The National Advisory Council for Human Genome Research (NACHGR) was convened for its sixteenth meeting at 8:30 a.m. on February 5, 1996, at the Embassy Suites Chevy Chase Pavilion, Washington, D.C. Dr. Francis Collins, Director of the National Center for Human Genome Research, called the meeting to order.
The meeting was open to the public from 8:30 a.m. to 3:00 p.m. on February 5. In accordance with the provisions of Public Law 92-463, the meeting was closed to the public from 3:00 p.m. on February 5 to adjournment on February 6 for the review, discussion and evaluation of grant applications.
Dr. Anita Allen
Dr. David Botstein
Dr. R. Daniel Camerini-Otero
Dr. Neal Castagnoli*
Dr. Ellen Wright Clayton
Dr. Troy Duster
Dr. David Housman
Dr. Rodney Rothstein
Dr. Diane Smith
Dr. Lloyd Smith
Dr. M. Anne Spence
Dr. Shirley Tilghman
Dr. David Valle
Dr. Lennette Benjamin
Dr. Leroy Hood
*Ad Hoc Member
Dr. Beverly Emanuel, American Society of Human Genetics
Ms. Rosalie Goldberg, National Society of Genetic Counselors
Dr. Kurt Hirschhorn, American College of Medical Genetics
Jane Ades, Committee Management Officer
Carol Almeida, Budget Analyst
Midge Bajefsky, Program Assistant
Dr. David Benton, Assistant to the Director for Scientific Data Management
Joy Boyer, Program Analyst
Erin Burgess, Budget Officer
Jean Cahill, Grants Management Officer
Cheral Canna, LGDR
Dr. Francis Collins, Director
Dr. Carol Dahl, Program Director, Sequencing Technology Branch
Linda Engel, Chief, Office of Scientific Review
Dr. Elise Feingold, Program Director, Mapping Technology Branch
Leslie Fink, Chief, Office of Communications
Dr. Tom Fogle, Visiting Scientist
Dr. Bettie Graham, Chief, Mapping Technology Branch
Dr. Mark Guyer, Assistant Director for Program Coordination
Dr. Kathy Hudson, Assistant Director for Policy Coordination
Dr. Elke Jordan, Deputy Director
Robert Kuska, Writer-Editor
Carol Martin, Computer Specialist
Jean McKay, Program Policy Analyst
Tara Mowery, Grants Technical Assistant
Dr. Kenji Nakamura, Scientific Review Administrator
Diane Patterson, Grants Management Specialist
Jane Paull, Grants Technical Assistant
Dr. Jane Peterson, Chief, Mammalian Genomics Branch
Dr. Rudy Pozzatti, Health Scientist Administrator
Michael Royal, Budget Analyst
Dr. Jeffery Schloss, Program Director, Mammalian Genomics Branch
Ommie Smith, Program Assistant
Dr. Robert Strausberg, Chief, Sequencing Technology Branch
Mathew Thomas, OD/DIR
Elizabeth Thomson, Acting Chief, Ethical, Legal, and Social Implications Branch
James Vennetti, Executive Officer
Dr. J. J. Anderson, NIGMS
Bill Applegate, American Society of Clinical of Pathologists
Dr. Wendy Baldwin, OD/NIH
Robert Boyd, Knight-Ridder
Dr. Mary Clutter, National Science Foundation
Dr. Cheryl Corsaro, DRG
Lyle Dennis, CR Associates
Dr. Dan Drell, Department of Energy
Dr. Steven Fodor, Affymetrix
Dr. Raymond Gesteland, University of Utah
Phillip Harriman, National Science Foundation
Betty Mansfield, Human Genome News
Cheryl Marks, NCI
Paul Moore, Capitol Publications
Mary Moy, SRI International
Dr. Ari Patrinos, Department of Energy
Sara Radcliffe, SmithKline Beecham
Michele Robinson, BioWorld Today
Dr. Gerald Rubin, University of California at Berkeley
Dr. Jay Snoddy, Department of Energy
Joan Weiss, Alliance of Genetic Support Groups
Susan Wallace, HUGO
Lisa White, The Blue Sheet
Dr. Jordan introduced Dr. Neal Castagnoli, an ad hoc member of the Council, Dr. Gerald Rubin, who would make the scientific presentation to Council, and the liaisons to the Council from the professional societies: Dr. Kurt Hirschhorn, representing the American College of Medical Genetics; Dr. Beverly Emanuel, representing the American Society of Human Genetics; and, Rosalie Goldberg, representing the National Society of Genetic Counselors. Dr. Jordan noted that Dr. Ari Patrinos, from the Department of Energy (DOE), would address the Council briefly during this session. Dr. Raymond Gesteland and Dr. Stephen Fodor were also present to serve as a resource to the Council regarding the grant applications considered by each of the review committees they chaired. Dr. Gesteland was the chair of the committee that reviewed applications in response to the RFA for "Pilot Projects for Sequencing the Human Genome." Dr. Fodor was the chair of the committee that reviewed applications in response to the RFA for "Improved Electrophoretic DNA Sequencing Technology."
