Att 3 - SOW final.pdf

Attachment 3 – Statement of Work

Statement of Work

I. Background information and Objectives

a. BACKGROUND

Substance use disorders (SUD) comprise a broad category of complex phenotypes that constitute a major public health challenge. The etiology of SUD encompasses genetic and environmental components, hampering the identification, validation, replication, and functional assessment of genetic-based therapeutic targets. However, new technological and scientific breakthroughs hold tremendous promise to tease out the underlying genetic and epigenetic signatures associated with SUD, including single nucleotide polymorphisms (SNPs), chromatin interactions, gene expression differences, rare variants, copy number variants, functional SNPs, indels and large chromosomal rearrangements. These technological advances, along with emerging methods to measure environmental exposures and generate human reprogrammed cellular derivatives (i.e., induced pluripotent stem cells (iPSC)), have the potential to increase our understanding of the etiology of SUD and accelerate the development of new therapeutic compounds and predictive/diagnostic tests.

In September 1998, National Institute on Drug Abuse (NIDA) issued a Request for Applications (RFA) entitled "Genetics of Drug Addiction Vulnerability," (RFA DA-99-003). This RFA sought to define chromosomal domains that confer susceptibility to SUD as a crucial first step in the effort to identify the genetic causes of SUD. Subsequent initiatives include program announcements (PA) entitled, "Molecular Genetics of Drug Addiction Vulnerability," "Fine Mapping Gene Variants for Drug Addiction Susceptibility in Humans," "Genetic Epidemiology of Substance Use Disorders," "Functional Genetics and Genomics of Drug Addiction," "Functional Genetics, Epigenetics, and Non-coding RNAs in Substance Use Disorders," "Discovering Novel Targets: The Molecular Genetics of Drug Addiction and Related Co- Morbidities," "Gene-Environment Interplay in Substance Use Disorders," a Program Announcement Special Review (PAR) entitled, "Avenir Award Program for Genetics or Epigenetics of Substance Use Disorders," and a Request for Applications (RFA) entitled "Functional Characterization of Genetic Variants and their Interactions: The Genes, Environment, and Health Initiative, Notice of Special Interest (NOSI): Human Molecular Genetics of Substance Use Disorders."

For SUD and other genetically complex diseases with modest genetic effect sizes, data sharing is often necessary to achieve sample sizes with adequate statistical power to detect genetic associations and prioritize potentially causative mutations. Through the creation and expansion of the NIDA Center for Genetic Studies (NCGS), NIDA has widely distributed the data and biologic materials collected from these initiatives and other projects to qualified investigators within the scientific community. This central facility will reduce the overall cost both to NIDA and to NIDA's investigators funded to do research on the genetics of SUD. The NCGS has thus far collected data and immortalized cell lines from over 85,000 individuals with approximately 450,000 biological samples.

The programmatic goals of this initiative are 1. Encourage and/or require more data-sharing (e.g.

combining DNA samples and phenotyping efforts) to achieve sufficiently high numbers of subjects such that studies are sufficiently powered to identify genetic variants and epigenetic modifications; 2. Provide a resource for deep genotyping, sequencing, and phenotyping to facilitate the identification of variants underlying SUD; 3. Harness the scientific value of pre-existing and future repository resources will help move the field of addiction genetics forward.

As the NCGS matures, biological big data sources hold the promise of revolutionizing molecular biology by providing critical information from state-of-the-art genomic sequence, gene expression experiments, and in silico comparative genomic studies directly relevant to substance use and abuse. Finally, a genomic cyberinfrastructure that enables interoperability and full access to distributed data, software and other information science resources by the scientific community will be essential to improve research productivity and enable scientific breakthroughs not otherwise possible.

b. OBJECTIVE

The objective of this contract is to maintain and expand the NCGS as a repository to:

(1) Receive de-identified clinical, diagnostic, pedigree structure, environmental exposure information and other phenotypic data along with blood samples or other biospecimens (e.g.

blood, cell lines, skin fibroblasts, DNA, RNA, serum, saliva, hair, urine, fecal matter) from funded grants and/or contracts supporting research on the genetics of addiction and addiction vulnerability;

(2) Process these data and materials to create databases, serum, DNA, RNA, and cell lines;

Widely distribute all data and materials in the NIDA Human Genetics Initiative to qualified investigators in the scientific community in a cost-effective manner;

(3) Maintain storage of data and biospecimens;

(4) As stipulated by NIDA staff, perform microarray typing on pre-existing and/or new de-identified biospecimens;

(5) As stipulated by NIDA staff, perform state-of-the-art* sequencing on pre-existing and/or new de-identified biospecimens for genomic and/or epigenomic analyses in bulk tissue and single cells;

(6) As stipulated by NIDA staff, perform state-of-the-art* sequencing on pre-existing and/or new de-identified biospecimens for RNA transcriptome analyses in bulk tissue or single cells;

(7) As stipulated by NIDA staff perform state-of-the-art* chromatin capture, chip-seq, as cut and run sequencing.

