[Federal Register Volume 84, Number 35 (Thursday, February 21, 2019)]
[Notices]
[Pages 5441-5445]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-02908]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Centers for Disease Control and Prevention

[Docket No. CDC-2019-0003]


National Health and Nutrition Examination Survey (NHANES) DNA 
Specimens: Guidelines for Proposals To Use Samples 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, with their permission, during 
NHANES III (1991-1994), NHANES 1999-2000, NHANES 2001-02, NHANES 2007-
08, NHANES 2009-10, and NHANES 2011-12 (Office of Management and Budget 
Control Numbers # 0920-0237/0920-0950). DNA samples 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.

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 samples has been previously 
announced in 2002 (67 FR 51585), 2006 (71 FR 22248), 2007 (72 FR 
59094), 2009 (74 FR 45644), 2010 (75 FR 32191) and 2016 (81 FR 69822). 
NHANES III Phase II DNA samples (1991-1994) are from participants ages 
12 or older (see NHANES III DNA Samples section for a description). For 
details about available NHANES III non-genetic data see https://wwwn.cdc.gov/nchs/nhanes/nhanes3/default.aspx.
    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 ages 20 years and older in survey years 
1999-2002 and 2007-12. DNA samples are available as collections from 
NHANES 1999-2002 (NHANES 1999-2000 and 2001-02 samples available as one 
collection), and NHANES two-year cycles 2007-08, 2009-10, and 2011-
12(see NHANES 1999-2002, 2007-08, 2009-10, and 2011-12 DNA samples 
section for a description). The availability of the NHANES 1999-2002 
DNA samples has been previously announced (2007 [72 FR 59094], 2009 [74 
FR 45644], 2010 [75 FR 32191], and 2016 [81 FR 69822]). The 
availability of the NHANES 2007-08 DNA samples has been previously 
announced (2009 [74 FR 45644], 2010 [75 FR 32191], and 2016 [81 FR 
69822]). The availability of the NHANES 2009-10 DNA samples has been 
previously announced (2016 [81 FR 69822]). The data release cycle for 
the NHANES corresponding to the period in which samples were collected 
for DNA is described in the following web links:

https://wwwn.cdc.gov/nchs/nhanes/ContinuousNhanes/Default.aspx?BeginYear=1999
https://wwwn.cdc.gov/nchs/nhanes/ContinuousNhanes/Default.aspx?BeginYear=2001
https://wwwn.cdc.gov/nchs/nhanes/continuousnhanes/default.aspx?BeginYear=2007
https://wwwn.cdc.gov/nchs/nhanes/ContinuousNhanes/Default.aspx?BeginYear=2009
https://wwwn.cdc.gov/nchs/nhanes/ContinuousNhanes/Default.aspx?BeginYear=2011

    Identifiable health information collected in the NHANES is kept 
confidential. 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

[[Page 5442]]

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, 2009-10, and 
2011-12 a separate consent form was signed by eligible participants who 
agreed to the storing of blood samples for future genetic research. DNA 
samples will be available for testing only from participants who 
consented to future research. Resulting data from DNA samples 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 DNA samples (2002 (67 FR 
51585), 2006 (71 FR 22248), 2007 (72 FR 59094), 2009 (74 FR 45644), 
2010 (75 FR 32191), and 2016 (81 FR 69822)).

    Proposals testing a complete NHANES DNA collection of samples: 
NHANES III, 7,159 samples; NHANES 1999-2002, 7,839 samples; NHANES 
2007-08, 4,612 samples; NHANES 2009-10, 4,893 samples; NHANES 2011-12, 
4,147 samples.

    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 must specify which DNA collection they are requesting and 
the tests to be conducted on DNA samples excluding tests that produce 
incidental findings. The investigator is required to include in the 
research proposal 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 NHANES DNA samples 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 website 
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 samples 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 samples already obtained from previous 
solicitations:
    Investigators who have obtained NHANES DNA samples from previous 
solicitations and have sufficient DNA left may request to do additional 
tests on the remaining DNA. These proposals must be submitted and 
approved before the initial proposal expiration date. The investigator 
is required to specify the test to be conducted on the samples 
excluding tests that produce incidental findings. The investigator must 
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 samples (NHANES III, NHANES 1999-2002, NHANES 2007-08, 
NHANES 2009-10, and NHANES 2011-12) 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 Samples

    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 samples are 
available from 7,159 NHANES III participants. Samples will be 
distributed in a total of 82 plates including four plates of quality 
control samples. NHANES III DNA samples are in limited supply and, 
thus, are not available as a partial set. Due to the method of 
extraction, NHANES III DNA samples are not appropriate for all projects 
and/or assays.

