The open session of the National Advisory Council for Human Genome Research was convened for its thirty-eighth meeting at 8:36 a.m. on May 22, 2006 at the Fishers Lane Conference Center, Rockville, Md. Francis Collins, Director of the National Human Genome Research Institute, called the meeting to order.
The meeting was open to the public from 8:36 a.m. until 4:45 p.m. on May 22, 2006. In accordance with the provisions of Public Law 92-463, the meeting was closed to the public from 4:45 p.m. on May 22, 2006 until adjournment for the review, discussion, and evaluation of grant applications.
Jeff Botkin, ad hoc, by teleconference
Mildred Cho, ad hoc, by teleconference
Andrew Clark, ad hoc
Vanessa Gamble, ad hoc
Steve Prescott, ad hoc
Chris Austin, OD
Maggie Bartlett, OD
Saveri Bhattacharya, DER
Christianne Bird, DER
Vence Bonham, OD
Joy Boyer, DER
Lisa Brooks, DER
Comfort Browne, DER
Brian Campbell, DER
Cheryl Chick, DER
Monika Christman, DER
Francis Collins, OD
Chris Davis, OD
Carla Easter, OD
Elise Feingold, DER
Adam Felsenfeld, DER
Phyllis Frosst, OD
Barbara Fuller, OD
Peter Good, DER
Bettie Graham, DER
Alan Guttmacher, OD
Mark Guyer, DER
Sarah Harding, OD
Jean Jenkins, OD
Rebecca Kolberg, OD
Tim Leshan, OD
Laura Liefer, DER
Carson Loomis, DER
Teri Manolio, DER
Elliott Margulies, OD
Jean McEwen, DER
James McWilliams, DER
Jessica Melone, DER
Mark Moore, DER
Patrick Nailer, DER
Ken Nakamura, DER
Taiwo Oladapo, DER
Kenneth Ow, OD
Brad Ozenberger, DER
Betsy Parker, OD
Allison Peck, DER
Jane Peterson, DER
Eddie Rivera, OD
Jerry Roberts, DER
Laura Lyman Rodriguez, OD
Jeff Schloss, DER
Geoff Spencer, OD
Shundel Stephenson, DER
Gary Temple, DER
Larry Thompson, OD
Elizabeth Thomson, DER
Susan Vasquez, OD
Fred Walker, OD
Melinda Weiss, DER
Kris Wetterstrand, DER
Diane Williams-Bey, DER
Joann Boughman, American Society of Human Genetics
Linda Brady, NIMH
Carlos Caban, NIH OER
Teresa Doksum, ABT
Evan Eichler, University of Washington
Mike Gilbreath, SSS
Susanne Haga, Duke University
Rod Howell, University of Miami
Michelle Rodriguez, SRI
Sharon Terry, Genetic Alliance
Wendy Uhlmann, National Society of Genetic Counselors
Elias Zerhouni, Director, NIH
Dr. Guyer introduced new council member Andrew Clark.
Dr. Guyer introduced new NHGRI staff member Carla Easter, Scientific Educator, Office of the Director.
Dr. Guyer welcomed members of the liaisons from professional societies: Joann Boughman from the American Society of Human Genetics, Rod Howell from the University of Miami, Michelle Rodriguez from SRI, Sharon Terry from the Genetic Alliance, and Wendy Uhlmann from the National Society of Genetic Counselors.
Dr. Guyer also welcomed press representatives, Teresa Doksum from ABT, Mike Gilbreath from SSS, and other guests, Linda Brady from the National Institute of Mental Health, Susanne Haga from Duke University, and the guest speaker, Dr. Evan Eichler from the University of Washington.
The minutes from the February 2006 Council meeting were approved as submitted.
The following dates were proposed for future meetings: September 11-12, 2006, February 12-13, 2007, May 21-22, 2007, September 10-11, 2007, February 11-12, 2008, and May 19-20, 2008.
Dr. Collins introduced Dr. Elias Zerhouni, Director of the National Institutes of Health, to present on future budgetary and scientific opportunities for the NIH. Dr. Zerhouni thanked the 31,000 advisors, council members, liaisons and other members of the community for their service and roles in the success of the NIH.
There are several factors that affect the NIH budget, including the federal trade deficit, defense and homeland security spending, Hurricane Katrina relief efforts, pandemic flu preparation, an emphasis in Congress and the administration on increases for the physical sciences, being in the post-doubling period for the NIH budget, and the 3.5% inflation rate for biomedical research. Tied into these are some common misconceptions for what drives the success rates at the NIH, namely placing more emphasis on applied rather than basic research, a shifting of research objectives toward solicited research, and the NIH Roadmap effort.