Dr. Jordan introduced Dr. Rudy Pozzatti, a new Health Scientist Administrator in the Office of Scientific Review, and Ms. Joy Boyer, who is on a one year detail to the NCHGR from the NIH Office of Science Education Policy. Dr. Jordan informed the Council that two members of the staff were no longer with the NCHGR: Ms. Anne Rufo, formerly NCHGR Legislative Officer, is now a legislative analyst in the NIH Office of Legislation Policy and Analysis; and Ms. Helen Simon, formerly the NCHGR Planning Officer, is the chief of the planning and evaluation office of the National Institute of Arthritis and Musculoskeletal and Skin Disorders.
The minutes from the September 11-12, 1995 NACHGR meeting were approved as submitted.
May 20-21, 1996, September 16-17, 1996, and January 27-28, 1997 were approved for future NACHGR meetings. Drs. Camerini-Otero and Rothstein will not be able to attend the May 20-21 meeting.
Dr. Collins announced, with deep regret, the deaths of two prominent genome scientists: Nat Sternberg, a pioneer in developing the P1 vector system for cloning large pieces of DNA; and John Wasmuth, director of the University of California-Irvine Genome Science and Technology Center. Dr. Wasmuth was instrumental in the discovery of the genes for achondroplasia. The NCHGR will seek the Council's advice on how to commemorate individuals, such as Drs. Sternberg and Wasmuth, who have made significant contributions to genome science.
In addition to the November 15 celebration, the NCHGR, under the guidance of Dr. Elke Jordan, organized a symposium entitled, "Visions of Sequence-Based Biology and Medicine." The purpose of the symposium was to identify scientific opportunities that would flow from the availability of DNA sequencing information together with efficient technology for generating and manipulating this information. The symposium speakers were asked to give their vision of how the genome project will change the science in their field of expertise. Dr. Eric Lander, who was the final speaker and gave a summation of the symposium, plans to put his remarks in writing for a larger audience. The symposium was well-attended, and Dr. Collins noted that Dr. Varmus not only gave the opening remarks, but was present for a large part of the meeting. The symposium represents the beginning of a multi-year process to determine what steps the NIH will take to ensure that the tools and resources stemming from the Human Genome Project are utilized most effectively and that mechanisms are in place to facilitate these activities. Anyone interested in obtaining a videotape of the symposium should contact the NCHGR Office of Communications, at (301) 402-0911.
Dr. Collins noted the effort and support of Congressman Porter for the bipartisan compromise that permitted the NIH to be funded through the end of FY96. However, the precise allocation of NIH funds to the Institutes, Centers, and Divisions had not yet been determined. Dr. Botstein observed that the turmoil over the budget is likely to be repeated over the next seven years, and that input from and the support of the scientific community is very important in ensuring that adequate levels of funding for scientific research are made available.
On September 29, 1995, the Senate Cancer Coalition, chaired by Senators Connie Mack and Dianne Feinstein, held a hearing on cancer genetic testing. Witnesses included Dr. Richard Klausner, NCI Director, Mr. Brad Margus, president of the A-T Children's Project, Ms. Fran Visco, president of the National Breast Cancer Coalition, Dr. Caryn Lerman, Georgetown University, Mr. Elliot Hillback, president and CEO of Integrated Genetics Laboratories, Mr. Harvie Raymond, vice president of the Health Insurance Association of America, and Dr. Collins. At this hearing, Dr. Collins discussed the recommendations developed by the ELSI Working Group and the National Action Plan on Breast Cancer (NAPBC) on the use of genetic information and health insurance. Dr. Collins applauded the efforts of these two groups, noting the effective combination of policy deliberations and a vigorous consumer effort.
