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Laboratory, Data Analysis, and Coordinating Center (LDACC)

Solicitation Number: LDACC-10-01
Agency: Department of Health and Human Services
Office: National Institutes of Health
Location: National Heart, Lung and Blood Institute, Rockledge Dr. Bethesda, MD
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LDACC-10-01
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Sources Sought
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Added: Dec 11, 2008 4:23 pm
SOURCES SOUGHT NOTICE for FEDBIZOPPS



NOTE: "Figure 1. Functional Organization of GTEx" and "Appendix A. Tentative Prioritized Tissue List - Autopsy/Transplant Donors" are provided as attachments and are located on a separate tab.



Notice Number: LDACC-10-01



Project Title: Genotype-Tissue Expression (GTEx) Project – Laboratory, Data Analysis, and Coordinating Center (LDACC)



I. Overview of the GTEx Project



The National Heart, Lung, and Blood Institute (NHLBI) is seeking small businesses with the capability to serve as a Laboratory, Data Analysis, and Coordinating Center (LDACC) for a new pilot program: the Genotype-Tissue Expression (GTEx) Project.



What follows below is a description of the entire project and instructions on how to respond to this notice with your capability statement. Please note, this Sources Sought Notice asks for a capability statement regarding the LDACC portion only. It is understood no one entity may have the requisite experience to perform all functions of the project. Therefore subcontracting may be appropriate. The components that may be considered for subcontracting as an example include: cell culture (fibroblast and lymphoblastoid), sequencing based RNA expression analysis, chip-based RNA expression analysis, genotyping; all of the components of the Tissue Receiving & Storage Center (TRSC) - tissue storage, histopathology processing, and expert pathology review.



A. Purpose of the GTEx Project



Genome-wide association studies (GWAS; See: http://www.genome.gov/gwastudies) have shown great promise in identifying genetic loci associated with common human diseases, such as heart disease, cancer, diabetes, and psychiatric conditions. Despite this progress, the majority of the single nucleotide polymorphisms (SNPs) and other genetic changes lie outside of the protein-coding regions of genes and often even outside of the genes themselves, making it difficult to discern which genes underlie the association and by what mechanism.



The Genotype-Tissue Expression (GTEx) project, an NIH Roadmap Initiative (http://nihroadmap.nih.gov/GTEx/), aims to provide a resource to the scientific community with which to study the relationship between genetic variation and human gene expression and regulation. This project will collect and analyze multiple human tissues from donors who have been characterized for germline genetic variation through dense genotyping. By analyzing global RNA expression within individual tissues and treating the gene expression levels as quantitative traits, variations in expression that are highly correlated with genetic variation will be identified as expression quantitative trait loci, or eQTLs. The SNPs that are correlated with a transcript level are known as eSNPs. Based on analysis of individual tissues, approximately 10% or more of gene transcripts are cis-eQTLs, meaning that the eSNP is located close to the gene. To identify trans-eQTLs, meaning those in which the eSNP maps far from the gene, or on a different chromosome than the gene it is regulating, much larger sample sizes will be required. This is because of the need to adjust for the large number of statistical tests involved in searching for correlation between every transcript and a very large number of genetic variants. Comprehensive identification of both cis- and trans-eQTLs will provide a valuable basis on which to study gene regulation, with an immediate application in interpreting GWAS study findings.



The GTEx project will begin with a 2.5- to 3-year pilot in FY10. As developed at a June 2008 GTEx Workshop (http://nihroadmap.nih.gov/GTEx/workshop0608), the primary goal of the pilot is to assess the feasibility of enrolling 160 donors identified through low post-mortem interval (PMI) autopsy or organ transplant settings and collecting high-quality RNA from thirty or more tissues per donor.



RNA quality will be measured by technical characteristics and performance on commercial expression arrays, and next-generation sequencing platforms will also be evaluated. The influence of factors such as mode of death and PMI on RNA quality measures will also be evaluated. For a small subset of tissues (approximately 5), collection from a similar number of living surgery patients will also be performed to compare to the quality of autopsy-derived tissues. Peripheral blood samples will be used as a source of DNA for whole-genome SNP genotyping assays and for establishment of lymphoblastoid cell lines, and fibroblast cultures will be established from skin samples from all donors. Analysis of cis-eQTLs from GTEx derived tissues will be compared, where possible, to existing, single-tissue datasets, and the optimal number of tissues needed to identify the majority of eQTLs will be evaluated.



Final quantitative scale-up criteria to be met during the pilot will be provided by the NIH before contract negotiation/awards are made, but will include factors and criteria such as:



• Enrollment of 160 autopsy/transplant donors, or at least 100 autopsy/transplant donors by the end of the pilot and at least 10 donors per month in each of the final three months of recruitment.



