[Federal Register Volume 81, Number 195 (Friday, October 7, 2016)]
[Notices]
[Pages 69822-69826]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-24349]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Centers for Disease Control and Prevention


National Health and Nutrition Examination Survey (NHANES) DNA 
Specimens: Guidelines for Proposals To Use Specimens and Cost Schedule

AGENCY: Centers for Disease Control and Prevention (CDC), Department of 
Health and Human Services (HHS).

ACTION: Notice.

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SUMMARY: The Centers for Disease Control and Prevention (CDC), located 
within the Department of Health and Human Services (HHS) announces 
reopening of the National Center for Health Statistics' (NCHS) National 
Health and Nutrition Examination Survey (NHANES) DNA Specimen 
Repository for research proposals. Blood samples for DNA purification 
were collected from study participants during NHANES III, NHANES 1999-
2000, NHANES 2001-02, NHANES 2007-08, and NHANES 2009-10 (Office of 
Management and Budget Control Numbers 0920-0237/0920-0950). Samples 
from these DNA Specimens are being made available to the research 
community for genetic testing. The information gained from research 
using these samples can be combined with the extensive amount of 
information available in NHANES which describes the prevalence/trends 
of disease, nutrition, risk behaviors, and environmental exposures in 
the US population. A more complete description of this program follows.

[[Page 69823]]


FOR FURTHER INFORMATION CONTACT:  NHANES Genetic Project Officer: Jody 
McLean M.P.H., Division of Health and Nutrition Examination Surveys, 
National Center for Health Statistics, Centers for Disease Control and 
Prevention, 3311 Toledo Road, Hyattsville, MD 20782, Phone: 301-458-
4683, Fax: 301-458-4029, EMail: [email protected].

    Authority: Sections 301, 306 and 308 of the Public Health 
Service Act (42 U.S.C. 241, 2421 and 242m).

SUPPLEMENTARY INFORMATION:

Background

    NHANES is a program of periodic surveys conducted by NCHS. 
Examination surveys conducted since 1960 by NCHS have provided national 
estimates of the health and nutritional status of the U.S. civilian 
non-institutionalized population. The goals of NHANES are (1) to 
estimate the number and percentage of people in the U.S. population and 
designated subgroups with selected diseases and risk factors for those 
diseases; (2) to monitor trends in the prevalence, awareness, treatment 
and control of selected diseases; (3) to monitor trends in risk 
behaviors and environmental exposures; (4) to analyze risk factors for 
selected diseases; (5) to study the relation among diet, nutrition and 
health; (6) to explore emerging public health issues and new 
technologies; and (7) to establish and maintain a national probability 
sample of baseline information on health and nutritional status.
    The availability of the NHANES III DNA specimens has been 
previously announced in 2002 (67 FR 51585), 2006 (71 FR 22248), 2007 
(72 FR 59094), 2009 (74 FR 45644), and 2010 (75 FR 32191). NHANES III 
Phase II DNA specimens (1991-1994) are from participants ages 12 or 
older (see NHANES III DNA Specimens section for a description). For 
details about available NHANES III non-genetic data see http://www.cdc.gov/nchs/nhanes/nh3data.htm.
    Beginning in 1999, NHANES became a continuous, annual survey rather 
than a periodic survey. For a variety of reasons, including disclosure 
and reliability issues, the survey data are released as public use data 
files every two years. In addition to the analysis of data from any two 
year cycle, it is possible to combine two cycles to increase sample 
size and analytic options. Blood samples for DNA purification were 
collected from participants aged 20 years and older in survey years 
1999-2002 and 2007-12. DNA specimens are available as collections from 
NHANES 1999-2002 (NHANES 1999-2000 and 2001-02 specimens available as 
one collection), and NHANES two-year cycles 2007-08 and 2009-10(see 
NHANES 1999-2002, 2007-08, and 2009-10 DNA specimens section for a 
description). Availability of DNA specimens from NHANES 2011-12 is 
forthcoming and will be announced in a future FRN. The availability of 
the NHANES 1999-2002 and NHANES 2007-08 DNA specimens has been 
previously announced (Thursday, September 3, 2009 [74 FR 45644], and 
Monday, June 7, 2010 [75 FR 32191]). The data release cycle for the 
NHANES corresponding to the period in which specimens were collected 
for DNA is described in the following web links: http://wwwn.cdc.gov/nchs/nhanes/search/nhanes99_00.aspx, http://wwwn.cdc.gov/nchs/nhanes/search/nhanes01_02.aspx, http://wwwn.cdc.gov/nchs/nhanes/search/nhanes07_08.aspx, and http://wwwn.cdc.gov/Nchs/Nhanes/Search/nhanes09_10.aspx.
    Identifiable health information collected in the NHANES is kept in 
strictest confidence. During the informed consent process, survey 
participants are assured that data collected will be used only for 
stated purposes and will not be disclosed or released to others without 
the consent of the individual in accordance with section 308(d) of the 
Public Health Service Act (42 U.S.C. 242m). During NHANES III, 
participants 12 years and older (parent or guardian signed the consent 
form if the participant was under age 18 years) signed a consent form 
to store a sample of their blood for future research. In NHANES 1999-
2002, 2007-08 and 2009-10 a separate consent form was signed by 
eligible participants who agreed to the storing of specimens for future 
genetic research. DNA specimens will be available for testing only from 
participants who consented to future genetic research. Resulting data 
from DNA specimen testing will be linked to the NCHS variables (public 
use and restricted) and available for analyses through an NCHS Research 
Data Center (RDC). Access to these data at an NCHS RDC is only through 
an approved proposal process mechanism to assure confidentiality.