NIH is required to report to Congress on the level of both basic and applied research being conducted across the institutes. By FY2007, the level of funds available for basic versus applied science will be higher than levels prior to the doubling of the budget. Dr. Zerhouni believes that it is important for the NIH to keep 56-57% of its budget devoted to basic research because private industry is focused on applied research. Advisory Councils make the decision to solicit grants is certain areas. NIH continues to invest a significant percentage of its budget in unsolicited research. In 1995, 91% of research was unsolicited, a number that grew to 93% by 2005. There was a small drop in 1999 as institutes saw they needed ways to start spending as the doubling started.
The NIH Roadmap was initiated as a way to fund emerging science that no single NIH Institute could support. In total, the NIH Roadmap accounted for $237 million dollars (0.8%) of the NIH budget in 2005. Funding will increase to 1% in 2006 and 1.2% in 2007. The Roadmap is an incubator - a venture space. It includes new ways to review grants, to develop shared resources. And it's not a single initiative. Over 345 awards were made in FY05: 40% basic discovery, 40% translational research, and 20% high risk research.
There are three fundamental drivers for the current budget situation. One includes the large capacity-building throughout U.S. research institutions and the correlated increase in the number of tenure-track faculty. The capacity building took longer than the doubling, ending well after the doubling was over. This has led to a significant growth in the number of applicants and applications occurring after 2003. By 2007, NIH will have doubled the number of applications it has received while grants become increasingly more expensive. During the five years of doubling of the NIH budget, there was an increase in the number of applications by 8,303. There have been as many new applicants in the last two years as during the previous five years.
Budget appropriations also play a role as new funding has been below biomedical research inflation levels since 2003. The only increases we received were as a result of a vision for some new initiatives.
The other factor is the budget cycling phenomenon. Available funding comes from money no longer committed to grants funded 4-5 years earlier and any increases in the budget. The NIH budget peaked in FY05, therefore money for 2006 grants draws from the 2001 and 2002 pool. As a result, NIH will see an improvement in the level of funding for grants in future years, even if no budget increases occur, because the available money from grants ending will be higher.
Dr. Zerhouni asked Council members to serve as an advocate to the public to express the need for sustainability in biomedical research. At a recent budget hearing, he said he made the case that biomedical research isn't a hundred yard dash, but a marathon. You don't give water to a marathon runner for the first 10 miles and tell him to go the rest of the way alone.
The current success rate per application understates the funding rate per applicant. The success rate for applicants has been higher than the success rate for applications in FY05 and FY06. In FY06, while 19.8% of applications were funded, 25% of applicants received funding. The chance of any one person receiving funding is 50% for an applicant through 3-4 application cycles.
For the NIH to continue to succeed it must clearly communicate the realities of conducting biomedical research, develop adaptive strategies to protect both knowledge and discovery, and increase the number of competing grants. The NIH must support new investigators, an effort that has continued through the New Pathway to Independence Program, which allows post-doctoral students to apply for five-year grants to complete the last two years of their post-doctoral training coupled with three years of R01 research funding dependent on tenure track attainment.
The NIH must also convey a unified message - that it's the best investment that the Federal Government has ever made - and about its positive impact at the local, regional and national level. With an aim of transforming medicine in the next twenty years, basic discovery will continue to provide the foundation for medical advancements and an emphasis on public health and preventive medicine must be fostered. Finally, patients must have a role in their care.
Some Council members felt there was a risk in communicating with the public and Congress about the practical benefits of NIH research as it may convey a sense that research on specific diseases is the primary focus and that basic research should be of secondary emphasis. There was also the question of communicating with the general public and finding ways to translate to members of Congress the education and knowledge necessary to describe the most important issues facing biomedical research. Since 85% of NIH funding is spent to support other institutions, NIH activities are misunderstood in Congress. The role of the NIH requires clarification as a discovery engine, not the deliverer of services. Dr. Zerhouni emphasized that this is the responsibility of all NIH stakeholders and encouraged them to invite their members of Congress to a local lab to let them interact with young scientists.
Dr. Zerhouni was presented with a copy of the special Nature compendium that contains papers describing the sequence of all human chromosomes.
The Association of American Physicians (AAP) elected Leslie G. Biesecker, M.D., a senior investigator in NHGRI's Genetic Disease Research Branch, and Maximilian Muenke, M.D., a senior investigator in NHGRI's Medical Genetic Branch, into distinguished membership during the April 30th annual meeting.
David Haussler, a Howard Hughes Medical Institute investigator, Joe Ecker, Professor at the Salk Institute and contributor to the ENCODE Project, and Titia De Lange of Rockefeller University, an NIH Director's Pioneer Awardee supported by NHGRI, were each elected to the National Academy of Sciences on April 25th, in recognition of their distinguished and continuing achievements in original research.