• The six highest-priority tissues are collected from 70-80% of all donors, and the 24 next highest-priority tissues are collected from at least 70-80% of all donors within the final three months of recruitment.



• At least 70-80% of all samples have an RNA Integrity Number (RIN) of at least 4-6, and for the six highest-priority tissues, at least 70-80% have a RIN of at least 6-8.



• At least 85-95% of donors are successfully genotyped using high-density genotyping SNP arrays with SNP call rates of 90-98%.



The GTEx Pilot Project also aims to determine the optimal number of tissue types needed to sample, based on the redundancy of eQTL results across multiple tissue types, and to evaluate the effects of mode of death, postmortem interval, and sample collection factors on RNA quality and eQTL results. If the aims of the GTEx Pilot Project are achieved, the project may be expanded, in the following 3 years, to involve multiple tissues from an additional ~900 donors.



B. Organization of the GTEx Pilot Project



The GTEx Pilot Project comprises two main initiatives: (1) The Laboratory, Data Analysis and Coordinating Center (LDACC), the subject of this Sources Sought Notice (see II. below), and (2) the Donor Recruitment and Tissue Collection Centers (DRTCC), which will involve a separate request for proposal (RFP). A third functional area, the Tissue Receiving and Storage Center (TRSC) may be included within the LDACC or DRTCC initiatives, or funded separately. Some of the brain tissue may be sent to an NIH-supported Brain Bank funded separately.



The GTEx Pilot Project also includes development of a GTEx database (within the National Center for Biotechnology Information (NCBI)) and a separate Request for Applications for the development of improved statistical data analysis methods.



The functional relationship of these components within the overall GTEx Project is shown in Figure 1.



C. GTEx Project Phasing Schedule



The GTEx Project will be conducted in three phases, with an optional fourth phase, as outlined below. The first three phases will be conducted over two and one half to three years, beginning in FY10. The optional phase four, for three additional years, will be executed if the Pilot Project meets its goals and funding is secured.



Phase 1 - Planning & Testing (5-7 months)

Phase 1 will involve finalizing IRB approvals, where required, and development and harmonization of final protocols for donor recruitment and sample collection, shipping and tracking, and optimizing protocols for histopathology processing and molecular analysis of tissues. This phase will involve biweekly teleconference calls and one in-person meeting between DRTCCs and LDACC Investigators. A small number of donors will be enrolled at each site from which the top 6 tissues will be collected, to test the sample collection, handling, shipping, and tracking procedures.



Phase 2 - Active Pilot Data Collection (16-18 months)

Phase 2 will involve active collection of tissue from the targeted 320 donors (160 autopsy and 160 surgery patients) over a maximum of 16 months of subject enrollment. There may be a ramp-up in the number of tissues collected from each donor, dependent on feasibility assessed in Phase 1. Molecular analyses at the LDACC will be ongoing during this phase, and will be completed within 2 months of sample receipt.



Phase 3 - Preliminary Analysis and Evaluation of Pilot (6-8 months)

Phase 3 will involve statistical analysis of all available molecular and process data in order to assess whether scale-up criteria were met. Results will be used to inform the design and timing of an optional phase 4.



Phase 4 - Optional Scale-up (36 months)

Phase 4 is an optional, three-year, scale-up phase, to enroll approximately 900 additional donors, collecting the optimal number of tissues from each, analyzed with the most comprehensive, yet cost-effective, quantitative RNA expression analysis platform.



Proceeding to Phase 4 is contingent on achieving the GTEx Project goals and the availability of adequate funds.



D. DRTCC Initiative: The Donor Recruitment & Tissue Collection Center (DRTCC) initiative will consist of 2-5 sites that will identify and enroll donors and acquire multiple tissue samples from each, using best practices for sample collection, handling, fixation, and storage.

The total number of autopsy or organ transplant donors to be enrolled by the DRTCCs is 160, and the total number of surgical donors is also 160. Ideally, 50-70 tissues per autopsy/transplant donor will be collected, while 4-6 tissues per surgical donor will be collected, yielding a total of 8800-12,000 tissue samples. These samples will be obtained over 15 to 18 months. (See Appendix A for a tentative list of target tissues.)



The collected blood samples and tissue aliquots will be shipped to the Tissue Receiving & Storage Center (TRSC), described in II.C., for histopathology analysis and long-term storage. The TRSC will forward a portion of the blood and tissue samples from each donor to the Molecular Analysis Laboratory (within the LDACC) for processing and analysis.



