SOW Final 07-23-12.pdf

ATTACHMENT 3

STATEMENT OF WORK

FOR THE

SUPPORT OF COLLABORATIVE STUDIES OF

EXPOSURE TO ENVIRONMENTAL CONTAMINANTS IN RELATION

TO CHILD HEALTH IN THE GENERATION R STUDY

JULY 23, 2012

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Background

The Generation R Study enrolled pregnant women and their partners and is following them and their children over time (Jaddoe et al., 2006; Jaddoe et al., 2008). Nearly all pregnant women in

Rotterdam were eligible. Enrollment began in 2002 and ended in 2006. Nearly 10,000 pregnant women and their offspring were enrolled. Women in the study provided biologic specimens and completed questionnaires about themselves and their children, and in-person follow-up examinations take place on a regular basis. The Generation R Study has many specific goals, although the general purpose of this study is to find causes of serious diseases among mothers and children.

In February of 2004, NIEHS began supporting an increase in the number of urine specimens collected from each pregnant woman from 1 to 3 (at <18, 18-25, and > 25 weeks of gestation).

As each pregnant woman presented for an ultrasound examination of her fetus, she provided a spot urine specimen that was divided into three 20 ml aliquots and frozen at -20 o C in polypropylene containers. Two of these aliquots are reserved for collaborative studies with

NIEHS. Before NIEHS initiated collection of additional urine specimens, urine was collected only at the <18 weeks of pregnancy (initial) study ultrasound visit. When the collection of additional urine specimens was implemented, all women presenting for their study ultrasound (at

<18, 18-25, and >25 weeks of gestation) provided a urine specimen that was stored, regardless of whether urine specimens had been collected at earlier ultrasound visits. Thus, for Generation R

Study subjects enrolled from February 2004 through January 2006, there exists a complete set of

3 urines for 2,025 women, 2 urines for 970 women, and 1 urine for 356 women. The urine specimens collected with NIEHS support can be used to assess the level of exposure to selected environmental contaminants and other compounds. The Generation R Study Management Team at Erasmus University governs the use of the samples and associated data.

As part of the Generation R Study in-person follow-up examination of children at age 5 years, the examination will include: 1) the Berkeley Puppet Interview for children's self perceptions in

6 domains (academic competence, achievement motivation, social competence, peer acceptance, depression-anxiety, and aggression-hostility); 2) the Diagnostic Interview Schedule for

Children (DISC-IV) for ADHD Diagnoses and other Clinical DSM Disorders; 3) an Autism Trait

List (SCQ), administered by a child psychiatrist (in selected children after pre-screening on e.g.

parent/teacher reported symptoms; 4) an assessment of cognitive performance using both verbal intelligence and non-verbal intelligence testing (Dutch SON-R test). Thus, examining levels of environmental contaminants, as measured in urine specimens, in relation to risk of attention deficit hyperactivity disorder, cognitive abilities, and other neuropsychiatric and behavioral abnormalities will be possible. The age 5 follow-up is scheduled to end in 2011.

This contract will provide partial support for some ongoing activities of the Generation R Study and will support one or more specific projects initiated by NIEHS investigators. The ongoing work of the Generation R Study relevant to this contract includes: a) specimen storage and management in support of research, and b) data processing, storage, and management in support of research. Support of specific projects initiated by NIEHS investigators will have two components. First, the contract will support personnel in the Netherlands to provide general administrative and scientific liaison and facilitation with the Generation R Study and to assist

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NIEHS scientists with implementing NIEHS-initiated projects based on the Generation R Study.

Second, through contract options, the contract will provide support for one or more specific projects; this includes the cost of laboratory analyses of Generation R Study specimens and one postdoctoral fellow in the Netherlands.

The environmental studies based on the Generation R Study are coordinated by Dr. Frank Pierik, who is located at TNO (Nederlandse Organisatie voor Toegepast Natuurwetenschappelijk

Onderzoek, or Netherlands Organization for Applied Scientific Research), which is a separate organization from Erasmus University where the Generation R Study is based. For that reason, this contract is negotiated with TNO, which will subcontract work as needed with Erasmus

University. Dr. Pierik shall also be designated as Principal Investigator for this contract unless otherwise agreed upon by the Contracting Officer’s Technical Representative (hereinafter COR) and the Contracting Officer.