NHANES 1999-2002, 2007-08, 2009-10, 2011-12 DNA Samples

    The laboratory will distribute aliquots of purified, high molecular 
DNA in normalized concentrations of 50.0 ng/[mu]L. Some samples may 
fall below this threshold. A sample of 40 microliters of each samples 
will be supplied. The amount of DNA in each sample may vary but will be 
on average approximately two micrograms.
    There are purified DNA samples from 7,839 NHANES 1999-2002 
participants. These samples will be distributed into 90 plates 
including four plates of quality control samples.
    There are purified DNA samples 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 samples available from 4,893 NHANES 2009-10 
participants. These will be distributed into 58 plates including 
approximately three additional plates of quality control samples.
    There are purified DNA samples available from 4,147 NHANES 2011-12 
participants. These will be distributed into 49 plates including 
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. 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.

[[Page 5443]]

Procedures for Proposals

    The investigator should follow these instructions for preparation 
of proposals. Proposals 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 
April 22, 2019.
    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 in the 
research project should be included. CDC investigators need to include 
their Collaborative Institutional Training Initiative (CITI) training 
expiration date. 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.
    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 Research 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.
    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 not be maintained by 
NCHS.
    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 CITI training expiration date.
    (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 
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 DNA samples. 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.
    (B) Data analysis: Note: All resulting data are restricted access 
data and must be analyzed in the NCHS Research Data Center (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 samples 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 and describe how potential 
incidental test results will be handled. As of its publication in 
February 2017, the most recent report, ``Recommendations for reporting 
of secondary findings in Clinical Exome and Genome Sequencing, 2016 
update (ACMG SF v2.0): A policy statement of the American College of 
Medical Genetics and Genomics'', lists 59 genes where specific variants 
on these genes are pathogenic for 27 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

[[Page 5444]]

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 samples 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, informing that test 
results are available for secondary data analyses after submission and 
acceptance of proposals, will occur once the quality assurance review 
timeframe has ended. For a list of currently available variant data 
see: http://www.nhgeneticvariant.com/.
    Proposals for secondary data analyses linking NCHS restricted data, 
NCHS public use data, or non-NCHS data to data resulting from DNA 
sample 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 this notice and 
will include all proposals submitted as of that date.
    Electronic submission of proposals is 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 samples with CDC/NCHS prior to the 
release of the NHANES DNA samples. Investigators must agree to: (a) Use 
the samples only for the approved tests; (b) use the test results only 
for purposes as stated in the approved proposal; (c) not link the 
results of the proposed research to any other data; and (d) not use the 
DNA samples for commercial purposes, as set forth in a legally binding 
Materials Transfer Agreement (if non-government researchers) or 
Interagency Agreement (if 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 samples.

Approved Proposals: Post-Testing Procedures

    After DNA samples are received and testing is complete, the 
investigator must send the resulting data back for DHANES/NCHS quality 
control(QC) assessment. While DHANES/NCHS QC assessment is under way, 
the investigator can submit a NCHS RDC proposal (http://www.cdc.gov/rdc) to conduct additional quality assurance review. Once the 
investigator's quality assurance review is complete and the results 
returned to DHANES/NCHS, the test results will be made available to the 
public. Data are made public through the NCHS RDC and at this point 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 
samples testing will be made available to the public for potential 
requests for proposals 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 
website and/or available via email.

Progress Reports

    The investigator must submit a progress report 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, but 
only with the written approval of the NHANES Genetic Project Officer). 
Test results from all studies using NHANES DNA samples 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.

[[Page 5445]]



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                                                                    1999-2002,      1999-2002,
                                                                  2007-08, 2009-  2007-08, 2009-    NHANES III
                           Total costs                              10, 2011-12     10, 2011-12    complete set
                                                                   complete set     partial set
----------------------------------------------------------------------------------------------------------------
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...................................................         118,369               *  ..............
    2007-2008...................................................          69,641  ..............  ..............
    2009-2010...................................................          73,884  ..............  ..............
    2011-2012...................................................          62,605  ..............          54,050
    III.........................................................  ..............  ..............  ..............
Cost per additional proposal: **
    1999-2002...................................................           5,918             ***  ..............
    2007-2008...................................................           3,633  ..............  ..............
    2009-2010...................................................           3,694  ..............  ..............
    2011-2012...................................................           3,131  ..............           2,702
    III.........................................................  ..............  ..............  ..............
----------------------------------------------------------------------------------------------------------------
* Cost calculated upon request.
** Additional research using DNA samples 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.


    Dated: February 14, 2019.
Sandra Cashman,
Executive Secretary, Centers for Disease Control and Prevention.
[FR Doc. 2019-02908 Filed 2-20-19; 8:45 am]
BILLING CODE 4163-18-P