(8) Support the creation of reprogrammed cellular derivatives, such as induced pluripotent stem cells (iPSCs) to facilitate the molecular and cellular study of brain development and addiction processes;

(9) Create a cyberinfrastructure that enables interoperability and full access to distributed data, software and other information science resources as well as research summaries and outbound links for all addiction related studies available through the NIH database of Genotype and Phenotype (dbGaP) system; Develop advanced encryption methods that allowing linking of data in the repository to other types of data.

(10) Facilitate NIDA genetic studies data (both genotype and phenotype) being uploaded into NIH databases such as BioSample, and the dbGaP systems.

*For proposal purposes, please note that the state-of-the-art technologies may change as technologies change which will drive down costs – Offerors should identify what state of the art technologies are.

II. Services to Be Performed

a. GENERAL REQUIREMENTS

Independently, and not as an agent of the Government, the Contractor shall furnish all the necessary services, qualified personnel, material, equipment, and facilities, not otherwise provided by the Government, as needed to perform the following tasks on data and biological materials received from grants and/or contracts supporting research on the genetics of addiction and addiction vulnerability.

(1) The Government Contracting Officer's Representative (COR) shall monitor all work under this contract. See Section G of the contract, which defines this position;

(2) Receive, process, and store de-identified biospecimens. Biospecimens includes blood and saliva as well as other biospecimens that include but are not limited to urine and fecal matter;

(3) Extract DNA and RNA, from serum, peripheral blood mononuclear cells (PBMCs) isolated from fresh whole blood specimens, fibroblastoid cell lines, or other biospecimens;

(4) Freeze and store DNA, serum, and cryopreserve PBMCs, fibroblastoid cell lines, whole blood or other biospecimens, as described;

(5) Transform cryopreserved whole blood or isolated PBMCs to lymphoblastoid cells using the Epstein-Barr virus (EBV) transformation protocol, if required;

(6) Transform fibroblasts cell punches into fibroblastoid cell lines, if required;

(7) Amplify cellular density utilizing irradiated feeder technology in a high throughput manner when needed;

(8) Collect, maintain, store, and distribute de-identified clinical and biological data; Develop advanced encryption algorithms to facilitate integration of data in the repository with other types of data.

(9) Perform DNA/RNA genotyping and/or State-of-the-art* sequencing on bulk tissue and in single cells at the request of the COR;

(10) Assay epigenetic modifications and protein-DNA interactions in bulk tissue and in single cells at the request of the COR;

(11) Make all applicable electronic information technology materials Section 508 compliant.

The purpose of this contract is to provide resources to support the NCGS. NIDA reserves the right to have the contracted services benefit NIDA and any other component of the National Institutes of Health (NIH).

b. SPECIFIC REQUIREMENTS

(1) Receive de-identified clinical, diagnostic, environmental exposure information, and other phenotypic data. When applicable, also include pedigree structures. These data should be incorporated into phenotypic databases suitable for immediate genetic analyses.

Phenotypic Data - The Contractor shall receive electronic files, consistent with NIH and NIDA data sharing plans, in American Standard Code for Information Interchange (ASCII) or another format (e.g., SAS system file) of diagnostic and pedigree structure information (when applicable), environmental exposure information and of comprehensive clinical data obtained from the administration to subjects of a structured diagnostic interview (e.g., Diagnostic Interview for Genetic Studies). The Contractor will receive data without personal identifiers and thus unlinked to their sources; such materials are "anonymous" and de-identified samples. In collaboration with staff on the projects where the data were collected, the Contractor shall carefully verify all information in the database needed to establish pedigree structures and final best estimate diagnoses.

The Contractor shall maintain all phenotypic data in a relational electronic database (e.g., Oracle) in a format that permits rapid and efficient production of files for distribution. A file of pedigree structure, when applicable, produced from the databases shall be immediately suitable for linkage, association, and other genetic analyses. Given that this is a highly detailed and complex task, the Contractor shall ensure the project is staffed at all times by personnel who are recognized experts in creating such files and in conducting statistical genetic analyses published in peer-reviewed scientific journals.

The Contractor shall receive de-identified data obtained from any and all genetic analyses of these materials, for incorporation into genotypic databases.

Genotype and Sequencing Data - When genotyping has previously been conducted by the submitting scientific investigator, the Contractor shall minimally receive electronic files of all available genotypes or sequences completed for each uniquely coded subject and also DNA marker names, allele sizes in base pairs and corresponding frequencies, and relative map distances for each marker. The Contractor also shall receive results from sequence and mutation analyses, functional variant characterizations and from any and all other genetic analyses performed on these data and biological materials (for example, microarray data).

The Contractor shall maintain all of these genotyping data in electronic databases in a format that permits rapid and efficient production of files for distribution. A file of genotypic data produced from the databases shall be immediately suitable for linkage and other genetic analyses. Given that this is a highly detailed and complex task, the Contractor shall staff the contract at all times by personnel who are recognized experts in creating such files and in conducting statistical genetic analyses published in peer-reviewed scientific journals.

(2) Receive de-identified blood samples collected from patients and their relatives.

Harvest serum and peripheral blood mononuclear cells (PBMCs), and if sufficient numbers of PBMCs, extract DNA with possibility for RNA extraction. Saliva samples and other biospecimens may be received on occasion for DNA and RNA extraction, and/or for purposes of storage.