Dr. Collins described several bills that are pending in Congress to address health insurance, privacy, and genetic information. Senator Hatfield introduced a bill that prohibits the use of genetic information in decisions about insurance and employment, and includes broad privacy protections for genetic information. A companion bill was introduced in the House by Congressman Stearns. Congresswoman Slaughter has introduced a bill that is modeled after the ELSI Working Group/NAPBC recommendations, and Senator Feinstein is considering introducing similar legislation. Senator Bennett has introduced a bill to protect the confidentiality of medical records that provides protection for information related to the past, present, or future physical and mental health of individuals. The NCHGR has been asked to provide comments on this bill, which is similar to one that was introduced last year by Congressman Condit.
Senators Kassebaum and Kennedy continue to pursue consideration of their health insurance reform bill in the Senate. This bill would prohibit health insurers from using, among other factors, medical history or health status to limit or deny health insurance coverage. During Committee consideration of this bill, Senator Harkin introduced an amendment to include genetic information on the list of factors that health insurers could not use to limit or deny coverage. This amendment did not pass; however, the Committee members agreed that genetic information is implicit in health status and medical history. While many states have begun to address discrimination in health insurance, Dr. Collins noted that many people obtain their health insurance through self-insured, employer-based plans, which are not subject to state insurance regulations.
A paper that outlines the key issues and presents a series of recommendations resulting from the July 1994 workshop was published in the December 13, 1995 issue of the Journal of the American Medical Association, entitled "Informed Consent for Genetic Research on Stored Tissue Samples." Ellen Wright Clayton was the lead author. The authors concluded that individuals should give informed consent before their identifiable stored tissues are used in genetics research.
Several pathology organizations have expressed their concerns about the impact that the above recommendations may have on their work. Therefore, on January 19, the NCHGR and the Association of American Medical Colleges (AAMC) co-sponsored a meeting entitled, "Genetics Research on Human Tissues: Conflicting Implications for Scientific Discovery, Informed Consent, and Privacy." The purpose of the meeting was to explore ways to continue promising genetic research while appropriately addressing informed consent and privacy concerns. The participants viewed this meeting as an important first step in an ongoing dialog about this important issue. Pathology organizations and the American Society of Human Genetics are developing their formal positions on this issue; the American College of Medical Genetics has published their position.
To obtain more information about the prevalence of the BRCA1 185delAG mutation in the Jewish population, the NCI and the NCHGR have initiated a "snapshot" study of members of the Ashkenazi Jewish population in Washington, D.C. area. Samples will be collected and analyzed for the frameshift mutation, but results will not be reported back to the participants. There has been a logistical delay in initiating the study, due to the OMB clearance process for questionnaires. The NCHGR plans to supplement the Cancer Genetics Study Consortium grants to allow for the expansion of their protocols for those individuals who wish to know the results of their test. Key questions still remain about the prevalence, penetrance, and outcome of various treatment options for those with BRCA1 mutations. Therefore, Dr. Collins and Dr. Klausner have discussed formation of a national research consortium for presymptomatic testing. The NCI is planning to convene a study group to determine the feasibility of such a consortium.
Dr. Hirschorn, representing the American College of Medical Genetics (ACMG), noted that the ACMG newsletter has published statements discouraging testing until the issues of how to handle anonymous testing and informed consent have been addressed. Dr. Collins expressed an interest in obtaining these statements, and noted that the National Action Plan on Breast Cancer (NAPBC) is considering a similar statement. However, OncorMed and Myriad have mailed information to physicians offering testing for BRCA1 mutations. Dr. Clayton noted that the American Society of Clinical Oncologists (ASCO) believes that oncologists may appropariately offer BRCA1 testing with extensive counseling in the clinical setting. Dr. Collins replied that ASCO is still considering whether or not to support testing outside of a research protocol. Others, including the State of New York and the ELSI Working Group Task Force on Genetic Testing, are considering the issues surrounding genetic testing, as well.