One or more of the DRTCCs will also conduct a study of the GTEx consent process, to assess its impact on surgical donors and families of deceased donors in order to optimize the consent process utilized in phase 4, should it be funded.



II. Laboratory, Data Analysis, and Coordinating Center (LDACC): The LDACC, which is the subject of this Sources Sought Notice, will provide two major functions: a Data Analysis & Coordination Center and a Molecular Analysis Laboratory. NHLBI reserves the option to fund a third function, a Tissue Receiving & Storage Center (TRSC), either as part of the LDACC, separately, or as a component of one of the DRTCCs, depending on the offerors’ facilities, experience and skills of personnel, and total TRSC cost.



A. Data Analysis and Coordination Center



The Data Analysis and Coordination Center will have overall responsibility for coordinating the many GTEx components, most notably the LDACC and DRTCCs. This will require close coordination with multiple Donor Recruitment and Tissue Collection Centers (DRTCCs), funded separately, to finalize study protocols and data collection forms; to design and implement a donor and tissue tracking system, including sample barcoding; and to establish (and/or monitor) an expert pathologist review system for collected tissues. The LDACC will also monitor study progress and quality of DRTCC and laboratory performance, and prepare statistical and other reports, as needed, establish and manage Project Committees and an Observational Study Monitoring Board (OSMB), and provide monthly detailed reports to the NIH Project Officer on the progress of the study. In addition, the LDACC will:



(1) Design and implement a comprehensive Laboratory Information Management System (LIMS), including barcode-based identification of all GTEx-related patient information and tissue samples.



The LIMS will track and provide real-time access to all related patient and tissue information, including: identification of the tissue donor; verification of proper patient or family consent; GTEx-defined clinical history and family history; inventory of all patient tissue samples collected and type of collection vessels; shipment of patient samples from the DRTCC to the LDACC. The information for these tasks will be collected by the DRTCC.



The LIMS also will track receipt of patient samples at the TRSC; transfer of samples and derived materials within each location of the LDACC; status of sample analysis; results of analysis by the LDACC; and storage of tissue samples at the TRSC.



(2) Work closely with the DRTCCs to design a standardized set of data collection forms and barcoded labels to link all clinical, family, and associated information about donors and their tissue specimens.



(3) Work closely with the DRTCCs to design a standardized set of tissue specimen collection containers and barcoded labels to link and track every specimen and associated aliquot processed at the DRTCCs.



(4) Create a database of all clinical and family history and related information collected on each donor, together with all laboratory data generated by the Molecular Analysis Laboratory from the donor tissues.



(5) Perform basic analysis of data resulting from genotyping and expression analyses performed by the Molecular Analysis Laboratory, including data quality filtering and normalization of global RNA expression and genotyping chip data. The evaluation of cis expression quantitative traits (eQTLs; defined as RNA expression levels correlated with SNPs within an arbitrary distance from the transcription start site of the gene), and analysis of next-generation sequencing-based expression data, will be performed through the GTEx Database and statistical methods RFA, funded separately.



(6) Submit an NIH-specified subset of data (all laboratory data, including raw output files and associated metadata, and specified clinical information collected from each donor) to NCBI (part of NIH) for inclusion in the GTEx database.



The LDACC will work closely with NCBI to deposit individual-level clinical and phenotypic information into the NCBI dbGaP database ( http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap&cmd=search&term= ) and individual-level expression results, both raw and processed data, into the NCBI GEO database ( http://www.ncbi.nlm.nih.gov/sites/entrez ). A controlled access system, similar to the current GWAS data within dbGaP, will be developed separately from this solicitation, using data provided by the LDACC. It is anticipated that summary statistical calculations of correlation between genetic variants and RNA expression values will be provided, without restriction, to the scientific community through the GTEx database developed by NCBI.



(7) Establish quality criteria and monitor, analyze, and report these measures for the number of donors and tissues at each DRTCC, the laboratory processing of all specimens, and overall progress of the study for the Observational Study Monitoring Board (OSMB) and NIH Project Officer. These data reports will be included in monthly progress reports to the NIH Project Officer.



(8) Provide detailed monthly reports on the progress of all DRTCC and LDACC Pilot Project activities to the NIH Project Officer.



(9) Participate in yearly reviews, at the NIH campus in Bethesda, MD, with other GTEx participants and the NIH GTEx administrative staff.



B. Molecular Analysis Laboratory



This facility will:



(1) Receive incoming tissue aliquots from the Tissue Receiving & Storage Center (TRSC) and process these tissue aliquots to yield purified DNA and RNA. Test samples may be received within 4 months of contract award, while full sample shipments are expected within approximately 6-9 months of the contract award. During the interim, the Molecular Analysis Laboratory will verify and develop, wherever needed, tissue-specific protocols that will yield high-quality RNA and DNA from the highest priority tissues, listed in Appendix A.



