GENETIC TESTING AND THE CLINICAL MANAGEMENT OF NONSYNDROMIC HEREDITARY HEARING IMPAIRMENT Release Date: December 20, 2000 PA NUMBER: PAS-01-036 National Institute on Deafness and Other Communication Disorders (http://www.nidcd.nih.gov/) National Human Genome Research Institute (http://www.nhgri.nih.gov/) Letter of Intent Receipt Dates: February 15, April 15, and August 15, 2001 Application Receipt Dates: March 14, 2001, June 26, 2001, October 26, 2001 THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA. PURPOSE The National Institute on Deafness and Other Communication Disorders (NIDCD) and the National Human Genome Research Institute (NHGRI) invite research grant applications to study genetic testing as it may relate to the clinical management of nonsyndromic hereditary hearing impairment. There is a broad range of issues that must be addressed to comprehensively determine the clinical validity and utility of genetic testing for hereditary hearing impairment. Such issues include the correlation of genetic and audiologic information, the utilization of genetic information in clinical management and outcomes, and the impact of genetic testing on the behaviors and attitudes of individuals with hearing impairment and their families. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This Program Announcement (PA), Genetic Testing for Hereditary Hearing Impairment, is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non- profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Foreign institutions are eligible. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This PA will use the National Institutes of Health (NIH) R01 award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this PA may not exceed four years. This PA has three solicitation dates. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The earliest anticipated award date is September 28, 2001. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. Complete and detailed instructions and information on Modular Grant applications can be found at http://grants.nih.gov/grants/funding/modular/modular.htm FUNDS AVAILABLE The NIDCD intends to commit approximately $750,000 in FY 2001 and $750,000 in FY 2002 to fund up to five new awards in response to this PA. The NHGRI will also commit funds subject to availability. An applicant may request a project period of up to four years. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of the NIDCD and NHGRI provide support for this program, awards pursuant to this PA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, there are no plans to reissue this PA. RESEARCH OBJECTIVES Background In the last decade scientists have determined the chromosomal locations of hundreds of genes that segregate in families with a history of deafness. Approximately 20 of the genes whose mutations result in non-syndromic hearing impairment have been identified and isolated. Mutations in one or a few of these genes are important contributors to hearing impairment in some population groups. One example is the GJB2 gene that encodes a gap junction protein, Connexin 26. Mutations in this gene are reported to be the most common cause of autosomal recessive non-syndromic deafness in several parts of the world; however, the clinical phenotype may be variable. The degree of hearing loss in persons with Connexin 26-related hearing impairment varies even among individuals with the same GJB2 genotype, and there may be variability in the time of initial onset of hearing loss as well as variability in the rate of progression of hearing loss. With the identification of genes that contribute to hearing function, genetic testing becomes technically possible. This possibility does not necessarily imply that genetic testing should be performed. Prior to clinical implementation of genetic testing, several issues must be addressed to assess the clinical validity and utility of such tests. There are many unresolved issues regarding the prevalence and penetrance of mutations in various populations, the clinical utility of knowing the specific genetic mutation responsible for the hearing loss, and the short and long-term impact of genetic testing and information on individuals and their families. There is little information on the understanding of and attitudes about genetic testing or the level of interest in such testing, particularly among families in which hearing impairment has occurred. There are unique challenges pertaining to genetic testing for deafness and hearing impairment because these conditions are not considered to be disabling or undesirable by everyone. The screening of newborns for hearing impairment (phenotypic) is being initiated throughout the nation, identifying infants with hearing loss immediately after birth. At present, thirty-two states have enacted legislation that requires universal hearing screening for newborns. Identification of hearing loss at birth is presenting unique challenges. Not only are these infants with hearing impairment being identified much earlier in life, but infants with varying degrees of hearing impairment are now being identified, in contrast to the recent past where primarily only severe to profound hearing impairment was detected in the second or third year of life. Many unresolved issues remain for clinicians as they strive to characterize the auditory performance in the newborn who fails hearing screening, design intervention strategies to optimize communicative success, and ensure that a “medical home” exists for the infant with hearing impairment. The advances in the genetics of hereditary hearing impairment and the advances in the early identification of hearing impairment have now converged. These advances have led some to suggest genetic testing/evaluation for all infants who are identified with a hearing loss at birth, and some organizations and individuals have embraced this idea. For example, in January 2000 the American College of Medical Genetics published a policy statement on universal newborn