Dr. Collins described results from the landmark gene therapy trial conducted by Dr. Michael Blaese (Chief, Clinical Gene Therapy Branch, DIR, NCHGR) and colleagues, to treat patients with ADA deficiency. The trial began in 1990, and an update of the results was published in Science (October 20, 1995). The follow-up data showed that increased levels of T cells and active ADA enzyme can be sustained long after gene therapy has ceased. The authors reported that the vector is still present, and that the patients have improved immune function and have responded to a wide array of antigens.
Dr. Rubin, the Director of the Drosophila Genome Center at the University of California at Berkeley, described the activities of the Center. The goals of the Center are to: generate a map of Drosophila melanogaster genome by STS-content mapping of a P1 library to serve as templates for DNA sequencing; integrate sites of high biological interest into the physical map, including known genes, cDNAs, and lethal P-element insertion sites; and sequence the 120-Mb euchromatic portion of the Drosophila genome. Dr. Rubin described the role of model organisms in the determination of human gene function, noting that the genomic complexity observed in Drosophila is close to that of humans. In conclusion, Dr. Rubin made three recommendations: traditional and creative approaches to determine gene function in targeted model organisms be funded; additional model organisms should be low priority unless they offer unique opportunities to determine gene function; and the mouse genome should be sequenced.
Dr. Troy Duster, vice chair of the ELSI Working Group, reported to the Council on the recent activities of the ELSI Working Group. In an effort to learn more about what occurs at specific genome centers and to have the opportunity to meet with other people concerned with the scientific, ethical, and social issues related to the advances in human genetics, the October 9-10, 1995 meeting of the ELSI Working Group was held in Palo Alto, California. The Working Group visited the Stanford Genome Science and Technology Center and attended the Beckman Public Policy Symposium II, entitled "Genetic Testing: Expectations, Implications, and Options," held October 10 at Stanford University.
The ELSI Working Group Task Force on Genetic Testing has developed draft interim principles in the areas of the scientific validation of predictive genetic tests; quality assurance of laboratories performing genetic tests; and education, counseling, and delivery of genetic tests. These interim principles have been reviewed by the ELSI Working Group and will be made available for public comment in the next two to three weeks. The Working Group will discuss the interim principles and public comments at their May 2-3 meeting.
The ELSI Working Group is also developing a document on the use of genetic information in employment, and will make this document available for public comment. The Working Group submitted their statement on the book The Bell Curve to 19 journals, newsletters, and other publications. The statement has been referred to in Nature and published in part in Science as a letter to the editor; it is expected that it will be published in other journals. The Working Group is following the activities related to the education of health professionals in genetics, and perceives its role as a coordinator of ongoing efforts. Future efforts of the Working Group include the non-medical uses of genetics, intellectual property, training programs, and the psychological impact of genetic information on individuals and families. Regarding this last item, Dr. Spence noted that it was important to focus not only on the individuals or groups who have single gene disorders, but also on individuals and groups who have common diseases for which there is a genetic component.
Dr. Valle, who represents the NACHGR on the Advisory Committee to the NIH Director, reported on the findings of three ad hoc panels that were formed to advise the Director: Panel to Assess the NIH Investment in Research on Gene Therapy, chaired by Drs. Stuart H. Orkin and Arno Motulsky; the Ad Hoc Review Committee for the Recombinant DNA Advisory Committee, chaired by Dr. Inder Verma; and a third panel to assess the economic impact of biomedical research, chaired by Dr. Robert Zeckhauser.
The Panel to Assess the NIH Investment in Research on Gene Therapy noted that, while gene therapy has extraordinary promise, the enthusiasm to proceed to clinical trials has had an adverse effect upon the basic science studies needed in the pathophysiology of diseases. Among its recommendations are: "... a greater focus on basic aspects of gene transfer, and gene expression within the context of gene transfer approaches; ... increased emphasis on research dealing with the mechanism of disease pathogenesis, further development of animal models of disease, enhanced use of preclinical gene therapy approaches in these models; and greater study of stem cell biology in diverse organ systems." Dr. Valle noted that the report was very informative and a fair assessment of NIH gene therapy programs.