On April 26th, the Albany Medical Center Prize in Medicine and Biomedical Research was awarded to Dr. Seymour Benzer, a professor of Neuroscience, Emeritus (Active) at the California Institute of Technology.
On March 3rd, Dr. Elias Zerhouni, NIH Director, announced the appointment of Dr. Roger I. Glass, M.D., Ph.D., as the new director of the Fogarty International Center (FIC) and Associate Director of NIH for international programs. Dr. Glass will join the NIH in May, 2006.
Karen Kennedy, Science Program Manager for Molecules, Genes and Cells at the Wellcome Trust, has accepted a position at Genome Canada.
Several new NHGRI initiatives are underway. Two RFAs were released to solicit applications for research proposals to implement modENCODE, an ENCODE program for model organisms. The first called for research proposals to identify all of the sequence-based functional elements in the genomes of selected model organism genomes, specifically Caenorhabditis elegans and/or Drosophila melanogaster. The second solicited proposals to develop and implement a Data Coordination Center (DCC) for modENCODE. The DCC will be supported to develop, house, and maintain databases to track, store, and provide access to the data generated as part of the modENCODE Project. In addition, the DCC will import data from related projects that are relevant to the goals of the modENCODE Project. The receipt date for these RFAs is July 21st.
An RFA to solicit applications to conduct public consultation to inform the design of possible large-scale studies of genes and environment in common disease was released. Through this program, NHGRI would provide support for a specialized center to conduct a pilot public-consultation study to study how to obtain wide societal input to inform the design of a possible large U.S.-based longitudinal cohort study of the role of genes and environment in health and disease. The deadline for receipt of applications was May 10, and the applications will be reviewed at the September Council meeting.
A draft sequence of the rhesus macaque genome has been completed as a collaboration among the sequencing centers at the Baylor College of Medicine, Washington University and the Venter Institute. All three independently assembled the genome, and then the three assemblies were melded into one high-quality version.
NHGRI announced the new sequencing targets that were approved during February council. The projects include human structural variation, targeted BAC sequencing for primate "index species" and 2X coverage of the genomes of eight more mammals. Subsequent to the last Council session, NHGRI approved expanding the sequencing of the horse genome to full draft coverage.
Applications for the renewal of the NHGRI large-scale sequencing centers were received on April 11, 2006. The initial reviews will take place during the summer and Council review will take place in September.
Since the February Council meeting, the sequences of human chromosomes 3, 11, 12, 15, 17 have been published. With the additional publication of chromosome 1 just last week, papers describing the sequence of all human chromosomes have been published. On June 1, Nature will publish a compendium of all the human chromosome papers. Council members will each receive a copy.
An article in Nature by David Reich of Harvard Medical School reported a sequence comparison of the human, chimp, gorilla, macaque and orangutan sequences. Reich and his colleagues concluded that the evolutionary separation of humans from chimpanzees may have occurred much later than previously believed. Analysis of the X chromosome indicated closer sequence homology between chimps and humans than among the autosomes, indicating that species separation may have happened over many years and those ancestors may have interbred for thousands of years.
There were several NHGRI-coordinated meetings during the Cold Spring Harbor Biology of Genomes meeting in May. The Mouse Genome Sequencing Consortium met to discuss plans for the publication of the high-quality, finished mouse genome sequence. Another meeting was held to establish "The Human Genome Reference Consortium" to serve as a single, coordinated entity that will be responsible to the research community for the maintenance and correction of the human reference sequence; the Consortium includes the Sanger Institute, the Washington University Genome Sequencing Center, NCBI and EBI. Finally, the International Sequencing Consortium (ISC) held its fifth annual meeting, bringing together sequencing groups and funding agencies from around the world to continue their efforts to coordinate large-scale genomic sequencing projects.
As part of the Cancer Genome Atlas (TCGA) project, a partner initiative between NHGRI and the National Cancer Institute (NCI) to characterize genetic alterations in cancer comprehensively, NCI published an RFP in February calling for proposals to establish a Biospecimen Core Resource which would collect and quality control tumor samples, and prepare DNA and RNA for TCGA analysis; applications were received at the end of April. In March, the NCI published an RFA soliciting proposals for Cancer Genome Characterization Centers, which will be the TCGA component that will apply genomic analysis technologies to tumor genomes to identify potential candidate regions for sequencing; applications for the centers were received May 12th. As noted above, the applications for the NHGRI sequencing centers, which will participate in the TCGA, were received in mid-April. A Data Release Workshop to discuss the issues surrounding the release of sequence and phenotype data from the TCGA project was held in early May, immediately before the CSHL Biology of Genomes meeting. Attendees discussed informed consent, intellectual property and privacy issues, and made useful recommendations to the NHGRI and NCI.