Research Proposal

    Note: The following proposal types differ from those used in 
previous announcements for use of NHANES III DNA specimens (Thursday, 
August 8, 2002 [67 FR 51585], Friday, January 13, 2006 [71 FR 22248], 
and Monday, June 10, 2010 [75 FR 32191]).
    Proposals testing a complete NHANES DNA collection of specimens 
(NHANES III, 7,159 samples; NHANES 1999-2002, 7,839 specimens; NHANES 
2007-08, 4,612 specimens; NHANES 2009-10, 4,893 specimens):
    Note: If the investigator would like to propose a subsample of the 
complete set please contact the NHANES Genetic Project Officer to 
discuss feasibility.
    Proposals should investigate specific research hypotheses. The 
investigator will specify which DNA collection they are requesting and 
the tests to be conducted on DNA specimens excluding tests that produce 
incidental findings. The investigator will also include in the research 
protocol an analytic plan that includes a list of proposed NCHS 
variables (public use and restricted) that would be used for the data 
analyses. The investigator will conduct the tests of the approved 
variants or approved assays on samples of NHANES DNA specimens that are 
labeled with a lab identification number that is not directly linkable 
to the public use file and therefore, anonymous to the investigator. 
Investigators are required to provide the data obtained from DNA 
testing to Division of Health and Nutrition Examination Survey 
(DHANES)/NCHS for quality control assessment. Analysis and linkage of 
the resulting data are conducted in the NCHS RDC via a separate 
proposal.
    After the DHANES/NCHS has completed the initial quality control 
assessment, investigators will be given up to six months to conduct a 
comprehensive quality assurance review. The timeframe allowed for this 
review will depend on the number and characteristics of the tests 
submitted. At the completion of this review, the availability of the 
resulting data will be announced to the public on the NHANES Web site 
Genetic Variant Search: http://www.nhgeneticvariant.com/. The resulting 
data can be linked to other NCHS variables (public use and restricted) 
for secondary data analysis. For further information on available 
variant data visit: http://www.cdc.gov/nchs/nhanes/biospecimens/dnaspecimens.htm#Genetic.
    DNA specimen collections will be provided in 96 well plates to 
investigators and distributed as samples from a complete collection or 
from a subsample of a collection.
    Proposals testing DNA specimens already obtained from previous 
solicitations: Investigators that have obtained samples from NHANES DNA 
specimens from previous solicitations and have sufficient DNA left may 
request to do additional tests on the

[[Page 69824]]

remaining DNA. These proposals must be submitted and approved before 
the DNA specimens were scheduled to be destroyed or returned. The 
investigator will specify the test to be conducted on the samples 
excluding tests that produce incidental findings. The investigator will 
also include in the research protocol an analytic plan that includes a 
list of proposed NCHS variables (public use and restricted) that would 
be used for the data analyses.