The Ad Hoc Review Committee to review the Recombinant DNA Advisory Committee (RAC) recommended that steps be taken to make the RAC more efficient. The panel recommended that: the RAC should no longer review every clinical gene transfer protocol (the FDA is required by statute to do this before approval); reviews of protocols by the RAC in a open public forum should continue in several areas in which a particular protocol or new technology represents a significant departure from familiar practices (e.g., novel vectors, gene transfer in utero); the RAC should define the criteria and procedures for identifying specific protocols requiring public review; the RAC should continue to provide advice on gene therapy and other recombinant DNA issues; a mechanism should be developed that would enable the Office of Recombinant DNA Activities, the NIH, and the RAC to continue to have access to the data needed for monitoring clinical gene protocols.
The third panel, chaired by Dr. Robert Zeckhauser, was asked to examine the economic impact of biomedical research, which, the panel reported, was very difficult to measure.
In addition, another committee, chaired by Dr. David Nathan, is underway and will advise the NIH director on clinical research. Dr. Collins noted that Senator Hatfield has introduced a bill that would allow patient care costs incurred in the conduct of clinical research to be reimbursed by third-party payers.
Dr. Botstein, who was a member of the gene therapy panel, noted that, while the panel was aware of the paper by Dr. Blaese, et al on the ADA patients, these patients did not display the extreme phenotype of the disease. Dr. Botstein went on to state that gene therapy requires the rigor that is demanded of all science, and that there is no evidence that underlying problems associated with gene therapy (e.g., continued gene expression) have been solved. Drs. Collins, Valle and Botstein recognized that important reproductive decisions may be made by some couples based on unrealistic anticipated cures of genetic conditions by gene therapy.
Dr. Wendy Baldwin, the NIH Deputy Director for Extramural Research, met with the Council to discuss the impact of the closure of the federal government on the extramural community and to apprise the Council of NIH "reinvention" activities. Dr. Baldwin noted that funding of some types of grants has been delayed due to the furlough, and that the NIH made extensive use of its "Internet Home Page" to keep the extramural community apprised of the status of activities at the NIH. Dr. Baldwin described the revamping of the grant inquiry function of her office, which will result in more information available electronically. Dr. Botstein asked for an update on the status of the recommendations made in the report on the DRG. Dr. Baldwin replied that the slate of members of the Peer Review Oversight Committee has been approved by Dr. Varmus, that there have been structural changes in the DRG review process (some are occurring on a pilot basis within DRG, others will not happen until there is a new DRG director), and the search for a DRG director is underway.
Dr. Collins requested an update on the modular grant concept. Dr. Baldwin replied that this concept is being piloted for individual RFAs, and has been successful so far in specific settings. However, it might be difficult to move the process into the mainstream. Not all grants can be "modularized," and it may be problematic to ask a review group to review a mix of modular and non-modular grants. In response to a question on who determines if a grant is modular, Dr. Baldwin noted that this determination will be made before the release of a solicitation, and it is likely that small grants, FIRST awards, and similar mechanisms will be modular.
Dr. Ari Patrinos, the Associate Director of the Office of Health and Environmental Research, will attend NACHGR meetings and provide the Council with updates of DOE HGP activities. Dr. David Smith, the Director of the DOE Health Effects and Life Sciences Research Division, who previously provided updates on the DOE activities to the Council, has retired. Dr. Patrinos told the Council that he has assumed leadership for the DOE HGP, which is a high priority research activity of the DOE. While the DOE has been funded since the beginning of the fiscal year, the agency received a 10 percent cut in its biological and environmental research programs, namely, the radiation biology program and the global change program. The decrease in these programs translated into growth for the HGP budget. The DOE HGP efforts are in large-scale sequencing, informatics, and ELSI issues (primarily intellectual property and education). In response to queries about the DOE investment in the national labs, Dr. Patrinos noted that the DOE is striving for a balanced portfolio of research among academic centers and the national laboratories. In response to a question about the national laboratories, Dr. Patrinos noted that their role is being examined.
Dr. Mary Clutter provided the Council with an update on the Arabidopsis thaliana Genome Sequencing Project. This project, which is co-sponsored by the National Science Foundation, the U.S. Department of Agriculture, and the DOE, is a three year program to support the initiation of systematic sequencing of the genome of Arabidopsis thaliana. It is anticipated the project will be coordinated with similar efforts in Europe and Japan. An interagency program announcement was issued in October 1995 and applications were due January 16, 1996. Awards will be made in June 1996, and funding will start before September 1996.
