Attachment-1-Only-RSnG-Renewal-LC-2010-Feb24-9pm.pdf

Attachment 1

Attachment 1: Information Specific to this Solicitation

Section B – Brief Description of Supplies or Services

Section C – Statement of Work and Reporting Requirements

Section F – Deliveries and Performance

Section L – Additional Technical Proposal Instructions

a. General Description of the Program and Desired Results

b. Background Information

c. RS&G Committees and Panels

d. Estimated Level of Effort

e. Page and Formatting Limitations

f. Sample Technical Proposal Table of Contents

g. Travel

h. Offerors Must Address

i. Phasing

Section L – Additional Business Proposal Instructions

a. Sample Business Proposal Table of Contents

b. Cost Proposal Excel Workbook

c. Performance Based Acquisition/Performance Assessment Scheme

d. Packaging and Delivery of Proposal

Section M – Evaluation Factors for Award

Proposal Intent Response Sheet

Section B – Brief Description of Supplies or Services

The overall objective of the NHLBI DNA Resequencing and Genotyping (RS&G) Service Renewal is to continue to provide high quality, high-volume resequencing and genotyping for investigators to discover and type DNA variations needed to elucidate the genetic components involved in the cause, variable outcome and progression of heart, lung, and blood diseases and disorders. In the renewal, the RS&G Service will consist of two to five Laboratory Centers (LCs) capable of performing both massively high throughput, large-scale DNA resequencing and high throughput genotyping to discover and type DNA variations for heart, lung, and blood investigators and one Administrative Coordinating Center (ACC) to provide the logistical support for the entire RS&G Service.

The goal of this RFP is to fund two to five LCs. The ACC will be awarded through a separate solicitation.

Section C - Statement of Work and Reporting Requirements

Independently and not as an agent of the Government, the Contractor shall be required to furnish all the necessary services, qualified personnel, material, equipment, and facilities, not otherwise provided by the Government, as needed to perform the Statement of Work.

[Note: Tasks that occur during the entire period of performance are presented first, followed by special tasks related to each phase of the program.]

The Laboratory Center(s) shall:

During the entire contract performance period the contractor shall:

1. Provide personnel with expertise and experience in massively parallel DNA resequencing, high throughput genotyping, database management, informatics, general laboratory management, and quality control (QC) (used here and throughout encompassing quality assurance and quality control activities).

Offeror Must Address: Proposals should describe the experience of investigators and staff relevant to the proposed resequencing and genotyping efforts and plans for continued high-throughput, large-scale production of resequencing and genotyping data should the PI or other key personnel leave the LC.

2. On an annual basis, propose a Performance Assessment Scheme (PAS) for the upcoming period and submit information for evaluation of performance under the applicable PAS. At a minimum, the PAS should address production; QC for laboratory method, databases, and informatics; turn-around times; amount of data submitted to public databases; the increases in production and decreases in costs.

Offeror Must Address: The technical proposal should suggest a PAS for the first year.

The suggested PAS should provide an approach for calculating cost as compared to production and for determining increases in production without increasing costs. During negotiations the PAS will be finalized with NHLBI and incorporated into the contract. During performance, NHLBI may withhold or reduce workload and funds for any LC that substantially fails to meet its approved PAS for the year or fails to maintain state-of-the-art service. See Exhibit for a draft PAS.

3. Communicate with the ACC frequently and regularly. Provide requested materials and information promptly.

4. Attend and contribute to Steering Committee meetings, monthly conference calls, and subcommittee meetings or conference calls.

5. Attend OSC meetings, provide requested information in a timely manner, facilitate OSC activities, and respond to comments and suggestions of OSC.

6. Provide in a timely manner technical input to the NHLBI regarding projects submitted for use of the RS&G Service. Include possible approaches to accommodate varying project designs and to overcome potential complications.

7. Communicate frequently and regularly with NHLBI regarding LC activities. Promptly identify to NHLBI any concerns or barriers to performance and work to develop and implement prompt solutions. Provide financial information on a monthly basis.

8. Assist the ACC as needed to inform the research community of the availability of the

RS&G Service. Contribute ideas and information for the RS&G Service website.

9. Obtain from the Principal Investigator for each approved project a copy of the

Institutional Review Board approval prior to accepting samples for DNA resequencing or genotyping.

During Phase I - Transition/Early Production Period (Month 1-3):

1. Perform tasks 1-9 from the above list.

2. Produce a laboratory-specific Manual of Operations to contain:

a. Detailed description of the laboratory’s massively parallel DNA sequencing production pipeline including all aspects from sample receipt to usable sequence, the availability of a capillary sequencer pipeline for classic high-throughput sequencing including current uses, and the available high throughput genotyping methods including:

i. Rationale for each method noting its strengths, weaknesses, and its sensitivity and accuracy. Include biases, coverage, run times, and important specific data. For sequencing this would include read type -single ends or paired ends-, library production, amplification, capture, coverage, yield of sequence reads, and total bases per instrument run and lane. For genotyping this would include sample, platform, or design issues.