The Genetic Association Information Network (GAIN), a public-private partnership for whole genome association (WGA) studies, is proceeding rapidly since its initiation last September. The Foundation for the NIH (FNIH) will take on the role of managing the program's steering and executive committees. Dr. Collins serves as chair for both committees. Following the project launch on February 8, policies and solicitation materials were finalized and posted online on March 9 and applications were received up until May 9. Once project priorities are set, a technical group will assess the applications that offer the greatest scientific opportunities and programmatic balance for the GAIN portfolio, and the GAIN Steering Committee will set priorities in a meeting in September. WGA genotyping data combined with phenotypic and environmental data are expected to be available from the first GAIN study by February, 2007.
The Genes and Environment Initiative, (GEI), if approved by Congress, will provide $26 million per year for four years to identify major genetic susceptibility factors for diseases of substantial public health impact, and $14 million per year during the same period to develop new technology for acquiring environmental exposure data. GEI is included in the President's FY07 budget request. The aim is to perform whole genome association studies of common diseases and put funds toward replication studies and functional analyses. An NIH-wide Coordinating Committee has been established to develop this program and is co-chaired by David Schwartz at the National Institute of Environmental Health Sciences (NIEHS) and Francis Collins. A strong expectation for data sharing will be a component of this effort. Council members stressed the importance of monitoring for the misuse of information if placed on the web. A concept approval for three aspects of WGA genotyping will be discussed at this Council meeting, and further plans for GEI will be presented to Council as they develop. Council members stressed the importance of monitoring for the possibility of misuse of information placed on the web.
In a related matter, Dr. Elizabeth Nabel, Director of the Heart, Lung, and Blood Institute (NHLBI) has been nominated as the chair of a staff committee to develop a trans-NIH policy related to data release from genome-wide association studies (GWAS).
The Mammalian Genome Collection (MGC) External Steering Committee met on April 18th and 19th. Funding for the MGC is in its final year and a final list of gene targets will be developed by the end of 2006. As of May 1, 2006, 13,547 human genes as cDNAs had been submitted to GenBank.
The second annual meeting of the Centers of Excellence in ELSI Research (CEERs) was held April 26-28. The meeting focused on ensuring the interdisciplinary strength of these centers and training the next generation of ELSI researchers. The centers also devoted a significant amount of time during the meeting to identifying ways that they can interact more effectively with each other and with the genomic community.
The Office of Portfolio Analysis and Strategic Initiatives (OPASI) has been established to identify potential new initiatives that no single institute could oversee alone and to provide a pathway for common funding, as a continuation of the Roadmap process. Five consultation meetings with leaders of the scientific community are being held this summer to identify potential trans-NIH projects, with an expectation that some projects will be funded in FY08.
Julie A. Segre, Ph.D., an investigator in NHGRI's Genetics and Molecular Branch, along with researchers from NHGRI, NICHD and NEI, published a paper in the May issue of The Journal of Clinical Investigation showing that excessive production of connexin 26 disrupts the protective properties of the skin barrier. The findings suggest that the barrier function of the skin may be as important as the immune system.
A multi-institution team of experts, coordinated by geneticists from the NHGRI, is supporting efforts to identify more than 70 bodies still unidentified in the aftermath of Hurricane Katrina. Led by Joan Bailey-Wilson, co-chief of the Inherited Disease Research Branch, and Les Biesecker, of the Genetic Disease Research Branch, the scientists have undertaken the unprecedented work of linking specimens with family members.
Scientists at NIMH and NHGRI have discovered that the response of depressed patients to an antidepressant depends, in part, on which version of a gene they inherit. Having two copies of one version of the serotonin 2A receptor gene was found to increase the odds of a favorable response to the serotonin selective reuptake inhibitor (SSRI) citalopram (Celexa) by up to 18 percent, compared to having two copies of the other, more common version. Since the less common version was over 6 times more prevalent in white than in black patients - and fewer blacks responded - the researchers suggest that the gene may help to explain a proportion of the racial differences in the outcome of antidepressant treatment. Co-authored by Alex Wilson of the Inherited Disease Research Branch, the study suggests potential ways to begin prospective pharmacogenomics trials to improve patient response to antidepressants.