Dr. Elise Feingold presented a proposal for an initiative for large-scale functional analysis of the yeast genome. Dr. Feingold stated that the completion of the sequence of the yeast Saccharomyces cerevisiae is imminent, and the NCHGR proposes to invest a modest amount of funds to invite applications for research projects that will use innovative approaches to enrich the yeast sequence with biological information in rapid, comprehensive, and efficient ways, and to study biological phenomena important for human health. The NCHGR also plans to solicit participation from other components of NIH. Dr. Feingold noted that it would be desirable to make awards in FY96.
After discussion by the Council regarding the proposed amount of funding ($1-4 million total costs per year), funding mechanism (program announcement or request for applications), and focus (genomic only or broader to capture support from other NIH Institutes), the Council unanimously passed a motion by Dr. Botstein, and seconded by Dr. Tilghman, to go forward with an RFA that is focused on the genomic aspects (including infrastructure), and that the commitment by NCHGR should be for no more than $1 million per year.
Ms. Elizabeth Thomson, acting Chief of the ELSI Branch, described the NCHGR ELSI Program training support efforts. These efforts have been focused in two areas: (1) postdoctoral fellowships for scholars to pursue further education and research experience in an ELSI area; and (2) short-term courses to provide doctoral, post-doctoral, and professional individuals with an opportunity to combine knowledge about genome science and ethics. Ms. Thomson noted that neither the NCHGR ELSI Program nor the ELSI Working Group has identified a strong need to develop ELSI pre-doctoral training programs. However, since the ELSI Branch has received a small number of inquiries for information about the possibility of ELSI funding for pre-doctoral institutional training programs, the NCHGR requested that the NACHGR examine the need for such training programs and consider whether NCHGR should change its policy of not accepting applications for pre-doctoral training grants in the ELSI area.
Dr. Duster stated that there is a need for this kind of training activity in the ELSI area, and suggested that initial review groups make a determination about the suitability of training proposals. Ms. Thomson noted that NIH identifies areas for training; training grants are not investigator-initiated. Dr. Spence noted a greater need for the education of health care providers in genetics, and did not encourage the limited funding to be spent on pre-doctoral training. Many Council members agreed with Dr. Spence's statement, and others expressed interest in receiving comments from the ELSI Working Group on pre-doctoral training. However, the Working Group was to be advised that pre-doctoral training in ELSI areas was not encouraged by the Council. Ms. Thomson will follow-up with Dr. Duster on discussion of this issue at the next ELSI Working Group meeting.
The statement of understanding addresses the review of applications by the council and guidelines for NCHGR staff to negotiate adjustments in grant amounts and terms. A motion to accept the statement of understanding as written was made by Dr. Botstein and seconded by Dr. Rothstein. The council passed the motion unanimously.
For two meetings, the council has received the summary statements both as a hardcopy and on disk. While some council members found the disk version acceptable, most did not favor replacing the paper copies of the summary statements with the disk only. A motion to continue hardcopy summary statements was made by Dr. Diane Smith and seconded by Dr. Lloyd Smith. The council passed the motion unanimously.
The scientific presentation at the next council meeting (May 20-21) will be given by a member of the Cancer Genetics Study Consortia, and will focus on ELSI issues. Dr. Collins noted that the annual update to the council on the NCHGR Division of Intramural Research is planned for the May meeting, and suggested that Dr. Janet Rowley, the chair of the Board of Scientific Counselors, may be available to make this presentation. It was mentioned that there are no large RFAs to review in May.
Dr. Collins recognized three members whose terms of service on the NACHGR are completed: Dr. David Botstein, Dr. David Housman, and Dr. Lloyd Smith. Each was presented with a certificate of appreciation by Dr. Collins.
Dr. Jordan read the Conflict of Interest statement and reminded the council members that all review materials furnished to council members are privileged information. Conflicts involving institutional affiliations already had been identified. Members were asked to absent themselves also during discussions of any applications in which there was a personal or professional conflict not identified by staff.
Council reviewed 90 applications requesting $60,833,852. The applications included 18 regular research grants, six pilot projects, seven ethics grants, 43 in response to requests for applications, one area grant, three conference grants, one research career development award, one continuing education training program, eight small business innovative research (phase I) grants, and two fellowship grants. A total of 68 applications requesting $44,503,661 were recommended for approval.
The meeting was adjourned a 11:30 a.m., February 6, 1996.
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