Offeror Must Address: Proposals should describe current and projected laboratory capacity and turn-around times.

ii. Methods for optimizing and evaluating the resequencing or genotyping methods and platforms.

1. For resequencing this should include methods for preparing samples for use including amplification, library production or capture and quality checks. Include details of approach and read length. For instance, for capture include probes, capture conditions, blocking approach for repetitive sequences, etc;

standard ratio of genomic DNA to capture probes, enrichment rate, uniformity of capture, fold coverage, specificity of capture.

2. For genotyping this should include methods for sample preparation and quality checks, choice of platform, general design issues for the specific SNPs to be genotyped.

iii. Method to assess/determine false positive rate.

iv. Methods for sequencing or genotyping difficult regions.

v. Instrumentation and robotics necessary to perform the resequencing or genotyping, including plans for multiplexing and equipment calibration and maintenance procedures.

vi. Methods for incorporating technology development to increase capacity and production from the initial level to double or quadruple this by the end of the third year.

Offeror Must Address: Discuss what changes could be investigated and the expected increase in production for each change.

b. Detailed description of informatics used in the resequencing or genotyping effort to obtain usable data, including:

i. Methods for any primer selection and design for sequencing and design of capture probes; methods for marker selection for genotyping, assessment of success rate, and routine alternate procedures.

ii. Methods for processing raw reads, base-calling algorithm, quality checking and/or screening filters to remove poor-quality sequences, mixed sequences, etc; quality values.

iii. Method of sequence assembly, mapping, and annotation.

iv. Assessment of bias in procedures for sequencing or genotyping.

v. Procedures for data analysis, determination of polymorphism and allele frequency, and verification and validation of SNPs. Approach to determine insertions and deletions and copy number variations.

vi. Final data processing and formatting steps to prepare the data files for transmission to the investigators requesting resequencing or genotyping, and to public databases such as the database of Genotypes and Phenotypes (dbGaP) or the database of Single Nucleotide Polymorphisms (dbSNP) which are maintained by the National Center for

Biotechnology Information (NCBI). Include relevant information such as process for providing data to investigators, compression approaches, data clean up, file information and naming procedures, and data storage/query systems.

Offeror Must Address: Proposals should describe how proposed procedures to provide data to investigators have been used in the past, and how the investigators were able to utilize process and/or the data files.

vii. Data and laboratory information management systems to be used, including software, hardware, transmission requirements, backups, and security.

c. Detailed description of laboratory sample receipt, storage, and tracking methodology, including:

i. Required procedures for DNA preparation, aliquoting, labeling, and shipping, and minimum acceptable standards for DNA quantity and quality for samples submitted.

Note to Offerors: LCs shall not isolate genomic DNA from tissues or cells.

ii. Format for provision of tracking data and sample identification information for samples submitted.

iii. Methods for electronic tracking of samples; reduction of sample switches, losses, and cross contamination; tracking of work.

iv. Methods for temporary storage of DNA samples and return or destruction of samples upon completion of resequencing or genotyping.

d. Detailed description of laboratory QC procedures, including:

i. Methods to reduce or eliminate systematic errors.

ii. Source and frequency of use of internal standards, repeat samples, and blank samples.

iii. Procedures for computational checking and rechecking, assessment of reading errors and data consistency, and calculation of error rate and failure rate of primers or probes.

iv. Procedures for assessment of yield, processing, purification, and usability testing for oligonucleotide synthesis.

v. Methods to reduce or eliminate errors in computational and informatics aspects of the resequencing or genotyping effort.

vi. Procedures for identifying and implementing corrective actions based on QC opportunities detected.

Offeror Must Address: Proposals should describe how proposed QC procedures have been used in the past, what corrections were made to improve performance, and what were the results of these actions.

3. Work collaboratively with other RS&G Service LCs and the ACC to develop and implement RS&G Service-wide protocols, guidelines and procedures for the renewal period.

a. Attend and participate in the initial Steering Committee meeting to be held within one month of award of contracts for the LCs.

Note to Offerors: Plan on two Steering Committee meetings each year.

b. Establish RS&G Service-wide criteria for sample submission by approved investigators.

c. Establish RS&G Service-wide QC procedures and standards for resequencing and genotyping.

d. Establish RS&G Service-wide procedures for evaluating and incorporating new technologies and methodological advancements to maintain a state-of-the-art service, reduce per unit costs, and increase production, while maintaining or improving consistently high product quality.

e. Work with the ACC and the NHLBI to update the RS&G Service website, to include at a minimum a table listing the genes/regions that have been resequenced or genotyped, the population from which the samples were drawn, and contact information for the investigators requesting the resequencing or genotyping.

f. Work with the ACC and the NHLBI to develop and implement procedures to inform the research community of the availability of the RS&G Service.

4. Work collaboratively to prepare RS&G Service-wide and laboratory-specific materials for review by the OSC, and promptly revise materials in response to recommendations for implementation.

5. Following written approval by the COTR, implement approved laboratory-specific and RS&G Service-wide protocols and procedures for resequencing or genotyping, informatics, sample handling and tracking, QC, and data submission.