The tissue processing will include:



a. Homogenizing one frozen aliquot of tissue, to yield uniform material for nucleic acid analysis, so that duplicate experiments, or experiments performed using different protocols or platforms, utilize the same cellular mixture as starting material.



b. Extracting RNA, and possibly DNA, from homogenized aliquots using protocols optimal for each tissue, which will be proposed by the offeror and approved by NIH Project Officer, with storage of remaining material for future use.



(2) Perform whole-genome mRNA expression analysis, using commercially available microarray chip products, using RNA samples extracted from approximately 8,800 tissue aliquots. The ability to increase the number of samples, to 50,000 or more, to be analyzed during the optional phase four, should also be indicated.



(3) Perform genome-wide genotyping analysis using a commercially available microarray single nucleotide polymorphism (SNP) chip product containing at least 500,000 genetic variants (Affymetrix, Illumina, or comparable product) using the DNA sample from each donor.



(4) Perform next-generation, sequencing-based whole transcriptome analysis on a specified subset of 300 tissue RNA samples. Assuming the GTEx Pilot Project meets its goals and the optional phase 4 is executed to analyze samples from an additional 900 patients over a 3-year period, a sequencing-based RNA expression analysis platform may be preferred at that time. Thus we wish to evaluate the feasibility of this strategy both as to how GTEx collected tissues perform on these platforms, and how the data may be analyzed to obtain quantitative expression measures. The ability to increase the number of RNA sequence based analyses, to 50,000 or more, to be analyzed during the optional phase four, should also be indicated.



(5) Operate a cell culture facility that prepares EBV-transformed lymphocyte cell lines from white blood cells of donor blood samples, and prepares primary fibroblast cell lines from donor skin samples.



C. Tissue Receiving & Storage Center (TRSC).



NHLBI may fund the Tissue Receiving and Storage Center (TRSC) functions within the LDACC, within one of the Donor Recruitment and Tissue Collection Centers, or entirely separately.



This facility will:



(1) Provide specimen containers, tracking labels, and shipping material to an anticipated 2-5 DRTCCs, to accommodate the individual tissue aliquots outlined above (up to 60,000 tissue aliquots). Procedures for shipping and handling must be developed in coordination with DRTCCs. Specimens will be shipped to the TRSC in several states: frozen (liquid nitrogen), on wet-ice, and at room temperature (for formalin-fixed tissue, and blood and skin samples in culture media).



The TRSC will have an approximately five-month period, from the time of the contract award, to prepare for the receipt, initial handling, and storage of solid tissue and blood samples.



(2) Receive overnight shipments of frozen tissue from the DRTCCs. For each tissue aliquot obtained, the TRSC will send one frozen aliquot to the Molecular Analysis Lab for extraction of RNA for expression analysis. The remaining two frozen aliquots from each tissue sample will be placed in refrigerated storage (See (8), below).



(3) Receive overnight shipments of skin samples in media at room temperature. The TRSC will send these samples to the tissue culture facility, within the Molecular Analysis Laboratory, to establish a fibroblast primary cell line for each donor.



(4) Receive overnight shipments of blood samples. The TRSC will send an aliquot of the blood sample to the tissue culture facility, within the Molecular Analysis Laboratory, to establish an EBV-transformed lymphoblastoid cell line for each donor. The TRSC will send the remainder of the blood sample to the Molecular Analysis Laboratory for extraction and analysis of genomic DNA from white blood cells.



(5) Tissue aliquots received in fixative will be paraffin embedded, aliquoted on a microtome, placed on a single microscope slide, and stained with hematoxylin & eosin. The tissue processing should be highly standardized, ideally using an automated system, which should be described.



(6) Design and implement a system to digitally scan histopathology slides of all tissue specimens undergoing molecular analysis and store images in the LDACC database, accessible for review by outside pathologists. These images will be linked to other individual-level data, which will also be made available to approved users of the controlled access data, available through the GTEx Database at NCBI. Please indicate the system you envision using for this task.



(7) Establish and coordinate a panel of expert pathologists to review pathology slides from all tissue specimens, to verify the organ source of the tissue and to characterize the pathophysiologic state of the tissue. The resulting interpretations will be entered into the LDACC database, using a data collection form developed by the LDACC for each tissue type.



(8) Provide long-term storage for the remaining tissue aliquots (most in liquid nitrogen, some possibly at -20 C in frost-free freezers or refrigerated at 5 C) in temperature-controlled freezers and refrigerators, with alarms and 24-hour monitoring systems.