The Contractor shall harvest serum from blood and extract DNA and possibly RNA from blood or PBMCs or other biosamples for storage.

The Contractor shall receive and process blood tubes drawn at one encounter from each subject and shall harvest serum and DNA from at least half of the sample. If sufficient PBMCs are available, extract DNA, and when requested RNA, from the vial of whole blood and freeze at least three vials of fractionated PBMCs. If needed at a later date, lymphoblastoid cell lines shall be possible in at least 95% of the frozen PBMC samples.

Serum and DNA shall be extracted in sufficient quantities for analysis (i.e. 200 microliter aliquots of serum and 30-400 micrograms of DNA). In addition, in such cases where DNA amounts get low due to high use and transformation attempts have failed or blood may not be feasible, the COR may request the Contractor to perform whole genome amplification and blood spot, serum, or saliva DNA extraction. These instances are expected to be rare;

however, the Contractor shall have sufficient expertise to cope with these potential occurrences.

The Contractor shall extract DNA and possibly RNA, bacteria, proteins, metabolites from other biosamples.

The Contractor shall receive and process biosamples from each subject and extract DNA, RNA, bacteria, proteins, metabolites as directed by the COR.

(3) Transform lymphocytes with a success rate greater than 95%.

When quantities of PBMCs are not sufficient for DNA extraction, high quality EBV transformed cell lines shall be attempted. Lymphoblastoid cell lines should be possible in at least 98% of the samples.

(4) Maintain, store, and distribute serum, DNA, RNA, cell lines, biosamples and files in databases for immediate genetic analyses by qualified investigators granted access by the COR to these data and materials. At the COR’s direction, the Contractor shall distribute these, and other biospecimens to qualified investigators.

Access to Data and Biological Materials - The Contractor shall obtain approval from its Institutional Internal Review Board and shall operate in accordance with Department of Health and Human Services regulations specified in 45 CFR Part 46 regarding protection of human subjects as these are applied to the distribution of data and biological materials to qualified investigators for purposes set forth in this contract. In addition, although all samples are de-identified and fall under exemption from Institutional Review Boards, the Contractor should obtain a certificate of confidentiality as an added assurance.

Investigators and collaborators who contributed data and biospecimens to the Repository at the NCGS shall be granted access to their own data in the Repository, as well as other data and biological materials maintained by the Contractor under one of two conditions: (1) the investigator receives funding under a peer-reviewed NIDA research grant application and/or contract to analyze these data; or (2) NIDA certifies the investigator as qualified.

The Contractor shall provide clinical, diagnostic, and pedigree structure data, environmental exposure and other phenotypic information, as well as DNA samples, serum, and other biospecimens , including cell lines and/or RNA, to all researchers who have been granted access by NIDA.

Use of Materials by Contractor - The Contractor shall not use data, serum, DNA, RNA or cell lines for any purpose, other than that specified in this contract, without written approval of the COR.

c. SPECIFIC TECHNICAL REQUIREMENTS

All the data and biological materials to be created, maintained, and distributed under the SOW for this contract shall be included under the rubric of the NIDA Center for Genetic Studies.

Descriptive information on the Center is available on the Internet at http://www.drugabuse.gov/about-nida/organization/workgroups-interest-groups-consortia/genetics-workgroup-gwg/nida-genetics-consortium-ngc. The Contractor shall receive all of the current data and biological materials currently existing in the Center and integrate it with the data and biological materials received and created over the life of this contract. The Contractor shall perform all services of the contract as specified in the tasks listed below, as directed by NIDA through NIDA's issuance of task orders.

There are two main components to this SOW; each is listed next to each task. Component A is biospecimen processing and Component B is data management. Note that Component A has two paths, Path 1 and Path 2.

For proposal purposes, Offerors shall propose for both paths. Please see Task 5 for additional details.

Task 1 (A and B) - Work Plan

The Contractor shall meet with the COR and Contracting Officer within 2 weeks of contract award to finalize a Work Plan.

Task 2 (A and B) - Receive and store existing biological materials and clinical data, and NIDA equipment; store new samples

To maintain continuity of sample processing, storage, and dissemination, the Contractor shall ensure that ample space exists to process and store samples.

For proposal purposes, the number of samples is 600,000, including up to 450,000 samples stored under the previous contract. MTAs must state that any biosamples transferred to the NIDA Center for Genetic Studies are the property of the United States Government for use of the entire scientific community.

Task 3 (A and B) - Preparation

The Contractor shall perform the following tasks:

(1) Prepare blood collection kits as needed for shipment to NIDA investigators. Recipients will use the kits to send whole blood samples of approximately 30 milliliters to the Contractor via overnight express delivery. The Contractor shall pay for and charge to the contract all shipments of blood from these projects.

(2) Accept blood samples and or biosamples and clinical data from investigators approved by NIDA to send and access samples. The COR will notify the Contractor of these investigators.

For proposal purposes, we do not expect this to be a frequent occurrence.

(3) Submit a protocol for receiving, storing, and distributing biospecimens other than blood, The COR will review and approve the final protocol, which will be in place within 4 calendar weeks after the contract award. Protocols shall be updated as technology becomes available.

