Statement_of_Work_for_DNA_collection_and_Analysis.doc

STATEMENT OF WORK FY 2016-2017

last modified November 3, 2016 A.

BACKGROUND INFORMATION

For twenty years the NIDCD has maintained highly successful collaborations in Pakistan to study the genetics of hearing and speech disorders. Researchers in the Laboratory of Molecular Genetics (Thomas B. Friedman, PhD and the Laboratory of Communication Disorders (Dennis Drayna, PhD) work with Professor S. Riazuddin’s Laboratory for Research in Genetic Diseases, previously at the National Centre of Excellence in Molecular Biology (NCEMB), Ministry of Education, Lahore and presently at the Shaheed Zulfiqar Ali Bhutto Medical University (SZABMU) satellite lab, Allama Iqbal Medical Research Centre (AIMRC), Jinnah Hospital, Lahore. This collaboration involves ascertaining families in Pakistan with hearing and speech disorders, and mapping and identifying the genes that underlie these disorders. Two protocols at the NIH have been approved for these studies: (1) Nonsyndromic hereditary hearing impairment-gene mapping" protocol OH93-DC-016, and (2) Genetic Studies of Stuttering, protocol 97-DC-0057.

Thomas B. Friedman, PhD, Chief, Laboratory of Molecular Genetics is the PI and Andrew Griffith, MD, PhD serves as the Medical Advisory Investigator for the hereditary deafness protocol. Dennis Drayna, PhD is the Chief of the Laboratory of Communication Disorders and PI on the stuttering protocol, with Carter Van Waes serving as the Medical Advisory Investigator.

DNA samples from over one thousand extended families have been collected for study under these protocols under previous professional service contracts (PSC’s) with Professor Sheikh Riazuddin. Professor Riazuddin’s laboratory is the premier research facility for research on human genetic diseases in Pakistan. He has established collaborations with many laboratories in Europe, the US and elsewhere. Most notable of these endeavors in addition to those at the NIH are collaborations with Richard J. Roberts previously at Cold Spring Harbor Labs; Lawrence Loeb and Eugene Nester at University of Washington, Seattle, Marc Van Montagu at Ghent University, Belgium, Hans van Bookhoven at Radbound University Nijmegen Medical Centre, Netherlands and Robert H. Ropers at Max Plank Institute, Berlin, Germany. These collaborations are built on the strengths of participating laboratories designed to advance common goals. The US National Science Foundation (International Program), the Rockefeller Foundation and the National Research Council have also funded some of these USA-Pakistan collaborations.

Dr. Riazuddin’s laboratory is funded by the Pakistani federal government, and works at the forefront of a number of areas in molecular biological research. It is advised by the following Foreign Scientists Advisory Council

Dr. Roger McMacken

E.V. McCollum Professor & Chairman

Department of Biochemistry & Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, U.S.A.

Dr. R.J. Roberts (Nobel Laureate)

Director of Research, New England Biolabs. Inc., Beverly, MA 01915-5510, U.S.A.

Marc Van Montagu, Institute Plant Biotechnology for Developing Countries, Department Molecular Genetics, Ghent University, K.L. Ledeganchstraat 35, B-9000

Gent, Belgium.

Dr. Eugene Nester, Department of Microbiology and Immunology, University of Washington

Mail Stop SC-42, Seattle

Seattle, WA 98195, U.S.A.

Dr. Lawrence A. Loeb, Director, Joseph Cottstein Memorial Cancer Res. Lab.

K-Block, Health Sciences Building, University of Washington

Seattle, WA 98195, U.S.A.

Prof. Jeongbin Yim, Department of Biochemistry, Seoul National University, Seoul, S. Korea.

Prof. Ken-ichi Arai, Professor Emeritus, Tokyo University, Tokyo, Japan

B.

PURPOSE AND OBJECTIVES OF THE PROCUREMENT

The purpose of this procurement is to benefit from the expertise of Dr. Sheikh Riazuddin and his research associates in Lahore, Pakistan. Dr. Riazuddin serves National Distinguished Professor, Higher Education Commission /Professor Emeritus SZAMBU/Principal Investigator in these studies. This contract is intended to fund several aspects of our continuing collaborative studies on nonsyndromic hereditary hearing impairment, speech disorders, particularly stuttering, and other disorders central to the mission of the NIDCD, all being carried out with studies of families in Pakistan. Continued enrollment of new families needs to occur, and continued clinical evaluation of the families needs to be performed. In supporting these collaborative activities, this contract will benefit from the presence of a long established and highly respected research laboratory in a region of the world where many families practice consanguineous marriage. Personnel from Dr. Riazuddin’s research laboratory will be encouraged to follow our long standing tradition of coming to the NIH for training as part of the collaboration established with Pakistan according to the guidelines sanctioned by our IRB, OPRR and the Division of International Services, NIH Fogarty Center. Historically, Drs. Drayna and Friedman have hosted numerous Pakistani trainees in our laboratories, and have a long history of successfully training Pakistani human geneticists and molecular biologists.

DNA samples from all families that are enrolled in this study will be sent to the Laboratory of Molecular Genetics and the Laboratory of Communication Disorders for analysis, along with a copy of the signed Informed Consent and clinical data for each participant. These samples have proven crucially important for the identification of many genes that cause hereditary hearing impairment and speech disorders.