A contract between NIEHS and TNO will allow NIEHS to rapidly field new studies based on those data. We anticipate conducting studies, e.g., on maternal pregnancy organophosphate pesticide exposure, as estimated by concentrations of pesticide metabolites in urine, in relation to outcomes such as general cognitive index. A previous NIEHS-Generation R collaborative study showed that levels of organophosphate pesticide metabolites in the urine of Generation R Study mothers were relatively high during pregnancy (Ye et al. 2008).

Statement of Work

Independently, and not as an agent of the United States Government, the contractor shall furnish all the necessary services, qualified personnel, material, equipment, and facilities, not otherwise provided by the United States Government as needed to perform the following:

1. Specimen storage and management

Ongoing activity - The Generation R Study specimen repository is located at Star Medisch

Diagnostic Centrum, Vlambloem 21, 3068 JE Rotterdam, the Netherlands. The repository has 150 m of space accommodating multiple freezers, including 6 for prenatally collected

(pregnancy) samples, and 4 freezers for children’s urine samples at the age of 5 years. The samples have been logged into the Labosys database along with the date of collection and the date of receipt, and the approximate combined amount of time the specimen spent at the collection site and in transit has been recorded. The average length of time between sample collection and receipt at repository was less than 4 hours.

The bar codes on the long term storage tubes were scanned into the Labosys database, and are regularly backed up into an Access database at the Generation R data office. The freezer racks have barcodes on them and, as the specimens were placed in the freezer, a link was established between the specimen and rack barcodes. The database includes a standard numeric field indicating low specimen volume, if present, and keeps track of the remaining vials and volumes when urine is taken from the repository.

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Freezer temperature charts and alarm logs are kept and available. The urine specimens are frozen at -20 C. Freezers have alarms that notify individuals if the temperature in the freezer rises 10 C above the respective temperatures noted above.

The contractor shall continue to store the previously collected maternal and child urine specimens as described above for a one year period beginning on the date of contract award.

2. Data processing, storage, and management

Ongoing activity - Database management for the cohort involves three linked databases with data on specimen locations, administrative data, and questionnaire data. Data on enrollment and tracking, and data from the questionnaires are in an Access database at the

Generation R Study data office in Rotterdam. The repository data are in a Labosys database at Star Medisch Diagnostic Centrum in Rotterdam. Results of laboratory analyses of urine specimens are stored in a study database.

The contractor shall continue to process, store, and manage the Generation R Study data as described above for a one year period beginning on the date of contract award.

Reports and other deliverables are described in the “DELIVERABLES” section, beginning on page 7 of the Statement of Work.

3. General administrative and scientific liaison and facilitation

The procedure for applying to use the study data and biologic materials shall be to submit proposals to the Principal Investigator at TNO, who will then present them to The

Generation R Study Management Team, the body governing the Generation R Study, for approval.

The contractor shall establish a reasonable schedule for evaluation of applications, and shall provide feedback on proposals to those scientists at NIEHS who have applied to conduct Generation R Study-based projects.

A procedure for obtaining the approval of human subjects in the Netherlands for NIEHS-initiated projects nested within the Generation R Study shall be established and described to NIEHS. All NIEHS-initiated projects will be submitted for such approval by the

Principal Investigator, or his designate.

A procedure for submitting data requests shall be established and described to NIEHS.

Analytical data files based on linked repository and questionnaire data that are for NIEHS use shall be created and issued by a Generation R Study programmer, with all requests and data being channeled through the Principal Investigator.

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The procedure for identifying specific specimens to be pulled for a given study shall be well defined and described to NIEHS.

A mechanism for Generation R database queries shall be established to allow exploration when projects are being considered by NIEHS.

A procedure shall be established for identifying potential collaborators from the

Netherlands for new projects implemented via this contract.

Additionally, a procedure shall be established for sending requests to the repository for pulling and shipping of specimens. This shall include a description of how replacement specimens are to be pulled in the event that the first or second choice specimen is not available (e.g., inadequate volume). The contractor will acknowledge receipt of request, and will report anticipated pull schedule, actual specimen pull dates, shipping date, and date laboratory results are received (see Deliverables on page 7 of the Statement of Work).

For five (5) years after laboratory results are obtained, NIEHS investigators shall have exclusive publication rights for designated projects based on laboratory results that we have funded. NIEHS shall be offered the opportunity to collaborate on projects that use the laboratory results NIEHS has funded. Note that this means for use on approved projects, others could access such data as soon as it is available from the laboratory (before five years have passed).