(4) Within 4 calendar weeks of contract award, receive from the COR all contract information for each of the grants and/or contracts awarded by NIDA supporting research on the genetics of drug addiction and addiction vulnerability that will provide data and blood samples at the time of the contract award.

(5) Within 2 calendar weeks of contract award:

a. Submit a detailed protocol for quality control measures to ensure that if EBV transformed cultures are generated, that they remain free of contamination by bacteria, mycoplasma, yeast, and other agents, and to prevent sample mix-ups.

These protocols shall include cost-effective and efficient means of quality control procedures (e.g. pooling samples to test for mycoplasma, while retaining high sensitivity and specificity). The COR will review the final protocol, which will be in place within 4 calendar weeks after the contract award. Protocols shall be updated as technology becomes available. The Contractor will be responsible for obtaining approval from the COR of updated protocols.

b. Submit a draft protocol for quality control to ensure that both acceptable safety standards and the viability of biological materials are maintained during shipping.

The COR will return the draft within 1 week of receipt. The Contractor shall obtain COR approval of the final protocol before receiving any blood under the contract.

c. Submit the data management protocol to ensure the creation of processing algorithms and software needed for the creation of phenotypic and genotypic databases.

Task 4 (A) - Unique Identification (ID) Numbers

The Contractor shall make certain all ID numbers are communicated to all the appropriate parties during contract performance.

The Contractor shall:

(1) Consecutively assign a unique Cell Repository ID number to each subject on whom a blood sample or other biospecimens is received (should be the same as the ID used for the clinical data, etc.)

(2) Assign a unique site ID number to each project with NIDA grants and/or contracts supporting research on genetics of addiction and addiction vulnerability. All subjects for whom clinical data are received from that project shall also be assigned this site ID number.

(3) Assign a unique subject ID number to each subject on whom clinical data are received from each project supporting research on genetics of addiction and addiction vulnerability through NIDA. This shall represent a concatenation of the site ID number and subject ID number assigned by each project, and shall result in an ID number that is unique within the entire database of all subjects across all projects.

(4) Use the unique Cell Repository ID and concatenated subject/site IDs to retrieve all data for a subject across databases of clinical, diagnostic, pedigree structure, and other phenotypic information along with genotype data, and shall be used by qualified investigators to request biological materials.

Task 5 (A) - Establish and store DNA, RNA, serum, and other biospecimens as directed by the COR, and, if required, permanent cell lines from blood or other biospecimens. The execution of this task is divided into two paths (Path 1 and Path 2) where the specific path is dependent on the quality of blood received (see flow diagram, below), unless otherwise requested by the COR.

The Contractor shall:

(1) Receive a blood sample of approximately 30 milliliters drawn at one encounter from each subject. The Contractor shall be responsible for the shipping costs to receive blood samples.

(2) Fractionate the blood, harvest the serum/plasma, and visually inspect the peripheral blood mononuclear cell pellet. Depending on number of tubes and the appearance of the cell pellet, proceed with the following tasks:

a. 2 Acid Citrate Dextrose (ACD) and 1 Ethylenediaminetetraacetic acid (EDTA):

Isolate PBMCs from the ACD tubes; DNA and plasma from the EDTA tube. If the fractionated PBMC pellet appears sufficient, immediately cryopreserve PBMCs (PATH 2). If the pellet is small, immediately transform with EBV (PATH 1).

b. 1 ACD and 1 EDTA: Isolate PBMCs from the ACD tube; DNA and plasma from the EDTA tube. If the fractionated PBMC pellet appears sufficient, immediately cryopreserve PBMCs (PATH 2). If the pellet is small, immediately transform with

EBV (PATH 1).

c. 2 ACD: Immediately transform with EBV and extract DNA from the transformed cell line (PATH 1) if pellet is small. There will be no plasma available.

d. 1 ACD: Immediately transform with EBV and extract DNA from the transformed cell line (PATH 1). There will be no plasma available.

(3) If cell lines are made, be responsible for:

a. The transformation of lymphocytes, including pooled polymerase chain reaction (PCR) or hybridization to test for contamination by mycoplasma, etc.

b. The storage of cell lines, including three or more backup vials per sample.

c. The regrowth of cell lines for DNA. Cell lines shall be expanded up to 1 x 109 for isolating DNA.

d. Any and all other tasks needed to establish and store cell lines.

(4) Establish high-quality lymphoblastoid cell lines with a minimum success rate of 95%, and shall be free of contamination by bacteria, fungi, mycoplasma, other cells, etc. The work plan shall also specify actions that shall be taken to maximize the transformation success rate and to ensure that it is maintained at a minimum of 95% during the performance of the contract.

(5) For backup, cryopreserve a portion of the whole blood or PBMCs received from each subject in the event of transformation failure or sample mix-up issues.

(6) Document in the work plan the precise transformation methods that will be employed, a rationale for their selection, reliability, feasibility, and documented evidence the method has been successful (minimum success rate of 95%) in a sufficiently large number of samples.

(7) Detail how cell cultures will be grown and divide each of these cell cultures among a number of ampules as required to maintain an adequate level of access to the cell lines (3-6 vials).

These will be frozen and stored in two locations, under conditions to retain the maximal viability.

