require that potential conflicts and overlaps be resolved before awards are made.

The PD/PI (or co-PI on a multi-PI application) of any other UDN Phase II application may not be the PD/PI (or co-PI on a multi-PI application) of a Metabolomics Core application. However, other individuals located at the same institution may be the PD/PI on a Metabolomics Core application. Funding multiple UDN Phase II awards at the same institution would require that potential conflicts and overlaps be resolved before awards are made.

At least one PD/PI on a multi-PI application must be well-established in metabolomics analysis.

Letters of support should clearly document commitments (including but not limited to staff or monetary commitments) to meet the requirements of the FOA during the period of award. Institutional commitment and willingness to sustain the program beyond NIH Common Fund support should also be indicated, however, a specific monetary commitment level is not required. Additionally, the Sustainability Plan proposed in the Other Attachments section should include the investigators’ plan for sustainability as NIH Common Fund funding ramps down.

Letters of support from all alternate sites with special expertise are not necessary, but may be included.

Yes, the UDN anticipates considerable communication and collaboration amongst the Metabolomics Core and the Model Organisms Screening Center, the Clinical Sites, and Sequencing Cores in evaluating UDN participants and the putative pathogenicity of any candidate gene variants. Clinical and sequencing data will be shared to the fullest extent possible.

A plan to meet the FOA expectations of throughput (analysis of approximately 75-125 clinical cases per year including cases referred to alternate sites with special expertise) should be accounted for in the budget. Meeting the FOA expectations should not require billing to the Clinical Sites or participants.

Yes, the slides from the Applicant Information Webinar are available at: https://commonfund.nih.gov/Diseases/grants/webinar.

Currently, the NIH does not have any formal plans for support of UDN resources after Common Fund support ends. How to transition the UDN to a sustainable national resource will be addressed at the sustainability workshop that is anticipated to take place in FY20.

The Sustainability Plan proposed should be relevant to maintaining the critical functions of the UDN component applied for. Ideas regarding sustainability for the network may be included, but are not required.

The single (or central IRB as referred to in Phase I of the UDN) IRB for Phase II of the UDN will be at the NIH. There will be no cost to the UDN sites to use this IRB.

Yes, there is an expectation that someone within the Metabolomics Core will have clinical expertise relevant to metabolomics and engage proactively in consultation with the UDN. However, there is no specific requirement detailing what this experience should entail.

Either, clinical expertise in the Metabolomics Core could be from an investigator associated with a UDN Clinical Site application, or from an investigator not currently associated with the UDN.

The Metabolomics Core should provide measurements from any two of the three types of metabolites listed in the FOA: glycans, lipids, and mitochondria. In addition, the Metabolomics Core is expected to provide access to resources and experts with knowledge in metabolomics beyond the scope of their own area of expertise, and provide metabolomics clinical expertise and consultation to the UDN Clinical Sites.