DNA Samples

    These DNA specimens (NHANES III, NHANES 1999-2002, NHANES 2007-08 
and NHANES 2009-10) were processed by the Centers for Disease Control 
and Prevention (CDC), National Center for Environmental Health (NCEH), 
Division of Laboratory Sciences (DLS).

NHANES III DNA Specimens

    The laboratory will distribute aliquots (samples) of crude DNA 
lysates extracted from cell lines. DNA concentrations vary and are 
estimated to range from 7.5-65.0 ng/[mu]L with an average of 
approximately four micrograms in 100 [mu]L. Samples will be provided in 
96 well plates that are bar-coded and labeled with a readable 
identifier. Quality control samples (5% of the total) will be sent at 
no charge, on separate plates as blind replicates. DNA specimens are 
available from 7,159 NHANES III participants. Samples will be 
distributed in a total of 78 plates with an additional four plates of 
quality control samples. NHANES III DNA specimens are in limited supply 
thus are not available as a partial set. Due to the method of 
extraction, NHANES III DNA specimens are not appropriate for all 
projects and/or assays.

NHANES 1999-2002, 2007-08, 2009-10 DNA Specimens

    The laboratory will distribute aliquots of purified, high molecular 
DNA in normalized concentrations of 50.0 ng/[mu]L. Some specimens may 
fall below this threshold. A sample of 40 microliters of each specimen 
will be supplied. The amount of DNA in each sample may vary but will be 
on average approximately two micrograms.
    There are purified DNA specimens from 7,839 NHANES 1999-2002 
participants. Samples from these specimens will be distributed into 90 
plates including four plates of quality control samples.
    There are purified DNA specimens available from 4,612 NHANES 2007-
08 participants. These will be distributed into approximately 54 plates 
including three plates of quality control samples.
    There are purified DNA specimens available from 4,893 NHANES 2009-
10 participants. Samples from the specimens will be distributed into 54 
plates with approximately three additional plates of quality control 
samples.
    Each 96 well plate will be bar-coded and labeled with a readable 
identifier. Quality control samples (5% of a collection) will be sent 
at no charge, on separate plates as blind replicates.

Proposed Cost Schedule for Providing NHANES DNA Samples

    Costs are determined by NCHS and include costs incurred from the 
contracting DNA Repository and DHANES administrative costs. The fee 
covers the costs of materials, equipment, labor, proposal review, 
administration and space for storage. For more details see Table 1 
below. In prior years, the DNA Repository was maintained by CDC. The 
DNA Repository is now maintained by a private contractor. The costs of 
contracting, along with annual inflation increases, are reflected in 
the proposed cost schedule.

Procedures for Proposals

    The investigator should follow these instructions for preparation 
of proposals. Protocols must be written using the outline below.

