- How many Model Organisms Screening Centers will be awarded?
- What are the top NIH priorities for awarding a Center?
- How will the UDN assign gene variants to the Model Organisms Screening Center?
- The Model Organisms Screening Center is anticipated to evaluate approximately 200 gene variants each year. Will the 200 gene variants involve 200 different UDN patients or multiple variants from each patient?
- For candidate variants, will the Model Organisms Screening Center have access to clinical/ phenotypic information and the full sequencing data from the respective patients?
- Does each variant assigned to the Model Organisms Screening Center require screening and analysis using all model organisms available to the Center? For example, does the FOA require analysis in both Drosophila and zebrafish models?
- Do all assigned gene variants require analysis using wet-lab approaches (i.e., in a model organism or cell-based assay)?
- Drosophila and zebrafish are required models in the FOA. Are other model organisms considered less valuable for UDN gene function studies?
- Is the Model Organisms Screening Center expected to confirm or rule out definitely the pathogenicity of all gene variants assigned to the Center?
The NIH anticipates making one award.
The NIH hopes to award the Model Organisms Screening Center application that can best assist the UDN in the diagnosis of UDN patients 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 UDN patient gene variants. In addition, the most competitive applications will propose a screening pipeline and analysis plan that can accommodate the diversity of patient 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 interaction/collaboration between the Model Organisms Screening Center and the UDN Coordinating Center (RFA-RM-12-020), Clinical Sites (RFA-RM-13-004), and Sequencing Cores (RFA-RM-13-018) in evaluating, prioritizing and selecting putative disease-causing gene variants (~200 per year) for analysis by the Screening Center. Nominated gene variants will be submitted to the UDN Steering Committee (comprised of the PDs/PIs from the above mentioned Centers, Cores and Clinical Sites along with the NIH Project Scientist) for review and final approval. By the time the Model Organisms Screening Center is awarded (anticipated in summer 2015), there will likely be a ‘batch’ of variants identified by the UDN requiring analysis by the Screening Center. However, after the initial startup period, we expect that the UDN Steering Committee will develop protocols and a work plan for identifying new variants.
4. The Model Organisms Screening Center is anticipated to evaluate approximately 200 gene variants each year. Will the 200 gene variants involve 200 different UDN patients or multiple variants for each patient?
It will depend, of course, on the number of candidate gene variants that are identified for a patient after whole genome/exome sequencing and bioinformatics investigation by the Sequencing Cores (RFA-RM-13-018) and Network. From past experience in diagnosing patients in the program, we anticipate that some patients 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 patient privacy.
6. Does each variant assigned to the Model Organisms Screening Center require screening and analysis using all models available to the Center? For example, does the FOA require analysis in both Drosophila and zebrafish models?
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 evaluating and analyzing specific gene variants will be essential to the success of the project.
Not necessarily. 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 and innovative strategies using available resources and funds to investigate the causality of gene variants in human disease. For example, the primary screening platform could involve a combination of wet-lab approaches (analysis in model organisms or cell-based assays), bioinformatics and/or utilization of publicly-available genomics databases and resources, or leveraging information available through existing collaborations. 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 patients.
Absolutely not. The Models Organisms Screening Center is intended to serve as a resource for the UDN with a minimum capacity to analyze UDN gene variants in at least two small animal models. Drosophila and zebrafish were included in the required list of organisms based on their tractable genetics, phenotyping and throughput capabilities, as well as a successful track record of using these models in other screening efforts involving the Undiagnosed Diseases Program. However, the UDN recognizes that each model organism (e.g., Drosophila, zebrafish, Xenopus, c. elegans, mouse, etc.) offers 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, 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. 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. In addition, after preliminary analysis by the Model Organisms Screening Center, gene variants may be candidates for future in-depth functional studies (e.g., in mouse models) supported through the Undiagnosed Diseases Gene Function Research R21 Program (e.g., RFA-RM-14-005).