As part of National DNA Day 2006, 53 Ambassadors from NHGRI, from both DIR and DER, visited 63 high schools, 70 percent of which were located in New England. 85 percent of these schools were outreach schools. There was also an online chat room staffed by 35 NHGRI investigators for a total of 10 hours. Over 2500 questions were asked during the online forum. 619 out of the 830 questions that were deemed answerable were addressed.
Washington, D.C. high school and undergraduate students participated in Genomic Careers Session at the Marian E. Koshland Science Museum DNA Day event. Dr. Collins, Dr. Vivian Ota Wang, and Dr. Bruce Fuchs spoke on topics in genetics and science education.
Teach the Teachers, a professional development session for 10 high school teachers, included tours of the primate house at the National Zoo in Washington, D.C. and the NIH Intramural Sequencing Center (NISC). The tour of NISC was used to linked information gathered from the National Zoo to laboratory activities. Additionally, it was a useful teaching exercise for DIR post-doctoral students to describe their work.
U.S. Surgeon General Richard H. Carmona, M.D., M.P.H., announced the availability of an updated version of a free, computerized tool in Spanish, designed to help Spanish-speaking families gather their health information. In addition, he praised the National Council of La Raza's Institute for Hispanic Health (NCLR/IHH) for developing its own family history consumer outreach program for Spanish-speaking Americans based on the framework made available by the Surgeon General's Family History Initiative.
Last year, the NIH received its first budget cut since 1970. The president's budget for FY2007 included the same level of funding for NIH as is in the FY2006 appropriation but, due to shifts in NIH priorities, NHGRI's FY2007 level (before Roadmap) would decrease by another 0.6%, for a total of $482.9 million. The House Appropriations hearing on the FY07 NIH budget was April 6 and the Senate Appropriations hearing was held on May 19. A short list of institute directors attended, including Dr. Collins who attended both sessions. In the Senate, an amendment to the budget, sponsored by Senators Arlen Specter and Tom Harkin, that would provide an additional $7 billion for biomedical research, education, and labor, passed the Senate easily, but has an uncertain future.
Sharon Terry led the Coalition for Genetic Fairness' attempt to garner more cosponsors for the Genetic Nondiscrimination Information Act, H.R. 1227. There is very little time left this year to get this done, but supporters are hopeful it will pass in the House. If the House bill were similar enough to the Senate bill, it would go to the President, who has expressed a willingness to sign it. Action must be taken in the next 6-8 weeks or it may not make it to the President's desk in 2006.
The Secretary's Advisory Committee on Genetics, Health and Society (SACGHS) met for its Spring meeting on March 27-28. The committee is drafting a report on large population studies and the policy issues involved, and hopes to complete it later this year. The report will address the opportunities such a study would present and the need to think through the policy implications of such a national effort.
Dr. Evan Eichler, Associate Professor of Genome Sciences at the University of Washington, presented on the impact and approaches to characterizing human structural variation. "Structural variation" refers to differences between individuals in genomic sequence that are larger than a single base pair. The connection between structural variation and disease has been recognized for many years. Structural variation should be considered as one of multiple influences on human genetic disease and disease susceptibility. Work by Jim Lupski at the Baylor College of Medicine has indicated that structural variation is the source of recurrent microdeletions and duplications within the population, types of variation that are not detected by linkage disequilibrium or association mapping techniques. As a result, there is a lot of interest in identifying the role structural variation plays in disease susceptibility.
Several approaches for characterizing structural variation have been developed in the last two years. One is an array-based comparative genomic hybridization method using oligonucleotides, BACs or cDNAs to hybridize samples so as to visualize losses or gains of signal intensity. This method is cost effective although it has a resolution of >50 kb and offers no information on genome structure. At this size, any given haplotype differs on the order of 70-100 copy number variations and the array-based method misses a significant fraction of the human genomic sequence. Oligo-microarray technology can also be used although multiple oligos are needed before it is possible to get any confidence of structural variation due to their highly variant nature. Such a method is flexible and fast - thousands of reactions can be run in only two weeks - although very expensive.
Another approach is to obtain paired-end sequences of fosmid ends (approximately 12X physical coverage), and align them against the human genome. This method can detect all types of structural variation with a resolution of between about 6kb and 40 kb, though it is expensive and has limited power in regions of perfect sequence identity. Finally, it is also possible to detect deletion polymorphisms from HapMap SNP data. This approach allows for detection of structural variations as small as 500 base pairs and provides precision by mining existing SNP data. The drawback is that it only detects deletions and not inversions and other structural variants.