(8) Ensure the DNA, RNA, serum, PBMCs/cell lines, and other biospecimens are linked to the associated clinical data, but not linked to the individual.

Task 6 (A) - DNA Extraction

The Contractor shall isolate, prepare, and store DNA from each blood sample or other biospecimen, and all other tasks required to extract, prepare, and store DNA not covered above.

Task 7 (A) - Serum Isolation and Storage

The Contractor shall:

(1) Upon fractionation, aliquot serum/plasma into up to (for proposal purposes) 10 vials of 200 microliters each.

(2) Store the serum/plasma so there are vials in different freezers and the vials are stored in an environment conducive for the greatest viability to be maintained until and through distribution.

Task 8 (A) - Cell Line Transformation Failures, Corrective Action, and Quality Control

Technical problems and high failure rate may arise when establishing cell lines from blood samples that are from immunocompromised subjects.

The Contractor shall:

(1) Have the ability to use available technology to enhance viability of cell line creation when alternative technologies do not work.

(2) Report these difficulties to the COR within 2 calendar weeks of the determination of failure and shall request the issue be addressed through consultations between the Contractor, COR and the investigator providing the samples. Additional blood from the subject may be requested/submitted in these cases.

(3) Detect and correct, as rapidly as possible, any problems in the Contractor's protocols that are responsible for transformation failure and closely monitor its success rate.

(4) Compare the DNA samples obtained from a subsequent cell line expansion against the sample obtained from the previous cell line expansion. This shall be done in every case to confirm that both DNA samples were derived from the same individual.

(5) Maintain a suitable off-site facility (this need not be a separate building but must include separate storage facilities and power source) for storage of an adequate number of vials of each cell line as a safeguard against accidental loss of cell lines. The back-up vials of each cell line will be sent to the off-site facility at the time they are ready for storage, thus allowing for parallel storage of all cell lines in the Repository. The lines will be stored at both sites for the life of this contract. All contract provisions applying to the use and handling of biological material in the Contractor's facility shall apply to any and all biological materials stored at the off-site facility.

(6) Create resources to extract DNA and/or RNA from these cell lines and other tissues for analysis of transposable elements, mobile DNA, and epigenetic modifications.

Task 9 (A) - Final (Laboratory) Verification of Pedigree Relationships and other Phenotypic Data Required for Sample Submission where Family Data Exist

The Contractor shall:

(1) Specify a cost-effective protocol for genotyping subjects on a predetermined set of markers, and submit it to the COR for approval. For approximately every 100 pedigree samples, 5% of subjects for whom blood is received shall be tested for Mendelian consistency.

(2) In circumstances where genotyping results are inconsistent with pedigree structure or other phenotypic information as provided by the grantee and/or contractor who collected the data, exchange information with the project staff who provided the pedigree structure information.

The Contractor shall work with project personnel to resolve the cause for the discrepancy, i.e., sample mix-up, Mendelian inconsistencies, etc. Include these instances as a category in the Contractors monthly progress report.

(3) In circumstances where genotyping results are inconsistent with pedigree structure or other phenotypic information as provided by the research project in which the data were collected, and only when scientifically appropriate, contact the research project and request a blood re-draw. Include these instances as a category in the monthly progress report.

(4) Upon resolution of the inconsistency between the genotyping results and the initial pedigree structure provided by a grantee and/or contractor, use the results from genotyping analyses to update and modify pedigree structure in all databases. If resolution is not obtained, discard data on the subject, modify databases accordingly, demarcate the subject, or pursue another course of action, as directed by the COR. Include these instances as a category in the monthly progress report.

(5) Catalog all inconsistencies in pedigree structure that are detected by qualified investigators gaining access to data and materials and who provide genotyping results to the Contractor.

The Contractor shall use the results from these genotyping analyses to update and modify pedigree structure in all databases.

Task 10 (A and B) - Distribution of De-Identified Data and Biological Materials

All investigators given access to data and biological materials shall be approved by the COR, in accordance with the most recent procedures described on the Internet at http://www.drugabuse.gov/about-nida/organization/workgroups-interest-groups-consortia/genetics-workgroup-gwg/nida-genetics-consortium-ngc.

All NIDA approved investigators given access to data and biological materials shall sign the most recent version of the Distribution Agreement available at http://www.drugabuse.gov/about-nida/organization/workgroups-interest-groups-consortia/genetics-workgroup-gwg/nida-genetics-consortium-ngc. Along with NIDA, the Contractor shall be a co-signatory of each Distribution Agreement.

The COR retains the right to modify existing access procedures and the Distribution Agreement.

Any and all data (clinical, diagnostic, pedigree structure, environmental exposure and other phenotypic information, along with genotypic information) and biological materials (cell lines, DNA and/or RNA samples) shall be distributed by the Contractor to grantees and/or contractors upon written request from the grantee/contractor with a copy to the COR. Other qualified investigators may gain access only upon written authorization of the COR and in accordance with current state or Federal laboratory procedures assuring appropriate usage of genetic material. Data and biological materials shall be provided to recipient biomedical research organizations and not to individuals.

The Contractor shall:

(1) Distribute, within 2 calendar weeks of request by the COR, high-quality documentation and data files in ASCII or other formats (e.g. SAS system files) that have been most recently updated.