6. Finalize the laboratory Manual of Operations by incorporating the RS&G Service-wide minimum quality control procedures agreed upon by the Steering Committee. The Manual of Operations shall incorporate revisions approved by the NHLBI based on recommendations made by OSC.

7. Perform resequencing or genotyping of candidate genes, candidate gene regions, or important regions in DNA samples for approved projects.

8. Produce at least 100 Gb of usable sequence with an error of 1 in 10,000 bases or less and at least 10 M genotypes with an error of less than or equal to 1%.

Note to Offerors: The actual number reflected in the contract will be based on anticipated capacity as demonstrated in the technical proposal, and agreed to during negotiations.

9. Except as explicitly authorized by NHLBI, maintain the confidentiality of the resequencing or genotyping data.

Note to Offerors: The LC shall not publish or use the generated data and results for any purpose other than those expressly authorized by NHLBI via the R&G Service Contract.

The LC may publish technical or methods papers as approved by the Steering Committee and the NHLBI.

10. Provide secure backup of all data essential to the RS&G Service, including but not limited to all resequencing or genotyping data generated, sample tracking and storage information, and QC information.

Note to Offerors: The data produced by the RS&G Service will not belong to the LC and must be stored in a separate database.

During Phase II – Full Production Period (Months 4 –36):

1. Perform tasks 1-9 from the list provided for the entire period of performance and finalize any tasks remaining from the previous phase.

2. Provide information and reports to the ACC in a complete and timely manner to expedite its role as facilitator for the RS&G Service committees and panels.

3. Obtain from the Principal Investigator for each project a copy of the Institutional Review Board approval for each project referred for use of the LC prior to accepting samples for DNA resequencing or genotyping.

4. Perform resequencing or genotyping of candidate genes, candidate gene regions, or important regions in DNA samples for projects assigned to the LC following recommendation by the Evaluation Panel and approval for access to the service by the

NHLBI.

5. Produce at least 500 Gb of usable sequence per year with an error of 1 in 10,000 bases or less at a cost per Gb to be negotiated and at least 60 M genotypes with an error of less than or equal to 1% at a cost per genotype to be negotiated.

Note to Offerors: The actual number reflected in the contract will be based on anticipated capacity as demonstrated in the technical proposal, and agreed to during negotiations.

6. Work collaboratively to prepare RS&G Service-wide and laboratory-specific materials for review by the OSC, and promptly revise materials in response to recommendations for implementation.

7. Implement recommendations from the Steering Committee and the OSC as approved by the NHLBI to maximize the RS&G Service’s effectiveness.

8. Submit the Monthly Status Report electronically to the ACC.

9. Provide information for the RS&G Service public website as maintained by the ACC.

This information shall include, but not be limited to, a table listing the genes/regions that have been resequenced or genotyped; laboratory information such as laboratory protocols, QC procedures, and QC data; links to relevant sites, tutorials, software, sample applications, help, answers to frequently asked questions; and user-friendly links for reporting problems and asking questions.

10. Provide technical expertise to assist investigators approved and assigned to use the RS&G Service to finalize the project.

11. Except as explicitly authorized by NHLBI, maintain the confidentiality of the resequencing or genotyping data.

Notice to Offerors: The LC shall not publish or use the generated data and results for any purpose other than those expressly authorized by NHLBI via the R&G Service Contract. The LC may publish technical or methods papers as approved by the Steering Committee and the NHLBI.

12. Provide secure backup of all data essential to the RS&G Service, including but not limited to all resequencing or genotyping data generated, sample tracking and storage information, and QC information.

Note to Offerors: The data produced by the RS&G Service will not belong to the LC and must be stored in a separate database.

13. Return or destroy all DNA from investigators approved for use of the RS&G Service within 90 days of completing the project or as agreed upon by the Steering Committee and approved by the NHLBI.

14. Develop and incorporate new technologies and methodological advancements for resequencing or genotyping to maintain a state-of-the-art service, reduce per unit costs, and increase production, while maintaining or improving consistently high product quality. Maintain or improve sequence quality in accordance with RS&G Service standards and procedures.

15. Submit detailed summary materials for the OSC to review at about month 30. This in-depth evaluation may be used to shift resources within the LCs if needed to improve the RS&G Service.

During Phase III - High Production Period (Months 37 – 60):

1. Continue all tasks from the entire period of performance and from Phase II - Production.

2. Produce resequencing or genotyping at a level double or quadruple the initial level of production.

Note to Offerors: Requests to use the RS&G Service may include larger regions of named genes and more samples.

3. Provide suggested plans for close-out and implement the NHLBI approved plan for close-out of the RS&G Service.

Note to Offerors: Plan for close-out to be agreed upon by the Steering Committee, reviewed by the OSC and approved by the NHLBI.

Reporting Requirements

In addition to those reports required by the other terms of this contract, the contractor shall prepare and submit the following reports in the manner stated and in accordance with ARTICLE F.1. DELIVERIES of this contract:

1. Manual of Operations

Detailed description of the laboratory’s massively parallel DNA sequencing production pipeline including all aspects from sample receipt to usable sequence, the availability of a capillary sequencer pipeline for classic high-throughput sequencing including current uses, and the available high throughput genotyping methods.