Each of these complementary approaches can be used to find both small and large variants. An initiative coordinated by NHGRI has begun to help fully characterize human structural variation in 48 HapMap samples. The aim will be to capture 95 percent of common variants with greater than 5 percent frequency in the population. It should be possible to identify ~1000 structural variants in this project. Future objectives for studies of structural variation will include developing a comprehensive map of common structural variation integrating the three existing discovery approaches, developing a sequence-based survey of normal variation that will provide a gold standard to benchmark future technologies, and developing a rapid and cost-effective genotyping technologies to systematically screen disease patients once a pattern of normal variation is understood. An ultimate challenge will be to focus on complex regions of the genome that cannot be interrogated using existing technologies.
Council members commented on the need to develop genotyping assays to detect structural variation and whether to wait until technology improves and costs decrease before pushing forward on a large scale.
Three RFAs will be issued for the continuation of the ENCODE Project, an initiative to define sequence-based functional elements in the genome. Launched in September 2003, the ENCODE Project includes over 30 projects for pilot production or technology development efforts that are funded by both NHGRI and outside sources. A January 2006 meeting with the ENCODE Scientific Advisory Panel was held to evaluate the projects and determine ways to scale the Project to the entire genome. The advisors were pleased with the progress of ENCODE, and thought that that 1-2 of the approaches being pursued were ready to scale up at this time. At the same time, the advisers also thought that, overall, ENCODE is not ready to ramp up. Accordingly, they recommended that the pilot projects should be extended for one more year to give the investigators some more time to prepare for the next, whole genome, phase. Since the January meeting, the ENCODE Consortium has submitted a set of five major papers to a leading international journal, and it is expected that dozens more will be submitted for publication (elsewhere) in the upcoming months.
The first of the ENCODE RFAs calls for research projects that would expand the ENCODE Project in two ways. Applicants could propose initiate a scaling up of the ENCODE Project to the entire genome and offer a more in-depth study of the ENCODE target regions, which comprise 1% of the genome. A consortium meeting is scheduled for July at which time it will be discussed how best to define completeness for the Project in practical terms. This RFA would be funded using the cooperative agreement mechanism. $23 million has been set aside for the first year.
The second RFA would establish a data coordination center (DCC) in support of the ENCODE Project. The DCC would store, display, and track data. It is anticipated that the DCC will use the U41 research resource mechanism. $1.5 million has been set aside to fund the DCC.
The third RFA will be to fund additional technology development efforts. Advisors thought it would be useful to develop methods for the validation of technologies being used by ENOCDE as the Project moves to scale up. $2 million has been set aside for three years of RO1 grants and two years of R21 grants.
Council approved the concept clearance unanimously.
Dr. Teri Manolio provided an update on the Genes and Environment Initiative (GEI) for concept approval. GEI has been proposed on the president's FY07 budget at a cost of $44 million dollars for four years. Genotyping and project selection may follow a CIDR-like model while data would be stored through the GAIN database that is being developed by the National Center for Biotechnology Information (NCBI). It is anticipated the database will consist of several data components, including whole-genome association genotyping, data analysis, replication and fine mapping, sequencing, functional studies, clinical translation, and bioinformatics/database management. Working groups will be assigned to develop each of these areas. The whole-genome association component will be the largest of these components and efforts are being made to assure funding in FY08. Genotyping facilities, application coordination policies and coordinating centers will be in place by June 2007.
RFPs are proposed to solicit for genotyping facilities and a coordinating center. RFAs and cooperative agreements will be used for investigators submitting samples and data. Genotyping facilities will receive DNA and assess quality, perform whole-genome SNP genotyping of samples, assess quality of genotyping data and transfer data to the DCC while working to resolve any issues with data. The coordinating center will have to manage genotype data, ensure comparability among genotyping facilities, manage phenotypic and environmental data, conduct basic analysis for individual or program-wide studies and resolve any issues with the data. It will be important for the CC to include staff who have expertise in working with phenotypic data. It is anticipated that separate support will be needed to pursue replication studies. The criteria for selecting studies will also emphasize the availability of evidence for an environmental component, the anticipated size of an environmental component, and the power to detect it. 75% of funding will be provided in the first two years for genotyping and analysis. GEI aims to target 15 studies of 2,000 subjects but the current budget will only cover approximately 12 studies. Total commitment will be approximately $48 million from FY07 - FY10, comprising approximately 46% of the total GEI genetics budget.
Council members commented on the potential for cost savings through improvements in technology and the importance of emphasizing that cost reductions are part of the project plan. Phenotypic information would not be gathered through these solicitations although it is hoped the overall project would include gathering phenotypic data. Council approved the concept clearance.