(2) This shall include the following:

a. Updated and verified diagnostic and pedigree structure (when applicable) and environmental exposure and other phenotypic information;

b. Comprehensive clinical information from a structured diagnostic interview;

c. Genotypic information from all qualified investigators given access to data and biological materials;

(3) Complete documentation of all variables and their coding.

(4) Prepare data for dbGaP and/or NIH BioSample submission on an as needed basis.

(5) Develop and maintain a secure password-protected site on the Internet, to permit the rapid and efficient distribution of electronic data files to qualified investigators granted access by the COR.

(6) Distribute high-quality biological materials. These include the following:

a. Lymphoblastoid cell lines;

b. At least 30 micrograms of DNA per aliquot;

c. Serum in appropriate aliquots; and

d. RNA, when requested.

(7) Submit a fixed price schedule along with the work plan that specifies the cost per DNA, serum, RNA, cell line sample, and other biosamples for shipment to qualified investigators.

This work plan shall include the following:

a. Frozen (dry ice) shipments of biological materials (viable cells and RNA).

b. Room temperature shipments of biological materials (extracted DNA).

(8) Distribute materials.

NIDA will provide DNA samples to each of the grantees and/or contractors that provide blood samples or other biospecimens and data to the Contractor.

(9) Ship cell lines and/or DNA samples to requestors approved for access by NIDA within 2 calendar weeks of receipt of request by the Contractor.

(10) Package and ship biological and hazardous materials in accordance with all state and Federal safety and shipping regulations, and with the Center for Disease Control procedures for packaging and shipping biological materials.

The Government shall retain ownership of cell lines and all equipment used to store the cell lines, as well as all other products (e.g., DNA, RNA, serum, databases, and documentation) produced under this contract.

Task 11 (B) - Receipt of De-Identified Data from Qualified Investigators

The Contractor shall:

(1) Execute Distribution Agreements which stipulate that qualified investigators who receive data and biological materials from the Contractor are obliged to provide to the Contractor the results of any and all genetic analyses derived from these data and materials 12 months after their award has expired or after publication, whichever comes first.

(2) Receive comparable data from future research projects supported by NIDA.

(3) Develop and provide to the qualified investigator submitting data a precise electronic format by which these data are to be received.

(4) Index all data by the unique concatenation of the subject and site ID number.

(5) Receive from qualified investigators data relevant to the establishment of paternity and laboratory verification of pedigree structure.

(6) Rapidly and efficiently incorporate all verified data received from qualified investigators into existing clinical, diagnostic, pedigree structure, environmental exposure and other phenotypic information, and genotypic databases. In some instances, this will require simply interfacing with other databases of large data sets (for instance with microarray data and imaging data).

(7) Distribute these data to other qualified investigators requesting access who are approved by

NIDA.

(8) Link to dbGaP and NIH data sharing policies.

Task 12 (B) - Qualified Investigator Database

The Contractor shall maintain a database of information about qualified investigators given access by NIDA who receive data and biologic materials. The database shall include:

(1) Minimally for each investigator, the following information: name and title of the research project's PI, mailing address, telephone and fax number, e-mail address, and recipient institution.

(2) For each investigator, the date of access notification given by NIDA to the Contractor, the number of DNA samples and/or other biological materials provided, the repository ID numbers of subjects from whom cell lines, serum, and DNA (and/or RNA) were sent, the date when genotypic data were requested, and the data when genotypic data were shipped.

(3) Continuously updated information including, but not limited to, subsequent shipments of DNA, and/or RNA and/or cell lines and serum. These updates shall be included in monthly reports to COR.

(4) Creation and maintenance of an e-mail list of all qualified investigators to enable rapid and efficient electronic communication among the investigators, the Contractor, and the COR.

Task 13 (B) - Clinical, Diagnostic, Environmental Exposure, Pedigree Structure, and Other Phenotypic Databases

The Contractor shall:

(1) Create an interface within the database that allows investigators (limited access and password protected) or administrators (total access and password protected)

(2) Receive on a regular basis from NIDA grants and/or contracts supporting research on genetics of addiction and addiction vulnerability electronic files in ASCII or another format (e.g., SAS files) containing clinical, diagnostic, environmental exposure and other phenotypic information, and pedigree structure information for all individuals for whom blood or other biospecimens has been received and includes all biological material available for distribution.

(3) Maintain separate databases for addiction to different drugs and co-morbid disorder on which data are contributed from the NIDA research grants and/or contracts.

(4) Create and maintain a database of clinical, diagnostic, environmental exposure and other phenotypic information, and pedigree structure (if a pedigree structure exists) information that for each subject minimally includes:

a. Subject ID number

b. Family ID number

c. Site ID number

d. Parental ID numbers

e. Sex

f. Death Status

g. Ethnicity (Geographic origin of ancestry)

h. Age

i. Twin status (if applicable)

j. Environmental exposure information (if applicable).

k. Final best estimate of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-IV and DSM-V) diagnosis for drug abuse and if applicable psychiatric disorders.

l. Quantitative measures (such as quantity/frequency, duration of exposure, impulsivity, biomarkers etc.) and PhenX.

m. Sources of information to establish diagnosis (medical records, interview, etc) and best estimate of the age at onset of illness.