2. Monthly Reports

Monthly Status Reports shall summarize performance. The report shall include in tabular form a listing the projects assigned during the month, the current status of samples received for resequencing or genotyping for these projects, a list of interactions between the approved investigators, a listing of completed projects and the date when data was sent to the approved investigator, a summary of data submitted to public databases, QC data, production and error rate. The report shall include a summary of problems encountered and how they were resolved, information sent to the ACC for inclusion on the RS&G Service website, information about interactions on special projects. Tabular information will be updated monthly to reflect overall status of all assigned projects, interactions/communications with investigators, receipt of samples, production measures and QC, and specific information for current projects in production.

Monthly reports shall start in month 4.

3. Quarterly Progress Reports

This report shall document and summarize all work results for the period covered. The Quarterly Progress Report shall be in sufficient detail to explain comprehensively the results achieved. The text shall be in letter form (up to five pages).

The face page of the report shall include: the contract number, title, period of performance being reported, contractor's information (name, address, telephone and facsimile numbers, e-mail address), and date of submission.

The report shall include:

a. Progress for the quarter with assigned projects;

b. Problems encountered during the quarter with actions to resolve them;

c. Discussion of efforts to increase production;

d. Report of each Key Performance Requirement in the PAS;

e. Interactions with investigators;

f. Summary of activities planned for the next quarter;

g. Summary of information/interactions with the ACC including those regarding the website, Steering Committee, OSC , Evaluation Panel;

h. Update on special projects, technical or administrative matters, staffing changes;

i. List of manuscripts in progress, those submitted for publication, and those submitted to PubMed; and

The first reporting period consists of the first full three months of performance including any fractional part of the initial month. A Quarterly Progress Report is not required for the periods in which an Annual Report or the Final Report is due. In the first year, the first Quarterly Progress Report will be the Summary of Phase I.

4. Annual Progress Report

The report shall be no more than fifteen pages in length. The Annual Progress Report shall document and summarize all work results for the period covered with a specific section to cover the last quarter’s progress as described for the Quarterly Progress Report.

Cover page to include contract number, title, and period of performance being reported.

Contractor’s information (name, address, telephone and facsimile numbers, e-mail address), and date of submission.

Specifically, the Annual Progress Report shall include:

a. Description of overall progress for the reporting period indicating where the completed work differs from the intended work for the reporting period. Include a report of the progress each project with a figure indicating production by year for the projects in the pipeline. Also include a report on increasing or improving production;

b. Summary tables of production, QC, status of projects assigned to the LC;

c. Current problems which may impede performance and proposed corrective actions;

d. Advancements made in relation to any of the technical tasks;

e. List of problems (technical or financial) encountered during the current reporting period which may have impeded performance and discuss corrective actions and how the problems were resolved and/or are being addressed;

f. Administrative matters and staffing changes;

g. Discussion of milestones met or missed from the PAS;

h. Activities planned for the next reporting period;

i. List of manuscripts in progress, those submitted for publication, and those submitted to PubMed;

j. Full disclosure of intent to file patent applications and copies of patent applications filed whether inside or outside the U.S. on materials, reagents, and procedures derived or established by the work supported under this contract; and

k. PAS Reporting: PAS will address production; QC for laboratory method, databases, and informatics; turn-around times; amount of data submitted to public databases; the increases in production and decreases in costs.

i. Detailed information for the evaluation using the PAS for the past year;

ii. Recommendations for the PAS for the upcoming year.

An Annual Progress Report is not required for the period the final report is due.

5. Final Report

This report shall consist of a summation of the work performed and results obtained for the entire contract period of performance and shall include a section for the Summary of the past year, Phase III year 2. The Final Report shall be in sufficient detail to describe comprehensively the results achieved. The report shall be no more than twenty pages in length. The Final Report shall be submitted on or before the last day of the contract performance period.

The cover page shall include the contract number, title, period of performance being reported. Contractor’s information (name, address, telephone and facsimile numbers, e-mail address), and date of submission;

The Final Report shall explain comprehensively the results achieved and address:

a. Description of overall progress for the last year indicating where the completed work differs from the intended work for the reporting period. Include a report of the progress each project with a figure indicating production by year for the projects in the pipeline. Also include a report on increasing or improving production;

b. List of problems (technical or financial) encountered during the current reporting period which may have impeded performance, discuss corrective actions and how the problems were resolved;

c. Summary tables of full production, QC, projects assigned to the LC;

d. Advancements made in relation to any of the technical tasks;

e. Discussion of milestones met or missed;

f. A list of manuscripts in progress and those submitted for publication;

g. Full disclosure of intent to file patent applications and copies of patent applications filed whether inside or outside the U.S. on materials, reagents, and procedures derived or established by the work supported under this contract;

h. Describe the full extent of the data and products disseminated; and

i. Final PAS will address production; QC for laboratory method, databases, and informatics; turn-around times; amount of data submitted to public databases; the increases in production and decreases in costs achieved in the final year.

Detailed information for the evaluation using the PAS for the past year.