Dr. Elizabeth Thomson discussed a concept clearance for an RFA for a limited competition proposal for the Centers of Excellence in ELSI Research (CEER). NGHRI released an RFA for the CEER program in 2004 with the goal of developing trans-disciplinary teams with both the expertise and flexibility to respond to the emerging ELSI issues with sequencing information and technology. The total ELSI budget is $18.5 million with $5 million set aside for the CEER program. Of the two dozen applications received, four were awarded as P50 grants (Case Western Reserve University, Duke University, Stanford University, and Washington University in St. Louis) and three funded under P20 grants (Harvard University, Howard University, and the University of North Carolina at Chapel Hill). The P50 awards were for five years and are currently in their second year. Two of the P20 grants were awards for 3 years and the other for 2 years. In order to limit competition and ensure controlled growth of the program, NHGRI staff has recommended to only allow the three P20 grants to apply for P50 grants at this time. The expectation is to re-release the CEER RFA in two years when the P50s are up for renewal.
Council disagreed with the concept proposal and recommended that competition be open to all applicants. Council's motion to modify the concept clearance to open the RFA to competition was approved.
Staff members in both DER and OD have been engaged in the development of a number of new policies that address issues of the availability of data from whole-genome genotyping and medical sequencing projects. The intent is to find ways to meet the twin objectives of realizing NHGRI's commitment to rapid and open data release from community resource projects (the so-called Fort Lauderdale Principles) and protecting research participants from any risks that might result from the release of identifiable information. There are several projects within NHGRI and at NIH that are attempting to deal with similar questions (including GAIN, GEI, GWAS, TCGA, and medical sequencing) and it will be important for the policies for these programs to be harmonized as much as possible.
Providing completely open access to individual genotype and/or sequence data, much less such data linked to phenotypic data, is problematic, at least at this time, for several reasons. Most of the projects are going to start by analyzing samples from existing research programs, and it is unlikely that the informed consent that those projects had obtained adequately addresses the possibility of release of the information to public databases. Even for prospectively collected samples, for which this question could be addressed in designing the informed consent documents, it is not clear what the types and degrees of risks are for individuals, family members, groups and society-at-large from unrestricted access to individual data.
Given these uncertainties, NHGRI is exploring an approach that would make individual genotype and medical sequencing data available through a two-tier system. The system would involve two databases. An open-access database, with data freely available, would contain information, from properly consented studies, that could not be used to identify an individual (e.g., individual sequence traces that could not be linked to one another, summary data, protocols). A controlled-access database would contain data that could be used to associate the genotype/sequence data with phenotypic data on an individual (coded) basis (e.g., from multiple genes, haplotype, and phenotypic data), although the data would be de-identified (all traditionally used, personally identifying information would have been stripped before deposition). Access to the controlled database would be provided to all investigators for scientific research by means of an NHGRI Data Access Committee that would manage a well-defined data access process.
A number of issues, such as whether IRB approval would be needed for any project that wanted to get controlled-access data, remain to be resolved. (Those who collect the specimens in the first place would certainly have to obtain IRB approval.) It would likely fall to the individual IRBs to determine whether projects requesting controlled-access data constitute human subject research. Another subject still be discussed is the utility of an independent oversight board that would monitor how users actually use the data obtained from the controlled-access database (e.g., whether they adhere to the terms of the consents and the Data Use Agreement, whether publications emerge from the research, and whether there are any adverse events attributable to misuse of the data). Staff must also consider the possibility of non-medical research use of the data.
Council questioned the usefulness of using an open database if there is going to be a controlled one. Dr. Guyer explained that this should be considered a pilot project for data access that can and should be reevaluated after a year.
A concept clearance for an RFA to solicit research in areas of research ethics, clinical translation, and justice and social policies related to large-scale sequencing efforts was presented to Council. Funding would be available to conduct research in this area in order to provide the basis for the development of any needed ELSI policies in these studies.
Council felt strongly that this research is needed. Some Council members asked if the CEERs could be given immediate supplements to start such work. Although similar work could occur through the CEER program, it was concluded that it is important to offer other segments of the research community an opportunity to participate. Council approved the concept clearance.
Dr. Carson Loomis spoke on the Molecular Libraries Screening Center Network (MLSCN). The MLSCN currently comprises ten pilot screening centers and a Small Molecule Repository (SMR) that is acquiring a unique compound library. The SMR currently contains 67,000 compounds, with the aim of achieving 100,000 compounds by the end of 2006; extensive quality control measures have been put in place for the compounds in the library.
There are two major approaches being taken to recruit assays into the Network for screening. One is a new mechanism, the X01, through which investigators can request access to screening services for assays that are ready to go for high-throughput screening (HTS). 135 X01 requests have been received for assay recruitment, 77 of which have been accepted into the network. The Molecular Libraries Roadmap Initiative also includes a small grant (R03, R21) program to support the development of new assays. For 2006, 167 applications for one-year assay development projects were received. It is expected that 33-35 awards will be granted, totaling $6 million.
