1. Identify types, numbers, and qualifications of personnel necessary for task completion: select, hire, train, and supervise such personnel, e.g., research technicians, technician team leaders, programmers, engineers, and other needed personnel. 2. Implement and support bioinformatic systems and processes as specified by the COR and/or CSO, for storage and retrieval of clinical, pedigree, genotypic, reagent, project tracking, quality control and other laboratory data. To provide such assistance, the contractor shall be required to furnish the following ?representative? types of services as well as other related activities which may be identified throughout the performance of the contract: a. Track laboratory information such as samples, reagents, quality control data, and equipment maintenance. Sample tracking through the experimental processes should be captured in a LIMS (Laboratory Information Management System). b. Monitor data quality using computerized systems to compile a standard set of quality control measures as appropriate to each technique, e.g., genotyping call rates, fold sequence coverage, percent region captured etc. The metrics shall be recorded for each project and reviewed on an ongoing basis. c. Use computerized systems to collect and store genotyping data for experimental and control samples. If required, maintain a computerized database for clinical and epidemiological (?phenotypic?) data when necessary according to the requirements of a particular project. Ensure data accuracy by uploading (as from spreadsheets) or extracting (as from databases) data from existing electronic sources. Where it is necessary to enter data, utilize current best-practice methods to minimize errors such as by scanning barcodes, using pull-down lists or template fields, with data validation enforced by comparison to known values, ranges, patterns or similar methods. d. Store and ensure that any data related to family structure, when available, are cross-referenced to any DNA samples and genotype data generated from the sample. When appropriate, these systems shall employ graphical user interfaces through which the contractor shall enter data using direct transfer, bar-code readers, or other automated systems. Stored data shall reside on server within CIDR with firewall security precautions in place to prevent access to any portion of the data except by users authorized by the COR. 3. Ensure the storage of clinical and family relationship (pedigree) data from Investigators using CIDR in the electronic database as specified by the COR. The contractor shall be required to furnish the following ?representative? types of services, as well as other related activities which may be identified throughout the performance of the contract: a. Enter computer readable data into the electronic information systems. If required by a specific project, ensure clinical, family, and phenotypic data are carefully entered and cross-referenced to any DNA samples and genotype data generated from the sample. b. Verify that data entry for an individual sample is accurate by using current and state-of-the-art validation systems. 4. Receive, process, and store DNA from individuals sent in by Investigators whose projects are being done at CIDR. To provide such assistance, the contractor shall be required to furnish the following ?representative? types of services, as well as other related activities which may be identified throughout the performance of the contract: a. Obtain necessary permission and approvals for the use of biological materials required for laboratory studies from an Institutional Review Board at the contractor?s institution. Maintain up-to-date documentation of all necessary Institutional Review Board and Animal Care and Use Committee approvals from outside Investigators governing specimens they have sent in for analysis at CIDR. b. Provide pre-labeled tubes or multiwell plates to Investigators who have been approved for CIDR services. Develop a ship and receipt tracking system that documents the shipping of supplies and the receipt of samples in labeled tubes containing DNA from the outside investigators. If necessary, quantify the amount of DNA and aliquot the DNA into several equivalent labeled samples at concentrations to be specified by the COR. Up to 500,000 DNA samples shall be obtained over 5 years. At the completion of a specific Task, arrange for remaining biological samples to be shipped back to the investigator, stored at CIDR or destroyed. The specific action to be taken will be agreed upon by the Investigator, the COR and in some cases, the Institute(s) sponsoring the specific task. c. Ensure that adequate oversight and caution is used by employees working with materials that present biological and/or chemical hazards. Materials classified biological or chemical waste shall be disposed of in accordance with Federal, State and local Regulations. The Contractor shall provide oversight for waste disposal. d. Develop an inventory system for tracking and storage of DNA samples, synthetic DNA (oligonucleotide) primers and platform specific genotyping reagents used in genotyping and sequencing, and other reagents used protocols related to quality control and data production services to. i. Ensure storage of inventory and quality control information about DNA in the database which shall