All procedures such as those described, and any related forms, addresses, guidelines, pertinent schedules, and database codebooks shall be made available in English in an electronic format.

The Principal Investigator or designated study personnel shall travel to NIEHS annually to attend meetings to discuss study management, project plans, and collaborations. The dates of travel shall be mutually agreed upon by the COR and Principal Investigator. The COR shall have final approval of the number of persons traveling for such meetings.

The contractor shall allow up to 7 ml of child urine to be used for NIEHS-designated projects executed via option (described below), in addition to any required maternal pregnancy urine (of similar volume per collection time).

Reports and other deliverables are described in the “DELIVERABLES” section, beginning on page 7 of the Statement of Work.

4. Options

a. Option 1 – Extend base contract for 1 year.

The services and support described in items 1-3 above shall be continued for a one-year period. This option may be executed up to 4 times.

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b. Option 2 – Specific project with laboratory analysis

An epidemiologic study (or studies) shall be performed that is based on the analysis of the Generation R Study urine specimens. Such studies shall require the analysis of the specimen material at a laboratory designated by the COR. Approval for specific studies by the appropriate committees (Generation R Study Management Team and

Institutional Review Boards in the Netherlands) shall be obtained prior to undertaking studies.

The Generation R Study repository personnel shall handle indicated specimens as follows:

1) Using a list of specimens approved by NIEHS, the material shall be removed from the freezers by a robot and divided as needed. Choice of laboratory shall follow FAR 52.244-5a, Competition in Subcontracting:

“The Contractor shall select subcontractors (including suppliers) on a competitive basis to the maximum practical extent consistent with the objectives and requirements of the contract.” The contractor will obtain bids for the laboratory analysis, including information on quality control performance characteristics of the assay, and history of promised versus actual delivery date. The repository shall ship the frozen samples to the laboratory designated by the COR, for analysis.

2) The Generation R Study personnel will provide datasets, reports, and specimen lists, as described in the “DELIVERABLES” section, below.

3) The COR will designate what the outcomes and exposures will be in such studies—these will be determined after a peer review process that will carefully assess each study proposal.

This option can be exercised up to 5 times during the contract.

(For budget estimation purposes, assume that Option 2 will be exercised once in each year of the contract. Use the Example project below to estimate cost.)

Example Project (for proposal purposes)

For technical proposal purposes, assume that the type of study to be conducted via this option is as follows:

From the group of approximately 1,200 Generation R Study subjects who will have data on the 5-year assessment of cognitive performance and who have three serial maternal pregnancy urine specimens available, we will select 600 at random. Three urine specimens per subject will be analyzed for organophosphate pesticide metabolites (6 dialkyl phosphates), phthalates, BPA, creatinine, and specific gravity. Exposure estimates based on the average of three measures per subject will be examined in relation to a number of outcomes, but the primary focus will be on cognitive performance at age 5. Using the same data, additional

Attachment 3 - SOW 7 studies will be possible on body composition at age 5, reflexes at 3 months, and results on several neurodevelopmental scales, such as the Child Behavior

Checklist at several ages. An example of such additional studies would be to see if the relation of organophosphate pesticide metabolites, phthalates, and BPA with components of the Child Behavior Checklist replicates findings reported by others.

c. Option 3 – Support a postdoctoral fellow for 2 years

This option is to provide support for a postdoctoral fellow in the Netherlands for two years. The fellow will write scientific papers for publication that have been mutually agreed upon by Generation R Study investigators, TNO, and the COR. Over the duration of the contract, this option will be exercised only once.

The postdoctoral fellow will be based in the Netherlands and he or she shall be jointly mentored by scientists from the Netherlands (TNO and Erasmus University) as well as from NIEHS. This shall be accomplished through regular telephone conferences and e-mail correspondence. The fellow shall be invited by NIEHS to spend part of the fellowship at NIEHS. NIEHS shall be involved in the process of hiring the applicant, for example, by participating in the screening of the applicants.

5. Compliance with Memorandum of Understanding

A Memorandum of Understanding regarding the agreement to be codified in this contract was signed by NIEHS, Netherlands Organization for Applied Scientific Research (TNO) and Erasmus Medical Center, dated 3 September 2010. All details of the contract will comply with the Memorandum of Understanding unless specifically negotiated otherwise.