Proposal Timeline

     Submission of Proposals: Can be submitted on an ongoing 
basis.
     Scientific Review: Within two months of proposal 
submission.
     Institutional Review Date: Within six weeks of final 
proposal acceptance.
     Notification of approval: Approximately 30 days after 
Institutional Review.
     Anticipated distribution of samples: Approximately 60 days 
after all approvals are obtained.
    Note: Timeframe may vary depending on the nature of the proposal 
and the results of each level of review. Unforeseen circumstances could 
result in a change to this schedule.
    DNA Specimen Program will begin accepting research proposals on 
December 6, 2016.
    In addition to the cover page, the research proposal should contain 
the title of the research project, the name, address phone number and 
Email address of the lead investigator along with the name of the 
institution where the testing will be conducted. Office of Human 
Research Protections assurance numbers for the institutions engaged in 
the research project should be included. CDC investigators need to 
include their Scientific Ethics Verification Number. Email submission 
of the proposal is required.
    The proposals should be a maximum of 20 single-spaced typed pages, 
excluding figures and tables. Please use appendices sparingly. If a 
proposal is approved, the title, specific aims, name, and phone number 
of the author will be maintained by NCHS and released if requested by 
the public. Unapproved proposals will be returned to the investigator 
and will not be maintained by NCHS.
    Applications will have a Scientific Review by the Genetic Project 
Officer and the Technical Panel. The Technical Panel is comprised of 
two members: A Genetic Research Scientist and a Genetic Epidemiologist. 
The members review each proposal for scientific and technical merit.
    After the proposal is approved by the Genetic Technical Panel and 
the Genetic Project Officer it will be submitted for Institutional 
review. All proposals will undergo Institutional Review by the NCHS 
Human Subjects Contact and the NCHS Ethics Review Board (ERB) for any 
potential human subjects concerns to ensure appropriate human subjects 
protections are provided in compliance with 45 CFR 46, and by the NCHS 
Confidentiality Officer for disclosure risk. The ERB will review the 
proposal even if the investigator has received approval by their 
institutional review panel.
    Proposals should include the following information:
    (1) Cover sheet: Include the name of the institution where the test 
will be conducted and Office of Human Research Protections assurance 
numbers for the institutions engaged in the research project. CDC 
investigators need to include their Scientific Ethics Verification 
Number.
    (2) Abstract: Please limit the abstract to 300 words.
    (3) Specific Aims: List the broad objectives; describe concisely 
and realistically what the research is intended to accomplish, and 
state the specific hypotheses to be tested.
    (4) Background and Public Health Significance:
    (A) Describe the public health significance of the proposed 
research.
    (B) Discuss how the results will be used. Analyses should be 
consistent with the NHANES mission to assess the health of the nation. 
The Scientific Review will ensure that the proposed project does not go 
beyond either the general purpose for collecting the blood samples for 
DNA in the survey or the specific stated goals of the proposal.
    (5) Design, Method, and Data analysis: The appropriateness and

[[Page 69825]]

adequacy of the methodology proposed to reach the research aims, and 
the appropriateness of using the NHANES (a complex, multistage 
probability sample of the national population) to address the goals of 
the proposal will be assessed.
    (A) Research Design and Methods: Describe the analytic and 
statistical methods to be employed. Include power calculations. For all 
proposal categories, include a detailed description of the laboratory 
methods. The characteristics of the laboratory assay, such as 
reliability, validity, should be included with appropriate references. 
The potential difficulties and limitations of the proposed procedures 
should also be discussed. Address adequate methods planned for handling 
and storage of samples of DNA specimens. Proposals must specify 
specific variants or the standard assay(s) that will be used to test 
the proposed research hypotheses and include a statement of why the 
specific standard assay(s) is/are necessary to test the proposed 
hypotheses. The standard assay is a commercially available assay for a 
curated set of variants. (1) Proposals will be provided with quality 
control samples at no additional cost. Approved projects must run these 
quality control samples and submit these results along with the results 
from the NHANES DNA samples, unless the Genetic Project Officer has 
approved an alternative quality control review plan. (2) Proposals 
using residual samples should have residual quality control samples and 
investigators will be required to use these residual quality control 
samples. The proposal should address additional quality control 
procedures the laboratory will use to assure the validity of the test 
results and address adequate methods planned for handling and storage 
of sample specimens.
    (B) Data analysis: Note: All resulting data must be analyzed in the 
NCHS RDC Output: Please describe the data output that you would like to 
retain and take out of the RDC after analyses.
    (6) Additional information for NHANES:
    (A) Clinical Relevance of Research Findings: The consent document 
for DNA specimen storage and future studies states that individual 
results will not be provided to participants therefore no tests that 
would need to be reported back to the participant can be proposed. 
DHANES/NCHS will use the most recent American College of Medical 
Genetics and Genomics (ACMG) recommendations for reporting incidental 
findings to review the proposed tests and the potential incidental 
findings. Investigators must justify that the proposed tests do not 
produce sets of variants on specific genes listed by the most recent 
ACMG as reportable incidental findings as well as how potential 
incidental test results will be handled. As of publication the most 
recent report, published July 2013, ``ACMG Recommendations for 
Reporting of Incidental Findings in Clinical Exome and Genome 
Sequencing'', lists 56 genes where specific variants on these genes are 
pathogenic for 24 conditions.
    (B)Data Transfer: Specify the secure method to transfer resultant 
data to NCHS. Investigators must use a device that meets federal 
information processing standards (FIPS 140-2 and FIPS 197).
    (C) Period of Performance: Specify the project period. The period 
may be up to three years. At the end of the project period, any unused 
samples must be returned to the NHANES DNA Specimen Repository or 
destroyed by the investigator. Extensions to the period of performance 
may be requested.
    (D) Funding: Include the source and status of the funding to 
perform the requested laboratory analysis. Investigators will be 
responsible for the cost of processing and shipping the samples (See 
table).
    (7) References.
    (8) Resumes/CV: Please include a 2-page CV for each member of the 
research team in this document (not as attachments).