include but is not limited to the following information: subject ID numbers, number of labeled vials or plates of samples, 260/280 absorption readings and ratios, picogreen fluorescence readings or other methods of quantification (if required for the project), volume, DNA concentration, and location of vials or plates of samples in storage system. Each specimen given to the contractor shall have a unique ID number assigned to it and shall remain with the sample during processing. Each specimen shall be identified by barcode. In addition, a DNA barcode (DNA fingerprint) shall be obtained for human samples undergoing complex analyses. ii. Ensure storage of oligonucleotides and reagent kits and mixes which shall include but is not limited to the following inventory and quality control information: primer set ID numbers, number of labeled vials, oligonucleotide synthesis quality control data from manufacturer, lot number, volume, DNA concentration, date of arrival from manufacturer, and location of vials in storage system. iii. Employ electronic databases into which the contractor shall enter biological sample, DNA and oligonucleotide quality control data either using the keyboard or bar-code readers. iv. Store DNA, DNA oligonucleotides, and other reagents used in sequencing and PCR protocols in refrigerators or freezers as specified to maintain the integrity of all reagents. v. Serve as point of contact at all times in the event of freezer or refrigerator failures, notifying the COR and his/her designates of the need for service and ensuring removal of specimens to appropriate back-up freezers when necessary vi. Provide uninterruptible power supply (UPS) hardware to provide temporary power for all critical servers, data storage equipment in case of power failure affecting the building. UPS power should be sufficient to allow orderly and safe equipment shut down or the transition to emergency power supplied by the owners of the building. The contractor is responsible for obtaining back up cooling for freezers and refrigerators in the event of a prolonged outage. vii. Provide back-ups of all critical data off-site in a certified data storage facility designed to protect stored data from physical (fire, water, power outage) and human threats. e. Employ electronic worksheets into which the contractor shall enter sample identification and quality control data from DNA, oligonucleotides, and other reagents on line either using the keyboard or bar-code readers. 5. Implement and apply methods for genotyping up to 92,000 samples per year in the first two years and up to 150,000 samples per year in years three through five, prepared and submitted by researchers whose applications to use CIDR have been approved by the Board of Governors. Of these samples, 60,000 may be for whole genome association studies requiring between 250,000 and 5,000,000 SNP genotypes per sample in the first two years and up to 50,000 of the 100,000 samples in years 3 through 5 may be for whole genome association studies requiring between 250,000 and 5,000,000 SNP genotypes per sample. For genome-wide association studies assays shall be designed to capture >90% of the variation in human DNA when taking human linkage disequilibrium into account. This measure should be calculated for each of the three major human ancestral groups. 6. Implement state of the art massively parallel DNA sequencing methods (i.e., NextGen Sequencing) to determine the sequence of genomic DNA. Services will include the capacity to carry out whole exome sequencing of human DNA for ~1,000 exomes per year and whole genome sequencing on human and mouse DNA for ~40 samples per year in years one and two. The contractor shall be required to furnish the following ?representative? types of services, as well as additional related activities which may be identified throughout the performance of the contract: a. Employ methods for carrying out genome-wide linkage studies in humans and mice using panels of SNP markers or sample sequencing methods documented to cover the genome (mouse or human) at a density to allow linkage analysis within families. The COR shall specify whether this genotyping method shall be continued at any given time or whether it shall become necessary to change genotyping method. b. Use a panel of SNP assays to produce a genetic unique ?bar code? of all human samples received for genotyping at CIDR as a means of pre-validation of samples designated for either sequencing or SNP genotyping. Analyze these results and flag samples for which there is a gender inconsistency, Mendelian inconsistency (if family structure allows), or failure to generate genotypes of sufficient quality and quantity. Report this information back to Investigator who submitted the sample for replacement or discard at the Investigator?s discretion. Quantitate DNA amount for samples that failed in the barcode reaction. Where appropriate, report this information back to Investigator who submitted the sample for replacement or discard at the Investigator?s discretion. The COR shall specify whether this genotyping method shall be continued at any given time or whether it shall become necessary to change genotyping method. c. Implement a flexible SNP genotyping platform that allows human SNP genotyping using sets of SNPs ranging in number from ~1500 per sample up to between 250,000 