Section F – Deliveries

Satisfactory performance of the contract shall be deemed to occur upon performance of the work described in Section C. and upon deliver and acceptance by the CO or the duly authorized representative, of the following items in accordance with the stated delivery schedule.

The following table provides an overview of deliverables and their respective delivery schedule:

Item Description Delivered to Delivery Schedule

a. Draft Laboratory Manual of Operations

COTR, CO and

ACC

End of second month

b. Final Laboratory Manual of Operations

COTR, CO and

ACC

End of third month

c. Monthly Reports RS&G Service ACC On or before the 7 day of each month starting January 7

d. Quarterly Progress Report

COTR and CO Due on or before:

April 1st :: December – February July 1st : March - May October 1st: June - August

e. Annual Progress Report COTR and CO Due annually on or before January 1st

- to include the September – November quarterly report

f. Final Report (hard and electronic copies)

COTR and CO On or before Contract Expiration Date

Unless otherwise indicated the CO and COTR shall receive one paper and one electronic copy.

Reports and Deliverables shall be provided to the ACC in electronic format and, at the request of the ACC, in paper copy.

The above items shall be addressed and delivered to:

Contracting Officer National Heart, Lung, and Blood Institute RKL2, Rm 6016, MSC 7902 6701 Rockledge Dr Bethesda MD 20892-7902

Contracting Officer’s Technical Representative National Heart, Lung, and Blood Institute RKL 2, Rm. 8202, MSC 7940 6701 Rockledge Dr Bethesda MD 20892-7940

RS&G Service Administrative Coordinating Center (To be Determined)

Section L – Additional Technical Proposal Instructions

a. General Description of the Program and Desired Results

The overall objective of the RS&G Service renewal is to continue to provide high quality, high-volume resequencing and genotyping for investigators to discover and type DNA variations needed to elucidate the genetic components involved in the cause, variable outcome and progression of heart, lung, and blood diseases and disorders. In the renewal, the RS&G Service will include the necessary number of LCs to meet anticipated production. LCs must be capable of performing both massively high throughput, large-scale DNA resequencing and high throughput genotyping to discover and type DNA variations for heart, lung, and blood investigators and one ACC to provide the logistical support for the entire RS&G Service. The ACC will be awarded through a separate solicitation.

Production: Each LC will produce at least 500 Gb of usable sequence per year with an error rate of no more than 1/10,000 bases (no less than 99.99% accurate) and be able to generate at least 60 M genotypes per year with an error rate of no more than 1%. The RS&G Service’s initial DNA resequencing effort (sum of all LC resequencing efforts is expected to be capable of providing at least a total of 1,000 Gb of usable sequence per year. The RS&G Service’s initial genotyping effort (sum of all LCs genotyping efforts) is expected to be capable of customized genotyping of at least 120 M genotypes per year. Project sizes for resequencing are expected to vary from 30 Mb to 120 Mb, but investigators may request larger projects. Projects may have larger regions in fewer samples or smaller regions in a much larger number of samples.

Genotyping projects may request 100 – 1500 SNPs per sample or could be up to 200K SNPs per sample using a disease or focused chip. Sample numbers may also vary from hundreds to thousands. By the end of the third year, each LC will be expected to have doubled or quadrupled its production. LCs will receive DNA samples from investigators approved to utilize the RS&G Service and will not be receiving any tissues or cells. An offeror may propose to perform up to 100% of the RS&G Program’s capacity for resequencing and genotyping. The Government reserves the right to make one LC award if it is determined that the offeror provides the best value to the Government.

The Principal Investigators (PIs) of the LCs are expected to work closely with each other, the ACC, and the NHLBI. The ACC (awarded under a separate solicitation) responsibilities will be to maintain the website, advertise and market the RS&G Service to the research communities;

process the requests for use of the LCs, provide logistical support for the three RS&G Service committees, and facilitate communication among the centers and with NHLBI.

Technology Development: To provide the best resequencing and genotyping to the Institute’s funded investigators and others involved in heart, lung, and blood related research the RS&G Service LCs will incorporate the new advances in sequencing and genotyping. Capacity will increase through the introduction of new technology and/or new products. For instance, the resequencing in the renewal will increase dramatically in capacity and decrease in cost by incorporating the new massively parallel sequencing platforms. Since the companies producing the new platforms and the investigators using them are still improving their production and capacity it is anticipated that there will be significant savings in future years. The new genotyping platforms have increased the number of custom SNPs that can be genotyped per sample. These improvements result in increased capacity and decreased cost. The availability of disease-specific or selective genotyping chips also will increase the amount of genotyping performed while decreasing the cost per genotype.

Laboratory contracts awarded under this RFP will provide resequencing and genotyping to investigators involved in heart, lung, and blood research through the RS&G Service. The offerors for the LCs will need to be able to accommodate a variety of project sizes. Specific research is dependent upon the requests from investigators. The projects will focus on the genomic regions of potential importance in the disease pathways of heart, lung, blood and sleep disorders. The approved requests for resequencing studies have varied from 2.5 to 85 Mb.