Public Availability of Data

    Data resulting from use of DNA specimens will be made available to 
the public for secondary data analyses via the NCHS RDC. After DHANES/
NCHS quality control assessment is completed, investigators will be 
given up to six months to conduct comprehensive quality assurance 
review in the NCHS RDC. The quality assurance review timeframe will be 
negotiated between the investigator and the NHANES Genetic Project 
Officer and will depend on the type, number, and characteristics of the 
tests submitted. The results of the quality assurance review will be 
provided to DHANES/NCHS and appropriate aspects will become part of the 
data set documentation. The public announcement, that test results are 
available for submission of proposals for secondary data analyses, will 
occur once the quality assurance review timeframe has ended. For a list 
of currently available variant data see: http://www.cdc.gov/nchs/nhanes/biospecimens/dnaspecimens.htm#Genetic.
    Proposals for secondary data analyses linking NCHS restricted data, 
NCHS public use data, or non-NCHS data to data resulting from DNA 
specimen testing will be reviewed by the NCHS RDC. See http://www.cdc.gov/rdc for proposal guidelines.

Submission of Proposals

    Proposals can be submitted immediately. The review process will 
begin approximately 60 days from the publication of the notice and will 
include all proposals submitted as of that date.
    Electronic submission of proposals are required. Please submit 
proposals to the NHANES Genetic Project Officer: Jody McLean M.P.H., 
Division of Health and Nutrition Examination Surveys, National Center 
for Health Statistics, Centers for Disease Control and Prevention, 3311 
Toledo Road, Hyattsville, MD 20782, Phone: 301-458-4683, EMail: 
[email protected].

Agency Agreement

    Investigators must secure funding and sign terms and conditions 
agreements for the use of the DNA specimens with CDC/NCHS prior to the 
release of the NHANES DNA samples. Investigators must agree to use the 
specimens only for the approved tests and use the test results only for 
purposes as stated in the approved proposal, not link the results of 
the proposed research to any other data, and not use the DNA specimens 
for commercial purposes via a legally binding Materials Transfer 
Agreement for non-government researchers or Interagency Agreement for 
government researchers. In addition, all investigators will be required 
to sign a Designated Agent Agreement (DAA) with CDC/NCHS in accordance 
with NCHS' confidentiality legislation, the Confidential Information 
Protection and Statistical Efficiency Act (CIPSEA; Title V of the E-
Government Act of 2002 (Pub. L. 107-347)). The DAA is the mechanism by 
which CDC/NCHS may authorize designation of agents to exclusively 
perform activities needed to produce approved data on CIPSEA protected 
NHANES DNA specimens.

