National Institute of Environmental Health Sciences, Contracts and Procurement Management Branch, OM, 79 T.W. Alexander Drive, P.O. Box 12874, 4401 Building, Research Commons, Research Triangle Park, NC 27709

A -- HIGH THROUGHPUT GENOTYPING FOR LOCATING HUMAN DISEASE SOL NIH-ES-96-27 POC Contact Velvet M. Torain, Contract Specialist, 919/541-0440; Phillip D. Jones, Contracting Officer, 919/541-0426 The National Institute of Environmental Health Sciences intends to negotiate a contractwith Johns Hopkins University, Johns Hopkins School of Medicine, 720 Rutland Avenue,Baltimore, Maryland to conduct high throughput genotyping for locating human disease genesfor the National Center for Human Genome Research's Division of Intramural Research/Center for Inherited Disease Research (NCHGR/CIDR). The CIDR is a unit within theNCHGR. Specifically, Johns Hopkins will be required to apply the tools necessary to locateand identify the genes contributing to the inheritance of such complex heritable traits inhumans. The tasks to be performed are (1) implement and support computer databases forstorage and retrieval of clinical, epidemiological, and genotype data. This will involvedesigning, constructing, implementing, and supporting the computerized database in which allclinical and epidemiological (''phenotypic'') data, DNA inventory and quality information shallbe stored; (2) implement new studies based on study design provided through the ProjectOfficer by developing questionnaires, contacting study subjects, obtaining necessaryclearances, etc. The Contractor shall obtain the families' cooperation or approval as necessaryfor implementation of the study; assist in the development and production of self-administeredquestionnaires, and interviewer-administered questionnaires, and assist in the preparation ofprotocols for collecting blood samples; (3) acquire clinical and epidemiological data fromselected families in which complex hereditary diseases are present and store data in electronicdatabase. The Contractor shall design, develop, and furnish to the Project Officer writtenprocedural manuals for abstracting, interviewing, and coding clinical and epidemiological data,identify and trace individuals for study, abstract, microfilm, and photocopy records afterobtaining appropriate permission, clearances, or approvals and maintain quality control overthe abstracting process; (4) store clinical and epidemiological data in electronic database. Thisshall be accomplished by coding clinical and epidemiological data into computer readable formfor the database, cross reference any DNA samples and genotype data generated from thesamples; (5) acquire, process, and store biological specimens from individuals participating inresearch studies. The Contractor shall design, develop, and furnish to the Project Officerwritten procedural manuals for collecting, transporting and storing biological specimens,extracted DNA, synthetic polymerase chain reaction procedures, furnish all equipmentnecessary to carry out extraction of high molecular weight DNA, perform quality controlmeasurements, and store DNA and other biological specimens at 4, -20 or -70 degrees C,develop an inventory system for tracking and storage of blood, DNA samples, synthetic DNA(oligonucleotide) primers used in genotyping, and other reagents used in DNA sequencing andpolymerase change reaction (PCR) protocols; (6) implement and apply methods for rapidgenotyping of large numbers of individuals from the DNA samples prepared and collected inCIDR. This shall be accomplished by employing methods for genotyping large numbers ofindividuals using, but not limited to, gel-based resolution of microsatelite markers or detectionof single nucleotide polymorphisms either by hybridization to oligonucleotides fixed in solid-phase or by the oligonucleotide ligase chain reaction method. The Contract shall ensure allgenotypic data obtained from each individual sample includes, but is not limited to, sample IDnumber, the marker at which genotype is being determined, and results of genotypingexpressed as allele sizes, etc., obtain genotype information for each sample and record datainto the database directly using software that ''reads'' the genotype output from the automatedsequences for each sample, develop software required to read genotype information fromeither gel based electrophoretic systems, chip-based hybridization systems, or ligase chainreaction methods, to allow the direct reading of genotype data into the database; (7) implementand apply computer-based statistical methods to locate gene responsible for complex heritabletraits in humans. The Contractor shall develop or import statistical methods for analyzingclinical and epidemiological data and the co-inheritance of DNA markers and various complextraits such as, but not limited to, multi variate regression, logistic regression, life tableprocedures, ANOVA, linkage analysis of discrete traits, quantitative trait linkage mapping,affected pedigree member methods, etc., implement statistical methods into usable computerprograms either by importing them from elsewhere or by designing and constructing them.Other Information/Requirements: it is estimated that approximately 25,000 questionnaires,completed by collaborating investigators, will be provided by the Project Officer to theContractor over a five year period and an additional 5,000 questionnaires, generated andadministered by the Contractor under direction of the Project Officer, will be completed by theContractor over a five year period. Approximately 25,000 DNA samples will be obtainedover five years either directly as DNA from collaborators or DNA extracted from human freshor frozen whole blood, white blood cells, or other human tissues by the contractor. A sampleof the types of diseases to be considered under this contract is as follows: Alcoholism,Autism, Breast Cancer, Dyslexia, Fetal Alcohol Syndrome, Hyperlipidemia, IgA Nephropathy, Lung Cancer, Macular Degeneration, Nephrolithiasis, Osteoporosis, Pharmacogenetics, Renal Agenesis, Schizophrenia, Tourette's Syndrome. The Contractor willhave at the time of submission of the proposal, or be willing to establish, permanent offices,equipment and technical facilities within one hour commuting time from both of the existingNCHGR facilities, the one located at Bethesda, Maryland and the one located in Baltimore,Maryland. This requirement will not be changed or modified under any circumstances.Establishment of such offices must occur within 60 days of award of a contract and be subjectto approval by the Project Officer as to suitability and adequacy. Frequent discussions andconsultations with NCHGR Project Officers necessitate that the Contractor be in closeproximity to minimize the expenses to the Government and delay in identifying and solvingproblems in ongoing research. The contractor shall provide a minimum of 13,000 square feetof space for the work. Approximately one-half of the space must be suitable for modernmolecular biology and provide sufficient electrical power, ventilation, and computernetworking to support the research equipment, including automated DNA sequencers,oligonucleotide synthesizers, high speed and ultra centrifuges, -80 =BOC freezers, andcomputers. The rest of the space is individual offices and conference rooms. The Contractorshall have a production facility capable of performing 1 million genotypings in the first year,increasing to a minimum of 2 million over the second year. The period of performance willbe for five years with a planned award date on or before August 30, 1996. It is anticipatedthat this project will require approximately 364,000 man-hours over five years. Authority: 41USC 253(c)(1), as set forth in FAR 6.302-1 -- Only One Responsible Source. Because of thecomplex research and development aspects of this project, successful completion includesinterdependent kinds of expertise, knowledge, and experience. Johns Hopkins is the onlysource that has the capability of database construction, patient outreach, questionnaire design,clinical data collection and entry, and statistical analysis. Johns Hopkins has the capability ofnot just providing genotyping service, but also providing a large tertiary care, referral medicalcenter through which patients with unusual hereditary diseases can be ascertained from all overthe world, experience and expertise in building relational databases that contain complex typesof data of variable certainty and accuracy, and experience and expertise in automatedgenotyping using florescent markers. Any other interested sources desiring consideration forthis requirement must fully identify their interests and capabilities to the Contracting Officerlisted above. See Numbered Note 22. (0029)

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