(5) Create a database sufficient to contain all clinical information derived from administration to subjects of a structured psychiatric diagnostic interview.

(6) Maintain and include all other phenotypic data provided by investigators.

(7) Maintain all data without personal identifiers. Data, serum, DNA, and PBMCs, other biospecimens and RNA, are unlinked to their original sources, but linked to each other.

Task 14 (B) – Pedigree Verification (when applicable)

The Contractor shall:

(1) Initially verify that data are suitable for immediate genetic analysis. Verify pedigree structure provided by grantees and/or contractors, such that generated data files will not produce fatal errors in existing pedigree structure verification programs currently available; e.g., MAKEPED in the LINKAGE package, FSP in the SAGE package.

(2) Exchange information with grantees and/or contractors and their staff who collected the data, in order to verify all diagnostic and pedigree structure information as described in Task 13 (3).

(3) Not verify the extensive array of clinical information derived from the administration of a structured psychiatric diagnostic interview to subjects, as described in Task 13.

(4) Grantees and or contractors who collect such data shall be responsible for the verification of it.

Task 15 (B) - Genotypic Databases

The Contractor shall:

(1) Ensure the receipt, if available, of electronic files containing genotypic data from research grants and/or contracts supported by NIDA, and also from qualified investigators in the wider scientific community who gain access to data and biologic materials. These results include, but are not limited to, genetic analyses such as: genotypes for each subject, DNA marker names, allele sizes in base pairs and corresponding frequencies, relative map distances for each marker, and functional variant characterizations and biological implications.

(2) Create an extensive relational database (e.g., Oracle) of such genotypic data from each subject that includes:

a. DNA marker names, allele sizes in base pairs and corresponding frequencies, and relative map distances, for genotyping projects

b. Gene sequence

c. Mutation analyses results

d. Functional characterization results

e. Results from any and all other genetic analyses of data and biologic materials

f. dbSNP, LocusLink, and/or UniGene reference, dbGaP, etc.

g. Number of samples tested

(3) Provide grantees and/or contractors, and other qualified investigators sending data, a precise file format (e.g. ASCII, SAS system file) to assure that the data may be easily and rapidly incorporated within the Oracle genotypic databases maintained by the Contractor.

Task 16 (B) - Database Quality Control and Updates

The Contractor shall:

(1) Maintain accurate databases that are regularly updated and verified.

(2) Thoroughly document all variables and updates, changes, or corrections to database information and note changes in the monthly report to the COR.

(3) Organize databases so as to permit rapid and efficient downloading and uploading of information.

(4) Assure that ASCII files and other formats (e.g. SAS system files) can be rapidly and efficiently generated from all databases.

(5) Maintain a daily back up of all electronic databases to protect against accidental data loss.

(6) Provide a format for all public data to be queried.

(7) Facilitate NIDA genetic studies data (both genotype and phenotype) being uploaded and housed in the NIH dbGaP system.

TASK 17 (B). Develop advanced encryption methods that allow integration of data in the NIDA Center for Genetic Studies with other data types but maintain confidentiality

Task 18 (A and B) - Provision of Data Updates

The Contractor shall rapidly and efficiently distribute updates via a secure password-protected site on the Internet. The updates shall include, but are not limited to, changes in clinical data, diagnostic status, pedigree structure, other phenotypic information and recently received genotypic data provided by other qualified investigators.

Task 19 (B) - Internet Resources

Access procedures, descriptive data, and other relevant information about the data and biological materials currently distributed through the NIDA Human Genetics Initiative are described on a site maintained by NIDA on the Internet at http://www.drugabuse.gov/about-nida/organization/workgroups-interest-groups-consortia/genetics-workgroup-gwg/nida-genetics-consortium-ngc. The Contractor shall:

(1) Maintain pages on the Internet that link to NIDA's web pages.

(2) Maintain on an Internet site with descriptive information about the NIDA Human Genetics Initiative databases created and maintained by the Contractor. The website shall be compliant with FAIR (Findable, Accessible, Interoperable, and Reproducible) principles. This information shall minimally include the following:

a. number of pedigrees

b. number of affected sibling pairs

c. number of affected subjects with DNA available

d. numbers of sibships of varying sizes of affected subjects

e. number of samples with environmental exposure information

f. complete cross-referenced list of the available biological samples

g. any other meta-data

(3) If other research designs are employed such as case-control studies, the Contractor shall provide:

a. number of individuals enrolled in the study

b. number of affected subjects with DNA, or other biological material available

c. diagnostic information of the subjects enrolled in the study

d. Documentation and display of availability of individuals with similar phenotypes

e. Database that is searchable by phenotype and provides links to dbGaP or other NIH-designated repository, such that meta- or mega-analysis can be performed.

f. These pages shall be updated at least monthly.

(4) Create and maintain a research summary page highlighting all of the publically available addiction related genetic studies housed within the dbGaP system.

(5) Maintain link to dbGaP (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gap), P3G Observatory (http://www.p3gobservatory.org/), NIDA Networking Project (http://nnp.drugabuse.gov/), NIH GWAS policies (http://grants.nih.gov/grants/gwas/index.htm), and others that are deemed appropriate in consultation with the COR. Maintain a link to Neuroscience Information Framework https://neuinfo.org/.