Genotyping studies have varied from 2 to 50 M. In the RS&G Service renewal the LCs should expect to receive applications for resequencing candidate genes and regions, and for custom genotyping and genotyping using specialized chips for disease specific questions (vascular disease, lung disease, etc). In addition, they will be expected to provide support for some animal projects and to incorporate technological advances in resequencing and genotyping as appropriate.

Phases: The work of the LCs will be in three phases. During Phase I, the Transition/Early Production Period (Months 1-3), LCs will prepare a draft of its Laboratory Manual of Operations, and work with the ACC and NHLBI staff to review and refine the established overall policies, guidelines and procedures for the RS&G Service. In Phase II, the Full Production Period (Months 4-36), LCs will perform resequencing or genotyping at their initial production levels while improving their capacity and production, so that by the end of month 36 they will have doubled or quadrupled production without an increase in cost. In Phase III, the High Production Period (Months 37-60), the LCs will perform at a level that is at least double their initial production.

The RS&G Service will continue to solicit requests from investigators for use of the service. The RS&G Service will emphasize resequencing and genotyping of human samples, but studies examining genetic variation in animals to identify regions that contribute to complex diseases in humans also will be accepted. The requests will be ranked by an Evaluation Panel of outside experts and prioritized by the NHLBI. The approved projects will be assigned to a RS&G Service contract LC for performance of the resequencing or genotyping. Investigators using the RS&G Service contract LCs will obtain high quality data for submitting R01 applications and manuscripts. Variation data will be submitted to national databases.

Contracts awarded will be performance based. LCs annually will propose specific goals and timetables. The performance of the RS&G Service will be reviewed and evaluated annually by an OSC comprised of a panel of independent experts. Each contractor will be evaluated on their production, capacity, and performance. In year three, the OSC will look more closely at the ongoing needs of the research community, changing technology, and the performance of the service as a whole. They will make recommendations to the NHLBI regarding any adjustments to the program due to changes in needs by the research community, in technology, performance issues, etc. The required production by each of the LCs will be specified in their contract. Metrics of success also will be specified in the contract and are expected to include the production amount and quality; costs; the use of the resource by the heart, lung, and blood research communities as judged by submission of requests, scientific distribution of the projects, the number of manuscripts and abstracts published, the number of grants submitted and awarded, and the amount of data submitted into the public databases.

Selected Examples: Specific research is dependent upon the requests from investigators studying the genomic regions of potential importance in the disease pathways of heart, lung, and blood disorders. The RS&G Service renewal will:

• Perform resequencing of candidate genes and regions and custom genotyping of human samples,

• Perform genotyping using specialized genotyping chips for disease specific questions (vascular disease, lung disease, etc),

• Include rodent and other animal sequencing and genotyping as appropriate, and

• Incorporate technological advances in resequencing and genotyping.

Minimum Capacity Requirement

Years 1-3 Number Error Rate Sequence per Center 500 Gb ≤1/10,000 bases Genotypes per Center 60 M ≤1%

Number ≤1/10,000 bases Sequence per Year 1000 Gb ≤1% Genotypes per Year 120 M

Years 4-5 Number Error Rate Sequence per Center 1000 Gb ≤1/10,000 bases Genotypes per Center 120 M ≤1%

Number ≤1/10,000 bases Sequence per Year 2000 Gb ≤1% Genotypes per Year 240 M

b. Background Information

The NHLBI established the Resequencing and Genotyping (RS&G) Service in the fall of 2004.

The existing contracts for the LCs run through September of 2010. This RFP will award new contracts for the LCs to continue the RS&G Service and will incorporate the recent technological advances in resequencing and genotyping.

The three LCs for the existing RS&G Service (two Resequencing Centers, one Genotyping Center) and the NHLBI coordinate their efforts through the RS&G Service Steering Committee.

Performance of the RS&G Service is reviewed annually by the RS&G Service OSC.

The RS&G Service has increased production and capacity through modifying existing production pipelines and the introduction of new technology. The combined sequencing capacity for the two Resequencing Centers has increased from 60 Mb per year in 2005 to the current level of 240 Mb per year. Genotyping technology improved dramatically in the first year of the RS&G Service resulting in an increase in genotyping capacity from 1 M to 12 M genotypes per year.

Requests for use of the RS&G Service are submitted to the ACC through the RS&G Service website (http://rsng.nhlbi.nih.gov). Requests are reviewed and ranked by an Evaluation Panel consisting of outside experts, and prioritized by NHLBI staff. As of May, 2009, the RS&G Service received 60 requests for resequencing and 45 for genotyping. The 105 requests came from 73 investigators at 52 different institutions. Average project sizes are 30 Mb for resequencing and 2 M for genotyping.