C.

CONTRACTOR REQUIREMENTS

1) Obtaining Informed Consent and enrolling additional volunteers from families with hearing loss, stuttering, and other speech disorders under a protocol approved by an Institutional Review Board (IRB) with a Federal-Wide Assurance (FWA) number. Dr. Riazuddin’s institution in Lahore, Pakistan maintains such a protocol, approved by their local IRB under FWA #00001758. Such families have proven essential in mapping and identifying novel deafness and speech disorder loci and genes. This aspect of the contract involves many hours of travel to remote areas of Pakistan. For all studies, annual Pakistani IRB review and approval of the applicable human subjects research protocols will be documented and forwarded to the NIDCD.

2) As needed, obtain audiograms, recorded speech samples, and associated clinical data for subjects currently enrolled in the projects.

3) In some instances extensive clinical testing is required as we attempt to better understand possible clinical manifestations of a particular mutation in organs other than those involved in hearing and speech. Copies of these detailed clinical reports will be sent to the Laboratory of Molecular Genetics or the Laboratory of Communication Disorders as applicable.

4) A goal for FY 2017-2020 will be to enroll families segregating hereditary deafness not due to mutations of reported DFNB genes and reported Usher syndrome genes. Performance for this aspect of the project will include obtaining informed consent, audiograms, electroretinograms, family histories and genealogies. Copies of consents, and other pertinent information along with DNA or blood or saliva samples will be sent to the Laboratories of Molecular Genetics and Communication Disorders along with an initial analysis of genotypes for known loci associated with deafness. A second goal is the ascertainment and enrollment of consanguineous families segregating stuttering, a disorder for which multiple as yet unidentified genes exist. Performance of this aspect of the project will involve gathering standardized recorded diagnostic speech samples and DNA from affected and unaffected family members. An additional goal will be to enroll and characterize families segregating other disorders that fall under the research missions of the NIDCD for further evaluation of their suitability for genetic studies.

To accomplish these goals, work will include ascertainment of appropriate families segregating deafness. Screens for linkage of the deafness to the known DFNA, DFNB and Usher loci will be done by Dr. Sheikh Riazuddin’s staff in Pakistan. DNA from one affected individual will be tested for GJB2 mutations using conventional PCR and Sanger sequencing. When a mutation is found, DNA of all individuals from that family will be sequenced for GJB2. Families segregating deafness and negative for GJB2 mutations will be checked for linkage of deafness to STR markers of the four deafness loci most prevalent in the Pakistani population. Thus, families will then be categorized into those linked to the known deafness loci and those unlinked. Families segregating deafness unlinked to the reported deafness loci presumably represent novel deafness loci. When feasible, genome wide scans will be performed jointly by Dr. Riazuddin’s and Friedman’s staff. Genomic DNA from linked and unlinked families will be sent to the LMG along with a pedigree and signed informed consents. As needed for a study or publication, clinical data regarding hearing or associated disorders may be requested.

Studies of speech disorders will focus on stuttering. Work will consist of obtaining blood/DNA samples and clinical speech evaluations and histories from the members of large families segregating these disorders. Work will include additional individuals from previously sampled families, as well as ascertainment and sampling from new families that may arise in the course of the contract period. Studies of other disorders that fall under the research mission of the NIDCD will involve ascertainment and characterization of families segregating the disorder, obtaining DNA samples and clinical diagnostic information from family members as warranted, and shipment of the information and samples for collaborative study at the NIDCD.

Performance period is May 15, 2017 – May 14, 2018, for one base year plus 4 option years. Payment will be requested for June 2017, assuming the majority of the goals for 2016-2017 are completed.

D.

GOVERNMENT RESPONSIBILITIES

The NIDCD will continue to provide information on carrier status on the deafness family members enrolled in this study. DNA samples from the enrolled families segregating deafness will continue to allow the Laboratory of Molecular Genetics, NIDCD to refine loci and identify genes responsible for inherited deafness. The LMG is a CLIA approved facility. DNA samples from the enrolled families segregating stuttering will continue to allow the Laboratory of Communication Disorders (LCD) to refine loci and identify genes responsible for inherited stuttering. The NIDCD will be responsible for maintenance of NIH IRB-approved protocols to support these studies, and for cooperation on writing and submitting scientific manuscripts to report research findings.

E.

REPORTING REQUIREMENTS AND DELIVERABLES

Potential families will be given information regarding our study through personal contact with Prof. Sheikh Riazuddin or his qualified designee. Blood samples and/or DNA samples, and clinical diagnostic information from family members will be delivered to the NIDCD.

F.

PROGRAM MANAGEMENT AND CONTROL REQUIREMENTS

Dr. Riazuddin will comply with regulations regarding the confidentiality of the identities and diagnoses of research subjects enrolled, and will be responsible for monitoring and proper accounting of expenditures in Pakistan.

G.

INSPECTION AND ACCEPTANCE CRITERIA

Materials received by the NIDCD will be examined to assure proper quality and suitability for enrollment in our study. This will include genotyping DNA samples, examining copies of Informed Consents, examining audiograms, recorded speech samples and speech diagnoses, and recorded speech samples, and SLINK pedigree analysis results.

H.

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