6. Roles and Responsibilities of Parties in the Netherlands Involved in this Contract

Entity Role Responsibility

TNO Contractor General administrative and scientific liason and facilitation

Coordinates execution of contract options

Deliverables (items 1-4)

Delivers datasets

Erasmus Subcontractor Specimen storage and management

Data processing, storage, and management

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DELIVERABLES

1. Reports

Within 3 months of the award of the contract, the contractor shall provide a list in English of all variables available on each subject, along with a codebook describing information associated with values assigned to each variable. The list shall be provided in electronic format to the COR.

2. Reports responding to database queries

Generation R Study personnel and the Principal Investigator shall support the planning of studies that will subsequently be executed via exercise of an option. This support of planning shall be accomplished by providing reports in response to queries .

The Contracting Officer Technical Representative at NIEHS will send database and other queries to the Principal Investigator. The queries will ascertain information such as expected number of cases of attention-deficit hyperactivity disorder among children of mothers who have three urine specimens and specified covariate data available, expected number of children who screen positive for autism and whose mothers have three urine specimens and specified covariate data available, expected number of children whose cognitive performance will have been measured and whose mothers have three urine specimens and specified covariate data available. Other conceivable queries will include items such as expected number of children who have DEXA and anthropometry data and whose mothers have three urine specimens and specified covariate data available. The reports will comprise answers to these queries. It is expected that up to four such queries per year will be posed. The contractor shall provide responses in English within 90 days of receipt of a query.

3. Reports on proposed option projects

For each option project proposed to the Generation R Study Management Team, the contractor shall acknowledge the name and date of applications received within two weeks of receipt and provide the anticipated date of review. Within 30 days of review, the contractor shall convey the outcome of the evaluation including providing feedback on the proposal in the event it was not approved.

Once a proposed option project has been approved by the Generation R Study

Management Team, prior to exercise of the corresponding option, the Contractor shall submit a cost estimate of the work to be performed within three (3) weeks of receipt of a request for an estimate from the COR. The cost estimate shall be submitted to the COR in

English using dollar values at current exchange rates in an Excel spreadsheet format.

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4. Semi-annual reports on responses to database queries and approved option projects

Semi-annually, beginning with the date of the contract, the contractor shall provide a report on the status of any outstanding Generations database queries posed by NIEHS.

Semiannually, beginning with the date of the first exercise of an option, the contractor shall provide a report on the approved option projects that includes up-to-date lists of all

NIEHS initiated projects that make use of Generation R Study data and specimens. The report shall provide a brief paragraph on the status of all such studies. This report shall be submitted in conjunction with the above semiannual report on database queries.

Both types of reports shall contain any other material deemed relevant to the contractor’s responsiveness to the terms of the negotiated contract.

Table listing reports

Item Description Quantity Format Delivery Schedule

1 Variable list 1 1 copy ASCII in 3 months after and e-mail, 1 copy in award of contract codebook Word or pdf

2 Reports responding To be 1 copy ASCII in 3 months after to database determined e-mail, 1 copy in query posed queries Word or pdf

3 Reports on proposed To be 1 copy in ASCII in Acknowledge receipt option projects determined e-mail, 1 copy in within 2 weeks; report

Word or pdf due 30 days after review (see SOW)

4 Semi-annual reports 10 1 copy in ASCII in Every 6 months after on responses to e-mail, 1 copy in award of contract database queries Word or pdf and approved option projects

The above items shall be delivered as described above to:

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Addressee Deliverable item no. Quantity

Dr. Matt Longnecker 1, 2, 3, 4 1

(longnec1@niehs.nih.gov)

Jennifer Smith

(smithj3@niehs.nih.gov) 1, 2, 3, 4 1

Datasets

Files with laboratory results from NIEHS-initiated studies and corresponding subject data from questionnaires shall be sent electronically or made available in an electronic format that NIEHS can download. The data shall be transmitted or made accessible to the NIEHS support services contract person assigned to the Generation R Study. The files shall be in standard format, and mutually agreed upon. Each file shall have data for individual subjects and shall include a code number to link data for subjects across files. This code shall be different from the national identity number (citizen’s service number), and NIEHS investigators will not have the file linking the study code ID with any personally identifying information. ALL PERSONALLY

IDENTIFYING INFORMATION SHALL BE REMOVED SO THAT SUBJECTS CANNOT

BE IDENTIFIED, DIRECTLY OR THROUGH IDENTIFIERS LINKED TO THE SUBJECTS.

mailto:longnec1@niehs.nih.gov mailto:smithj3@niehs.nih.gov