The completed projects have varied in scope, design and size. Data generated has been used by investigators in their manuscripts, abstracts, and new grant applications. Information has also been submitted to public databases. The resequencing projects have included the candidate genes involved in atrial fibrillation, the extremes of blood pressure, the vascular endothelial growth factor (VEGF) pathway, atherosclerosis, familial thoracic aortic aneurysms and dissection, genetic determinants of common essential hypertension, carotid artery disease risk, iron metabolism, venous thrombosis, pharmacogenomics of arrhythmia therapy, Diamond- Blackfan anemia, dilated cardiomyopathy, and loci identified through GWAS studies as influencing LDL cholesterol or HDL cholesterol and triglyceride levels. Completed genotyping projects include a study of the candidate genes for venous thrombosis, coronary heart disease, a replication study of candidate genes for cardiovascular disease, studies in chronic obstructive pulmonary disease (COPD), visceral adiposity, carotid artery disease, hypertension, cystic fibrosis, myocardial infarction and stroke, and lipid-relevant genes.

The NHLBI has funded several genome-wide genotyping association studies (GWAS) on existing cohorts with known phenotypes to further our understanding of the physiological and pathophysiological states underlying heart, lung, and blood diseases and disorders. These efforts include more than 15,000 individuals from the Framingham Heart Study, the Multi-ethnic Study of Atherosclerosis (MESA), and the asthma cohorts as part of the SNP Health Association Resource (SHARe) efforts; over 25,000 individuals through the funding of thirteen grants for the SNP Typing for Association with Multiple Phenotypes from Existing Epidemiology Data (STAMPEED), and individuals participating in the Women’s Health Initiative. The resulting GWAS data is available through the National Library of Medicine’s database of Genotype and Phenotype, dbGAP. Through these GWAS efforts, new genomic areas related to heart, lung, and blood sleep diseases and disorders have been identified. Requests to the RS&G Service are anticipated for targeted resequencing or genotyping to further define the regions found by GWAS efforts to be strongly associated with disease and for selective (custom) genotyping to validate or replicate newly discovered genetic variants in well-phenotyped populations. In addition, anticipated projects may want to use the new focused or disease specific genotyping chips being generated from data produced by the GWAS efforts.

The initial concept was focused only on human samples. The "NHLBI Working Group: Future of Genotyping" held in October of 2004 recommended that the NHLBI consider development of a Rodent SNP Mapping Center. This renewal will facilitate investigations into regions of importance by expanding to include animal studies for resequencing and genotyping.

c. RS&G Committees and Panels

The Steering Committee will consist of two individuals - the PI and a deputy - from each LC and the ACC, and the NHLBI COTR and Deputy COTR. During the first three months of the renewal, the Steering Committee will meet face-to-face once and hold frequent conference calls to review the common guidelines and procedures currently in use in all LCs and for the RS&G Service as a whole. Following approval by NHLBI, the LCs shall implement any changes to the approved common guidelines and procedures. In Phases II and III (months 4-60), the Steering Committee will meet once per year and hold monthly conference calls. In all phases, the Steering Committee will be responsible for reporting to the NHLBI on RS&G Service status, providing suggested changes to accomplish stated time, accuracy, and capacity goals, and recommending ways to improve the RS&G Service’s cost efficiency. If needed, subcommittees of the Steering Committee will be established. Each participating center and the NHLBI will have two votes.

The OSC will be composed of five to seven expert scientists from outside the RS&G Service plus the NHLBI COTR. The OSC may be enlarged permanently or on an ad hoc basis as needed. The areas of expertise will include, but are not limited to, massively parallel sequencing and high throughput genotyping QC; heart, lung, blood disorders; population genetics; quantitative genetics; bioinformatics; and related disciplines such as biostatistics, molecular genetics, and genomics. The NHLBI will determine the expert scientists to serve on the OSC after obtaining suggestions from the Steering Committee, the Evaluation Panel, and other experts outside the RS&G Service.

Once per year the OSC will meet face-to-face to evaluate the performance of the LCs and the ACC and make recommendations to the NHLBI regarding management of the RS&G Service.

When a specific aspect of the RS&G Service needs to be reviewed at another time in the year, the OSC will conduct a conference call. A more detailed review of the RS&G Service will be held in the third year of the renewal after the program has had about 2 years of full production.

This evaluation will determine if there should be shifts in the use of program resources.

The PI and Co-Investigator for each LC will attend the OSC meetings. Each LC will provide requested information in a timely manner. The OSC shall review the LCs for QC, success in maintaining state-of-the-art, readiness for and implementation of technology improvements, success in the R&D activities of the LC, success in meeting targets for increasing capacity and productivity, and overall performance. The OSC shall review the ACC regarding its success in meeting its objectives regarding logistical support for the RS&G Committees; acceptance, functionality, use of the web site; outreach/marketing of the RS&G Service; and overall performance.

The Evaluation Panel will comprise six to twelve expert scientists from outside the RS&G Service plus the NHLBI COTR. The NHLBI will determine the members of the Evaluation Panel after consultation with the Steering Committee and experts from outside the NHLBI and the RS&G Service. The Evaluation Panel will review requests from investigators for resequencing or genotyping and make recommendations, in priority order, to the NHLBI for studies to be allowed access to the RS&G Service in the upcoming period. The objective of the review is to assure that the LCs provide their services to the most meritorious, high caliber genetic studies focused on finding genes associated with a disease or trait of interest to the NHLBI. The review will consider each request regarding programmatic priority, feasibility, adequacy of the size and power, and amount of the RS&G Service resources required. Only investigators with a justifiable amount of resequencing or genotyping will be selected for the RS&G Service. The Evaluation Panel also will make sure that the proposals include the necessary approvals from the investigator’s Institutional Review Board and are in compliance with NHLBI guidelines and policies.