and 5,000,000 per sample. The SNPs used may be a standard set used for a number of projects or may be custom designed by the Investigator who has received approval for custom SNP genotyping service. The COR shall specify whether this genotyping method shall be continued at any given time or whether changes in technology render it prudent to change genotyping method. d. Implement a flexible SNP genotyping platform that allows mouse SNP genotyping using sets of SNPs ranging in number from ~380 per sample up to 12,000 per sample. The SNPs used may be a standard set used for a number of projects or may be custom designed by the Investigator who has received approval for custom SNP genotyping service. The standard set of SNPs shall be chosen to be informative between any two pairs of the most commonly used strains of mice. The COR shall specify whether this genotyping method shall be continued at any given time or whether changes in technology render it prudent to change genotyping method. e. Ensure all genotypic data obtained from each individual sample includes, but is not limited to, sample ID number, the marker at which genotype is being determined, and results of genotyping expressed as allele names or DNA sequence base call. When appropriate, each locus should be indentified by its ?rs? number as assigned in the dbSNP database. For each sample analyzed the following will be recorded: quality control variables such as reagent concentrations, reagent lots used, analytical platform or machine used, date of genotyping and the identity of the individuals carrying out the genotyping. Electronic worksheets shall be used for recording genotype quality control data into the database. f. Use or develop software to assign genotypes to data output from genotyping platform. Use additional software and / or human review and adjustment of data as necessary to provide high quality genotypes. If a robust suite of software tools has been developed to flag specific regions of the genome as harboring ?copy number? variation, these regions should be recorded in the datafile. Consult with COR/CSO about the reporting of copy number variation to investigators. g. Collect and store both raw and analyzed genotyping information for later review as needed. The raw data files from NextGen sequencing machines shall be converted into standard data formats before the raw image files are discarded. The COR shall specify the level and kind of raw data to be maintained. Critical data chosen to be archived will be stored as specified above. h. Develop or import and implement software required to read genotype information to allow the direct reading of genotype data into the database. i. Apply all necessary statistical analyses to monitor genotyping data to ensure accuracy, reproducibility, consistency with Mendelian inheritance when samples are from pedigrees large enough to warrant such analyses. Genotypes are to be determined by computer-assisted binning/clustering and other error checking software. j. In special cases, assist Investigators in identifying SNPs in regions or in genes of interest in order to put together a custom SNP genotyping panel for use on their samples. k. For SNP genotyping, produce genotype data for which the error rate (as determined by inconsistency rate between blind duplicates) is less than 0.1%. The inconsistency rate as determined from mendelian analysis must be less than 0.4% when the project supports mendelian inconsistency checking. For fixed content SNP assays, the missing data rate must be less than 2% for human samples, 5% for mouse samples. The contractor will have the ability to provide SNP genotyping results in a CLIA approved manner upon request for clinical studies. l. Upon request, provide the COR with written procedures for preventing DNA cross-contamination, to identify such contamination if it occurs, and to correct the source of contamination and prevent its recurrence. m. Provide access to specialized fixed content SNP genotyping panels including the following: 1) A panel of human immune response genes using ~200,000 SNPs 2) A panel of ~ 200,000 SNPs covering the genes in human metabolism. 3) A ?genotyping? platform capable of measuring DNA methylation in human samples using arrays that cover 10,000 to 250,000 potential sites of methylation in the human genome. 4) Assess and offer new fixed content panels as they become available. n. Provide NextGen DNA sequencing services aimed at the discovery of genetic variation in human and select model organism genomes. Services are to include platforms and reagents capable of producing sequence for the human ?exome.? At a minimum, the exome service will produce data covering the ~1% of the genome that codes for mature mRNA molecules. Additional coverage on the exome arrays can include regulatory sequences and non-protein coding mRNA. Exome sequence data should reliably cover >90% of the targeted area with each region sequenced at a sufficient depth and quality to score allelic, inherited variation. Current accepted minimum coverage is eight, high-quality reads of each called base. This level of coverage may increase as consensus standards for variant calling are developed. Capacity should be available to produce 1,000 exomes per year the first two years. Whole genome sequencing should be offered for human and mouse DNA samples. The resulting whole genome sequence data shall be used for variant scoring and discovery. The coverage and quality of whole genome data will follow the guidelines as outlined above. The "genome" is defined as the human or mouse reference genome provided by NCBI. The genomes of other organisms may be considered for sequencing only if they are consistent with the mission of CIDR and the pre-existing genomic resources for the organism meet a list of criteria developed by the NIH. Sequencing capacity shall be sufficient to produce 40 whole genomes per year in years one and two. The utility, capacity and demand for whole genome sequencing data will be assessed on an ongoing basis. 