Approved Proposals

    After DNA samples are received and testing is complete, the 
resulting data will be sent back to DHANES/NCHS for quality control 
(QC) assessment. While DHANES/NCHS QC assessment is under way the 
investigator can submit a NCHS RDC proposal to conduct comprehensive 
quality assurance review. Once the investigator's quality assurance 
review is complete and the

[[Page 69826]]

results returned to DHANES/NCHS, the test results will be made 
available to the public and the investigator can submit an NCHS RDC 
proposal to request linkage to NCHS restricted data, NCHS public use 
data, or Non-NCHS data to conduct their analysis.
    After the comprehensive quality assessment process has been 
completed by the investigator, a list of variants generated from NHANES 
specimen testing will be made available to the public for potential 
solicitation via NCHS RDC proposals. The list of variants will be 
available in the NHANES Genetic Variant Search (http://www.nhgeneticvariant.com/). In addition, DHANES/NCHS quality control 
assessment procedures will be posted on the NHANES Genetic Repository 
Web site and/or available via email.

Progress Reports

    A progress report will be submitted in the annual CDC/NCHS/ERB 
continuation report. An ERB continuation form will be sent to the 
investigator each year for project update. If an approved proposal is 
unable to obtain funding the proposal will be closed.

Termination of ERB Protocol

    At the end of laboratory testing the ERB Protocol will be closed.

Disposition of Results and Samples

    The provided DNA samples cannot be used for any purpose other than 
the specifically requested purpose outlined in the proposal and 
approved through the Scientific and Institutional Review. No DNA 
samples can be shared with others, including other investigators, 
unless specified in the proposal and so approved. Samples must be 
returned upon completion of the approved project or destroyed only with 
the written approval of the NHANES Genetic Project Officer. Test 
results from all studies using NHANES DNA specimens will be made 
available to the public for secondary data analyses. After the DHANES/
NCHS quality control assessment is completed, investigators will be 
given up to six months to conduct a more comprehensive quality 
assurance review. The final quality assurance review timeframe will be 
negotiated between the researcher and the NHANES Genetic Project 
Officer and characteristics of the tests submitted. Proposals for 
secondary data analyses will be reviewed by the NCHS RDC on a rolling 
basis; see: http://www.cdc.gov/rdc for proposal guidelines. All data 
analyses will be conducted via access modes available at NCHS RDC.

    Dated: October 4, 2016.
Sandra Cashman,
Executive Secretary, Centers for Disease Control and Prevention.

                                 Table 1--Cost Schedule for NHANES DNA Specimens
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                                                                    1999-2002,      1999-2002,
                                                                  2007-08,  2009- 2007-08,  2009-   NHANES III
                           Total costs                             10  Complete     10  Partial    complete set
                                                                        set             set
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Materials and Equipment--contractor: Plates, reagents, assays,             $1.51           $4.53           $0.75
 aliquoting and packaging samples; use of equipment.............
Labor--contractor: Processing, handling, and shipping; NCHS:                4.98           24.90            2.49
 Data quality control...........................................
Proposal review and Administrative expenses--contractor:                    3.02            6.04            1.51
 Inventory management and reporting; NCHS: Management of
 proposal process non-NCHS: Technical panel fees................
Space--contractor: Freezer use and maintenance..................            5.59            5.59            2.79
Cost per sample.................................................           15.10           41.06            7.55
Cost per new proposal:
    1999-2002...................................................         119,260              NA
    2007-2008...................................................          72,661
    2009-2010...................................................          73,884
    III.........................................................  ..............  ..............          54,050
Cost per additional proposal: *
    1999-2002...................................................           5,963              **
    2007-2008...................................................           3,633
    2009-2010...................................................           3,694
    III.........................................................  ..............  ..............           2,702
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* Additional research using DNA specimens already obtained from previous solicitations.
** This charge will be 5 percent of the original cost.
Note: Applicable CDC overhead and NCHS management and oversight charges will be added to these rates for
  proposals coming from Federal agencies.

[FR Doc. 2016-24349 Filed 10-6-16; 8:45 am]
 BILLING CODE 4163-18-P