The NHLBI Management Group will include a program staff from the Division of Cardiovascular Diseases, the Division of Lung Diseases, and the Division of Blood Diseases as well as the CO from the Office of Acquisitions. Program staff will serve as the COTR.

d. Estimated Level of Effort

The types of personnel and estimated levels of effort identified below are considered to be the average required for successful completion of the LC objectives. Effort is shown as a percentage of fulltime equivalent (FTE) labor. The personnel and levels of effort listed below are for information only and are not to be considered restrictive for proposal purposes.

Average for LCs:

Labor Category Phases I and II Phase III

Principal Investigator 25 25

Co-Investigator 50 50

Computer Specialist 300 400

Sr. Lab. Technicians 100 100

Laboratory Technicians 300 500

Coordinator 50 50

Total 825% 1125%

Note to Offerors: Offerors shall ensure that the PI and all other personnel proposed will not be committed on Federal grants and contracts for more than a total of 100% of their time. If the situation arises where it is determined that a proposed individual is committed for more than 100% of his or her time, the Government will require action on the part of the offeror to adjust the time commitment.

e. Page and Formatting Limitations

The Technical Plan (objectives, approach, methods of procedures, capacity, and schedule) of the Technical Proposal shall not exceed 30 single-sided pages or 15 double-sided pages. This page limitation does not apply to the cover sheet, abstract, table of contents, personnel, facilities, equipment and resources, other considerations, other support, cost information, and literature cited. Appendices shall be limited to 100 single-sided pages or 50 double-sided pages. Each page of the Technical Proposal must be numbered sequentially.

Offerors are encouraged to limit the overall size of the technical proposal, inclusive of appendices, attachments, etc. Type density and size must be 10 to 12 points. If constant spacing is used, 15 cpi (characters per inch) or fewer shall be used, whereas proportional spacing should provide an average of no more than 15 cpi. There must be no more than six lines of text within a vertical inch. Margins must be no less than ½ inch around, exclusive of headers and footers.

f. Sample Technical Proposal Table of Contents

1. Cover Page Page 1 Cover page should include: RFP Title and Number, Name of Organization, Name of Principal Investigator, Address, and Telephone Number.

2. Table of Contents Page 2

3. Abstract/Project Objectives Page 3

4. Technical Plan/Statement of Work Page 5

The Technical Plan shall not exceed 30 single-sided pages or 15 double-sided pages.

(1) Objectives Page #

(2) Approach Page #

(3) Methods Page #

(4) Schedule Page #

(5) Capacity Page #

5. Personnel Page #

(1) List of All Personnel in the Project Including Subcontractors, Consultants/ collaborators, by Name, Title, Department and Organization Page #

(2) Provide narrative for Principal Investigator/Project Director, Other Page #

Investigators and staff of expertise and qualifications

(3) Other Staff Page # [Note: Include a resume/CV/biosketch for PI and co-investigators in the Appendices]

6. Facilities, Equipment, and Other Resources Page # Describe all facilities, equipment, other resources available, and institutional support

7. Summary of Related Activities Page #

8. Technical Proposal Cost Summary Page #

9. Human Subjects and Animal Models Page #

10. IT System Security Plan Page #

11. Appendices Page #

g. Travel

The Principal Investigator and a senior staff from each LC should plan on travel to attend one Steering Committees during Phase I and once per year in Phases II and III (2 meetings in months 1-12). For budget planning purposes assume one meeting in Bethesda, MD and one in Chicago, IL with each lasting 1.5 days (lodgings 2 nights).

OSC meetings will be once a year and will be planned to coincide with one of the Steering Committee meetings. For budget planning purposes assume meeting will take place in Bethesda, MD and last 1 day (lodgings 1 night).

No travel should be included for Evaluation Panel meetings.

The ACC will be responsible for the logistics of these meetings.

h. Offerors Must Address

In order to document capabilities to perform the Statement of Work and to assure continuity of RS&G operations, offerors must address the following:

1. Proposals should describe the experience of investigators and staff relevant to the proposed resequencing and genotyping efforts and plans for continued high-throughput, large-scale production of resequencing and genotyping data should the PI or other key personnel leave the LC.

2. The technical proposal should suggest a PAS for the first year. The suggested PAS should provide an approach for calculating cost as compared to production and for determining increases in production without increasing costs. During negotiations the PAS will be finalized with NHLBI and incorporated into the contract. During performance, NHLBI may withhold or reduce workload and funds for any LC that substantially fails to meet its approved PAS for the year or fails to maintain state-of-the-art service. See Exhibit for a draft PAS.

3. Proposals should describe current and projected laboratory capacity and turn-around times.

4. Discuss what changes could be investigated and the expected increase in production for each change.

5. Proposals should describe how proposed procedures to provide data to investigators have been used in the past, and how the investigators were able to utilize process and/or the data files.

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