All screening data generated by the ML Screening Centers are submitted to the PubChem database, from which they are available to the entire community. To date, nine assays have been confirmed through the MLSCN and entered into PubChem.
Council thought it would be important to determine how many of the assays are from other institutions and private companies.
Dr. Chris Austin, Senior Advisor for Translational Research at NHGRI, presented an update on the NIH Chemical Genomics Center (NCGC), one of the Molecular Libraries Screening Centers. The mission of the NCGC is to develop small compounds as molecular probes to determine both gene pathways and cell function. The NCGC utilizes assays that are obtained through the MLSCN peer review process, although its capacity is now large enough that it can accommodate additional assays also. Once screened and quality assured, assay data are sent to PubChem. NCGC's screening approach is relatively unique, utilizing quantitative high-throughput screening (qHTS) to test all compounds in titration curves at the level of the primary screen. The advantage of qHTS over other HTS methods is that it identifies compounds that are initially missed by other techniques.
The NCGC is currently screening 60 assays, the majority of which are supplied from NIH intramural projects. 30% of the NCGC's effort is spent on technology development, through extensive collaborations.
Council members asked for an update on the disagreement between NIH and the American Chemical Society (ACS) over the establishment of PubChem. Dr. Austin was pleased to report that the situation has essentially been resolved. The ACS initially objected that PubChem, a free and open database for small molecules, threatened ACS's subscription database. An advisory group was established for PubChem, reporting to the NCBI Board of Councilors (BSC). At the BSC's December meeting, ACS representatives were present. There has been no further conflict on the issue since the meeting.
Dr. Alan Guttmacher, Deputy Director of NHGRI, described a trans-NIH program, jointly led by NHLBI and NHGRI to apply genomic approaches to understanding sickle cell disease and to develop new approaches to treatment.
The program was initiated after a planning meeting in December 2003. Although a great deal of money has been devoted to sickle cell research over the past few decades, not a lot of progress has actually been made in terms of find a cure for the disease. The planning meeting was organized to address the possibility of applying genomics as a new approach that could allow multiple areas of exploration. As a result of the meeting, a trans-NIH planning group was formed and developed nine different research programs, which included a Sickle Cell Disease Clinical Research Network, ELSI research, and a novel idea grants for high-risk funding. Other aspects of the effort include a program to train new investigators in genomic and proteomic approaches to hemoglobinopathies, a program to investigate chemical genomics approaches for drug development, refinement of hemoglobin gene transfer vectors, and research into modifier genes in sickle cell disease.
A second planning conference is tentatively scheduled for 2008. Council suggested that this conference should be opened up to biotechnology companies and other outside expertise.
Dr. Guyer read the Council Memorandum of Understanding (MOU), which must be reviewed and renewed once a year. The MOU describes council operations, the kinds of issues to be taken to the Council, and how the Council functions to approve grant applications. It also includes an agreement between the Council and NHGRI staff that delegates some administrative authority to make budgetary decisions to staff.
Council approved the MOU for another year.
September 2006 Council will include a review of the large-scale sequencing center applications. Council members will be asked to come on Sunday evening. NHGRI will contact Council members regarding the Sunday night session (Sunday, September 10, 2006). NHGRI staff is also considering whether NHGRI's 2003 Vision Statement remains comprehensive and complete for guiding the future of genomics research.
Council members expressed interest in hearing a discussion of epigenetics and NHGRI's involvement in the area. One proposal would be to invite Andy Feinberg of Johns Hopkins to speak to Council.
Other Council members asked if there are tiling path clone sets available from all of the genomes being sequenced. There is some interest on this topic from the biotechnology sector although paying for the tiling path is a concern of industry. NHGRI staff will investigate this topic.
Dr. Guyer noted two items of interest in the Council folders, including a report from the National Society of Genetic Counselors on its activities and a report on a workshop held to discuss long-term maintenance of genome sequence assemblies. The workshop discussed the importance of strict data deposition standards at the trace repository level as well as strict data quality standards.
Dr. Guyer read the Conflict of Interest policy to Council and asked the members to sign the forms provided.
In closed session, the Council reviewed 123 applications, requesting $100,183,522. The applications included 50 regular research grants, 9 pilot projects, 22 ELSI grants, 17 RFA grants, 8 center grants, 6 conference grants, 11 SBIR Phase I grants, 4 SBIR Phase II grants, 3 fellowship grants, 2 STTR Phase I grants and 1 other. A total of 88 applications totaling $82,119,153 were recommended.
Last Reviewed: May 22, 2012