7. Assist in the implementation and application of computer-based statistical methods to locate genes responsible for mendelian and heritable complex traits in humans. It is expected that not all projects shall require this level of assistance. To provide such assistance, the contractor shall be required to hire personnel and furnish the following ?representative? types of services, as well as other related activities which may be identified throughout the performance of the contract: a. Develop or import from elsewhere statistical methods for analyzing clinical and epidemiological data and the co-inheritance of DNA markers and various complex traits such as, but not limited to, multivariate regression, logistic regression, life table procedures, ANOVA, linkage analysis of discrete traits, quantitative trait linkage mapping, affected pedigree member methods, sibpair methods, identity by state and descent methods, transmission disequilibrium testing, association methods, and other methods developed by the statistical genetics community as specified by the COR. b. Implement statistical methods into usable computer programs either by importing them from elsewhere or by designing and constructing them. Test for power, robustness, and sensitivity by simulation studies and analysis of actual data sets in order to assess their applicability to a variety of complex hereditary diseases. Typical requirements for data analysis include lists, diagrams of pedigrees, cross-tabular and graphic representation of data, statistical analyses with parametric and nonparametric techniques, and multilocus linkage plots with likelihood surfaces, univariate tests of association for dichotomous traits in whole genome association studies. c. Apply statistical methods to identify regions of the human genome that contribute to the hereditary basis of human disease, providing significance testing for how likely such regions are to be involved in disease causation or predisposition. 8. At the end of each study, supply each CIDR user with electronic copies (on CD-ROM, encrypted with FIPS 140-2 validated encryption, detachable hard-drive, secure file transfer or other appropriate media) of genotype or sequencing data and project summary. Data is to be formatted so that it can be imported into standard packages used for statistical genetics, linkage analysis and sequence analysis. In many cases there may be more than one preferred file format required for downstream analyses. The contractor will actively investigate the standards used in the field. Tools to interconvert data formats will be developed or obtained. The contractor shall work with end users on data transfer issues. 9. Work with individual investigators and the curators of public databases (most notably, those curated by NCBI) to ensure compliance with NIH?s data sharing policies. These may be blanket mandates required of all NIH sponsored research or IC specific policies produced by CIDR members. The contractor will deposit any data produced deemed to be covered by a data sharing policy. There are many elements to such datasets. The contractor is not responsible for information that must flow from the investigator directly to the data repository. 10. Document all the individual steps in a specific study, and establish and maintain orderly records of all relevant material so that any aspect of a study can be reviewed by Government staff at any point during its course. Typical documentation shall include, but are not limited to, the following a. Up-to-date electronic records of all data as specified above. b. Maintain log of scientific decisions made during the study that affect the study design, conduct, or analysis. c. Refer all decisions that affect changes in the original estimated cost of a study (task) or its time schedule to the COR for approval and to the Chairperson of the Board of Governors (BOG) or his/her designee for consultation with the BOG representative of the Institute supporting the study. 11. Provide as an optional service, at the discretion of the COR, the opportunity for Investigators who gain access to CIDR services to have SNP genotyping data generated in a laboratory that has received CLIA (Clinical Laboratories Improvement Amendments) certification. The menu of CLIA approved services may expand. The structure of these services should be consistent with those being used in support of research studies. The contractor shall provide written documentation that CLIA approval for a specific set of methods has been applied for before undertaking such studies requiring CLIA approval. The contractor is responsible for providing staff with the credentials required by CLIA.