hearing screening. In it, they noted that it is “essential that all children with confirmed hearing loss be referred for evaluation and genetic counseling to a team which will typically include a qualified clinical geneticist and a genetic counselor.” These guidelines may be found at: http://www.faseb.org/genetics/acmg/pol-35.htm. The NIDCD has recently assembled two working groups in which the extramural research communities have considered these issues. First was the NIDCD Working Group on Considerations for Developing and Implementing Genetic Diagnostic Tests for Hereditary Hearing Impairment and Other Communication Disorders. The minutes may be found at http://www.nidcd.nih.gov/funding/programs/hb/genetic.asp. Second was the Third Workshop of the NIDCD Working Group on the Early Identification of Hearing Impairment in which this topic was identified as a research need. Those minutes may be found at http://www.nidcd.nih.gov/funding/programs/hb/earlyid_00.asp. This PA is designed to address the clinical relationship between genetic and audiologic/otologic information as well as to address the clinical validity and utility of genetic testing in the diagnosis, treatment and management of nonsyndromic hereditary hearing impairment, as well as psychosocial effects. Other This PA is broad in scope and nature and it is likely that these applications will be multidisciplinary. Responsive applications must have a clinical research focus that seeks to investigate questions surrounding the use or implementation of genetic testing for nonsyndromic hearing loss. There is a broad range of issues that must be addressed to comprehensively determine the utility of genetic testing for hereditary hearing impairment. Such issues include the correlation of genetic and auditory information, the utilization of genetic information in clinical management and outcomes, and the impact of genetic testing on the behaviors and attitudes of individuals with hearing impairment. Applications focusing solely on the prevalence and penetrance of genetic mutations thought to be involved in hereditary hearing impairment are not responsive to this PA; however, such applications are of interest to the NIDCD and should be submitted to the NIH on the regular R01 submission dates. The NIDCD and NHGRI are highly committed to furthering research on the ethical, legal and social implications of human genetics and genomic research, and have recently co-sponsored two NIH program announcements requesting research applications in this area. The program announcement calling for regular (R01) research grants in this area may be found at http://grants.nih.gov/grants/guide/pa-files/PA-00-133.html and the program announcement calling for small (R03) research grants in this area may be found at http://grants.nih.gov/grants/guide/pa-files/PA-00-132.html. Research objectives include, but are not limited to: o Developing longitudinal studies of individuals with deafness/hearing impairment to address genotype/phenotype correlations. This includes the natural history of hearing loss in individuals with various mutations in different populations. Necessary phenotypic information includes degree of hearing loss as well as age of onset and rate of progression of hearing loss. o Examining the correlation and interaction of genetic information with audiologic/auditory information beyond the audiogram, which includes delineating auditory (sensory) thresholds as well as auditory perception (speech and supra-threshold auditory abilities). o Developing clinical studies to determine the value of genetic testing as a complement to existing clinical screening procedures, diagnostic procedures and management practices. Areas of study include understanding the clinical validity and utility of genetic testing to screen for hearing impairment as well as understanding the short and long term effects of genetic testing for hearing impairment. o Determining the role of genetic testing and the utilization of genetic information in the optimization of models of service delivery for infants and young children with hearing loss (i.e., screening, assessment and habilitation/rehabilitation protocols, as well as medical management). o Developing adequate informed consent procedures on the use of DNA specimens for genetic testing and further genetic research related to hearing impairment. o Determining the impact of genetic testing and the utilization of genetic information on attitudes and behaviors of individuals with hearing impairment and their families. o Evaluating the psychosocial effects of genetic testing in the context of unique cultural issues associated with hearing impairment/deafness. o Evaluating methods of providing education and counseling to facilitate comprehension of genetic information and subsequent informed decision- making following the provision of genetic information. SPECIAL REQUIREMENTS Attention to informed consent issues is required. Informational materials to aid researchers in obtaining informed consent from individuals with hearing impairment or deafness may be found at: http://www.nidcd.nih.gov/news/releases/99/inform/toc.asp Evidence of Clinical Laboratory Improvements Act (CLIA) certification is required for all projects in which genetic testing results will be provided to research participants. In order to increase the scope and pace of the research, the NIDCD and NHGRI will organize a consortium of studies. Such an arrangement will allow researchers to compare findings on issues common to all the projects, to reduce duplication of effort, and to promote sharing of information. To facilitate such coordination, grantee workshops will be arranged on an annual basis in the Bethesda area. The budget request should take into account the need for funds for travel to these meetings for up to two investigators (the PI and one other) per year. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the PA. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NIDCD staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to Amy Donahue, Ph.D., at the address listed under “INQUIRIES” by the letter of intent receipt dates listed in SUBMISSION OF APPLICATIONS. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, email: GrantsInfo@nih.gov. The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in- time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. (Applications that request more than $250,000 direct costs in any year must follow the traditional PHS 398 application instructions.) The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: PHS 398 FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. Under Personnel, list all project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of all personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual's qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm - Complete the educational block at the top of the form page; - List position(s) and any honors; - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. - List selected peer-reviewed publications, with full citations; CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. The Applicants planning to submit an investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended/revised version of the preceding grant application types requesting $500,000 or more in direct costs for any year are advised that he or she must contact NIDCD program staff before submitting the application, i.e, as plans for the study are being developed. Furthermore, the application must obtain agreement from the NIDCD staff that they will accept the application for consideration for award. Finally, the applicant must identify, in a cover letter sent with the application, the staff member and Institute who agreed to accept assignment of the application. This policy requires an applicant to obtain agreement for acceptance of both any such application and any such subsequent amendment. Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at http://grants.nih.gov/grants/guide/notice-files/not98-030.html The title and number of the program announcement must be typed on line 2 of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) Send two additional copies of the application, and five sets of any appendices to: Chief, Scientific Review Branch National Institute on Deafness and Other Communication Disorders 6120 Executive Boulevard, Room 400-C, MSC 7180 Bethesda, MD 20892-7180 Rockville, MD 20852 (for express/courier service) SUBMISSION OF APPLICATIONS Applications will be accepted under these guidelines for three receipt dates beginning with the March 2001 application receipt date through the October 2001 date. Letter of Intent: February 15 April 15 August 15 Application Receipt Dates: March 14 June 26 October 26 NIDCD Committee Review: June October February 2002 Council Review: September January May Earliest Funding: September 28 April 1 August 1 Applications must be received by the application receipt date listed above. If an application is received after that date, it will be reviewed in the next cycle. The Center for Scientific Review (CSR) will not accept any application in response to this PA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by CSR. If the application is not related to the goals of the PA, the applicant may be contacted to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next review cycle. Applications that are complete will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIDCD in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the NDCD and NHGRI Advisory Councils. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? (2) Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? (3) Innovation: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? (5) Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research. o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. AWARD CRITERIA Award criteria that will be used to make award decisions include: o scientific merit (as determined by peer review) o availability of funds o programmatic priorities. INQUIRIES Inquiries concerning this PA are encouraged. The opportunity to clarify any issues or answer questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Amy Donahue, Ph.D. Chief, Hearing and Balance/Vestibular Section National Institute on Deafness and Other Communication Disorders 6120 Executive Boulevard, Room 400-C, MSC-7180 Bethesda, MD 20892-7180 Telephone: (301) 402-3458 Fax: (301) 402-6251 Email: amy_donahue@nih.gov Thomas Johnson, Ph.D. Hearing Program Officer National Institute on Deafness and Other Communication Disorders 6120 Executive Boulevard, Room 400-C, MSC-7180 Bethesda, MD 20892-7180 Telephone: (301) 402-3461 Fax: (301) 402-6251 Email: thomas_johnson@nih.gov Jean McEwen, J.D., Ph.D. Program Director Ethical, Legal, and Social Implications Research Program National Human Genome Research Institute 31 Center Drive Building 31, MSC 2033, Room B2B07 Bethesda, MD 20892-2033 Telephone:(301) 402-4997 Fax: (301) 402-1950 Email: jm522n@nih.gov http://www.nhgri.nih.gov/ELSI Direct inquiries regarding review issues to: Craig Jordan, Ph.D. Chief, Scientific Review Branch National Institute on Deafness and Other Communication Disorders 6120 Executive Boulevard, Room 400-C, MSC 7180 Bethesda, MD 20892-7180 Telephone: (301) 496-8683 Fax: (301) 402-6250 Email: jordanc@nih.gov Direct inquiries regarding fiscal matters to: Ms. Sherry Dabney Grants Management Branch National Institute on Deafness and Other Communication Disorders 6120 Executive Boulevard, Room 400-B, MSC 7180 Bethesda, MD 20892-7180 Telephone: (301) 402-0909 Fax: (301) 402-1758 Email: sherry_dabney@nih.gov Ms. Jean Cahill Division of Extramural Research National Human Genome Research Institute 38 Library Drive, MSC 6050, Room 613 Bethesda, MD 20892-6050 Telephone: (301) 402-1733 Fax: (301) 402-1951 Email: cahillj@mail.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.173. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.


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