(6) Maintain list of publications by all NIDA Genetics Consortium members with links to manuscripts.

Task 20 (A) - RNA Isolation

(1) Only by request of the COR, the Contractor shall isolate RNA from existing de-identified project samples from either bulk tissue or single cells.

(2) The Contractor shall isolate, prepare, and distribute RNA from the requested samples, and all other tasks required not otherwise covered above in Task 5.

(3) Maintain a Gantt chart or other project management system detailing progress of processing samples and submission of data to dbGAP or another repository as directed by the COR.

Task 21 (A and B) - Microarray Genotyping

(1) If directed by the COR, the Contractor shall conduct microarray genotyping, such as the smokescreen array or other relevant platforms, on isolated DNA and/or RNA from new and/or existing de-identified project samples and facilitate the storage of the accompanying data into publically accessible databases such as NIH dbGaP.

(2) The Contractor shall isolate, prepare, and distribute DNA and/or RNA from the requested samples, and all other tasks required not otherwise covered above in Task 5.

(3) Within 4 calendar weeks of the contract award the contractor shall provide a workplan and timeline for microarray genotyping as well as for submitting genotype and phenotypic data into publically accessible databases such as NIH dbGAP after having received all phenotypic data and samples.

(4) Maintain a Gantt chart or other project management system detailing progress of processing samples and submission of data to dbGAP or another repository as directed by the COR.

Task 22 (A and B) - State-of-the-art Sequencing

(1) Within 4 calendar weeks of the contract award the contractor shall provide the method for variant calling, sequence alignment, and efficiency of querying gene variants. The method used to assess sequence quality and accuracy should be described. The contractor should also describe the analyses and tools to store reads, assemblies, variants, and annotation of sequence data. The Contractor should provide instructions on how to analyze the data from files that are returned to the principal investigator. The Contractor shall obtain COR approval of the protocol before beginning work.

(2) If directed by the COR, the Contractor shall conduct State-of-the-art sequencing on isolated DNA and/or RNA from new and/or existing de-identified project samples from bulk tissue or single cells and facilitate the storage of the accompanying data into publically accessible databases such as NIH dbGaP.

(3) The Contractor shall isolate, prepare, and distribute DNA and/or RNA from the requested samples, and all other tasks required not otherwise covered above in Task 5.

(4) Within 4 calendar weeks of the contract award the Contractor shall provide a workplan and timeline for sequencing as well as for submitting genotype and phenotypic data into publically accessible databases such as NIH dbGAP after having received all phenotypic data and samples.

(5) Maintain a Gantt chart detailing progress of processing samples and submission of data to dbGAP or another repository as directed by the COR.

Task 23 (A and B) Epigenetic and Gene Regulation Assays

As directed by the COR the contractor shall perform epigenetic and gene regulation assays on bulk tissue and single cells.

(1) Maintain a Gantt chart detailing progress of processing samples and submission of data to dbGAP or another repository as directed by the COR.

Task 24 (A) - Reprogrammed cellular derivatives

The contractor shall submit a protocol for deriving induced pluripotent stem cells (iPSC) within 4 calendar weeks of the contract award. The Contractor shall obtain COR approval of the protocol before beginning work.

If directed by the COR, the Contractor shall support the creation of reprogrammed cellular derivatives, such as iPSC, from new and/or existing de-identified project samples.

Task 25 (A and B) - Administrative Tasks

(1) In accordance with Article C.2, the Contractor shall prepare an Annual Report and/or a Final Report at the end of the contract. The Contractor shall provide the Annual or Final Reports to the NIDA COR and NIDA Contracting Officer by the date specified in the Task Order. If there are active task orders, the price of this task shall be built into the per unit pricing.

(2) Within 2 months of initial contract award, the Contractor shall provide a one-time report that summarizes the status and activities of each task and sub-task outlined within the statement of work.

Task 26 (A and B) - Other Activities

The Contractor shall:

(1) Provide to the COR, at least 1 month prior to the completion of the contract, a full inventory of cell lines, DNA, RNA, serum or other biological materials. Also provide a system for the transfer of all cell lines and biological materials to a storage facility or successor Contractor at least 3 months before the expiration of the contract.

(2) Provide to the COR, at least 1 month prior to completion of the contract, a full inventory of all genotypic and phenotypic electronic databases. Also provide a system for the transfer of all electronic databases and files to a successor Contractor at least 3 months before the expiration date of the contract.

(3) Fully cooperate with NIDA and any successor Contractor, if applicable by providing resources to ensure the smooth and efficient transfer of all such data and biological materials.

(4) Provide to the COR, recommendations for improving Component B (data infrastructure) to facilitate easier data: access, analysis, queries, usability and visualization.

(5) Maintain a Gantt chart of progress being made in processing samples for genotyping, or sequencing and subsequent submission to a database. Meet monthly will COR to share Gantt chart and progress.

Task 27 – Advertising the NIDA Center for Genetic Studies.

(1) The Contractor shall advertise the resource of the NIDA Center for Genetics Studies through social media accounts (e.g.