Please indicate whether you have the capabilities to undertake the functions of the TRSC in addition to those of the LDACC.



This is not a request for proposals (RFP) and the Government is not committed to award a contract pursuant to this announcement. Small business concerns that believe their organizations possess the capabilities necessary to undertake this study should submit complete documentation of their capabilities to the Contracting Officer at the address below. Include the name and telephone numbers of a point of contact. When submitting this information, please reference this notice number: LDACC-10-01. We ask that the capabilities statement not exceed 14 single sided or 7 double sided pages in length.



Austin Sachs, Contract Specialist, Office of Acquisitions, DERA

National Heart, Lung, and Blood Institute, NIH, DHHS

6701 Rockledge Drive, Rockledge II, Room 6122, MSC 7902

Bethesda, MD 20892-7902

For overnight deliveries use zip code 20817, no MSC is required.



The capabilities statement shall include 1) the total number of employees, 2) the professional qualifications of scientific, medical expert, and technical personnel in accordance with the above outline requirements, 3) a description of general and specific facilities and equipment available, including computer equipment and software, and 4) an outline of previous activities and projects similar in content and/or magnitude to the proposed work in which the organization and the proposed personnel have participated; and any other information considered relevant to this program. Do not include budget information. The information provided must also establish the organization’s status as a small business. Two (2) copies of the capabilities statement must be received at the address in this announcement by close of business January 5, 2009. If this program is approved for implementation and it is determined to be a small business set aside, then a competitive RFP will be set aside for small business concerns. When released, the RFP will be available on the Federal Business Opportunities (FEDBIZOPPS) website.



NOTE: PREPARATION COSTS - This Sources Sought Notice does not commit the Government to pay for the preparation and submission of a capabilities statement. The NHLBI is a consolidated Office of Acquisitions and does the R&D buying for the National Human Genome Research Institute (NHGRI).



The following criteria will be used to evaluate the capability statements.

Both of these criteria are weighted equally.



1. PERSONNEL AND EXPERIENCE: Documented training, experience, and expertise of the professional, technical, and administrative staff with experience in related programs of similar scale and complexity, for management, development, implementation, and coordination of tissue sample acquisition and processing; histopathology procedures, molecular laboratory methods; tissue culture facilities and experience generating and maintaining immortalized lymphocyte cell lines and primary epithelial cell lines; microarray RNA expression analysis, data generation, and data analysis; genome-wide genotyping.



Knowledge of and experience with biostatistical analyses, data management, monitoring quality control; experience with the implementation and use of a full-scale Laboratory Information Management System for tracking samples, processes, and data generation at multiple facilities. Also needed are access to expert histopathology personnel; and experience with applications of next-generation sequencing to whole-transcriptome analysis, and resulting data analysis.



2. ORGANIZATIONAL EXPERIENCE AND FACILITIES: Adequacy and availability of the organizational and administrative structure to participate in a complex, multi-facility program, involving the analysis of a large number of clinical samples; secure processes for handling confidential patient information; experience in monitoring and reporting the quality and timeliness of such data. Availability and adequacy of the facilities and resources necessary for conducting study coordination, data management and analysis, including computer hardware, software, and other equipment needed to implement the requirements of the contract. Storage facilities and capacity for secure and monitored long-term storage of tissue samples in liquid N2, at -20 Celsius, and at 5 Celsius. Availability and adequacy of facilities and resources necessary for genome-wide genotyping, microarray expression analysis, next-generation DNA sequencing, and the generation and maintenance of human cell lines. Also, the ability to manage and administer subcontracts if appropriate.



- END OF SOURCES SOUGHT NOTICE -



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Figure 1. Functional Organization of GTEx

Type:
Other (Draft RFPs/RFIs, Responses to Questions, etc..)
Label:
Figure 1. Functional Organization of GTEx
Posted Date:
December 11, 2008
Description: Figure 1. Functional Organization of GTEx

Appendix A. Tentative Prioritized Tissue List - Autopsy/Transplant Donors

Type:
Other (Draft RFPs/RFIs, Responses to Questions, etc..)
Label:
Appendix A. Tentative Prioritized Tissue List - Autopsy/Transplant Donors
Posted Date:
December 11, 2008
Description: Appendix A. Tentative Prioritized Tissue List - Autopsy/Transplant Donors
:
Office of Acquisitions
6701 Rockledge Dr RKL2/6100 MSC 7902
Bethesda, Maryland 20892-7902
:
Austin Sachs,
Contract Specialist
Phone: 301-435-0345
Fax: 301-480-3430