[Federal Register Volume 87, Number 131 (Monday, July 11, 2022)]
[Notices]
[Pages 41129-41132]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-14702]



[[Page 41129]]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Centers for Disease Control and Prevention


National Health and Nutrition Examination Survey (NHANES) Stored 
DNA Specimens; Proposed Cost Schedule and Guidelines for Proposal To 
Use DNA Specimens

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 the 
availability of stored DNA specimens obtained from participants in the 
National Health and Nutrition Examination Survey (NHANES) and the 
proposal parameters and fee schedule for use. NHANES is one of a series 
of health-related surveys conducted by CDC's National Center for Health 
Statistics (NCHS).

DATES: The stored NHANES DNA specimens are available July 11, 2022. The 
fee structure for these specimens is effective July 11, 2022.

FOR FURTHER INFORMATION CONTACT: Jody McLean, Division of Health and 
Nutrition Examination Surveys, National Center for Health Statistics, 
Centers for Disease Control and Prevention, 3311 Toledo Road, 
Hyattsville, MD 20782, Telephone: (301) 458-4683; Email: 
[email protected].
    Authority: Sections 301,306 and 308 of the Public Health Service 
Act (42 U.S.C. 241, 242k, and 242m).

SUPPLEMENTARY INFORMATION: 
    Background: NHANES is a program of periodic surveys conducted by 
NCHS. NHANES has provided national estimates of the health and 
nutritional status of the U.S. civilian non-institutionalized 
population since the 1960s. 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.

DNA Specimens, Availability, and Resulting Data

    The availability of the NHANES III Phase 2 DNA specimens was first 
announced in 2002. NHANES III Phase 2 DNA specimens (1991-1994) are 
from participants ages 12 or older (see: https://wwwn.cdc.gov/nchs/nhanes/nhanes3/default.aspx for more information on NHANES III).
    NHANES III Phase 2 DNA specimens are crude DNA lysates extracted 
from cell lines; therefore, 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. DNA specimens are available from 7,159 NHANES 
III Phase 2 participants. Forty microliters of each DNA specimen will 
be distributed in 82 plates, including four plates of quality control 
specimens. NHANES III DNA specimens are in limited supply and thus are 
not available as a partial set (which is a request for less than the 
total number of participants available). Due to the extraction method, 
NHANES III DNA specimens are not appropriate for all projects and 
assays. For background information on all DNA specimens, see the NHANES 
Biospecimen Program report at https://www.cdc.gov/nchs/data/series/sr_02/sr02_170.pdf.
    In 1999, NHANES became a continuous survey, with data released 
every two years (see https://wwwn.cdc.gov/nchs/nhanes/continuousnhanes/default.aspx for more information on continuous NHANES). The 
availability of DNA specimens from the continuous NHANES was first 
announced in 2007.
    Continuous NHANES DNA specimens are available as collections from 
NHANES 1999-2002 (NHANES 1999-2000 and 2001-2002 specimens are 
available as one collection) and NHANES two-year cycles 2007-08, 2009-
10, and 2011-12. In continuous NHANES, DNA was purified from whole 
blood; aliquots of DNA were normalized to concentrations of 
approximately 50 ng/[micro]l, and 40 [micro]l of each DNA specimen will 
be distributed. There are purified DNA specimens from 7,830 NHANES 
1999-2002 participants. These specimens will be distributed into 90 
plates, including four plates of quality control specimens. There are 
purified DNA specimens available from 4,612 NHANES 2007-2008 
participants. These will be distributed into approximately 54 plates, 
including three plates of quality control specimens. There are purified 
DNA specimens available from 4,893 NHANES 2009-2010 participants. These 
will be distributed into 58 plates, including three additional plates 
of quality control specimens. There are purified DNA specimens 
available from 4,147 NHANES 2011-12 participants. These will be 
distributed into 49 plates, including three additional plates of 
quality control specimens.
    DNA specimens will be available for testing only from participants 
who consented to future research.
    The resulting data from DNA specimen testing will be linkable to 
variables (public use and restricted) and available for analyses 
through the NCHS Research Data Center (RDC; https://www.cdc.gov/rdc/index.htm) for approved proposals unless otherwise determined by the 
NHANES Project Officer. Access to these data at the NCHS RDC is only 
through an approved proposal process mechanism to assure 
confidentiality (see ``APPROVED PROPOSALS: Post-Testing Procedures'' 
section).

Parameters for DNA Specimen Use and Resulting Data

    1. Investigators must justify why they need a specimen from a 
national probability sample of the U.S. population for their study.
    2. Investigators must specify which NHANES cycles they are 
requesting DNA specimens from and the specific laboratory tests to be 
conducted on those specified DNA specimens.
    3. Only those proposals for which the laboratory testing will 
result in findings determined not to have clinical significance for 
participants will be approved. The consent document for DNA storage and 
future research use of DNA specimens states that individual results 
will not be provided to participants. Therefore, no proposals involving 
tests with clinical significance will be approved. DHANES/NCHS will use 
the most recent American College of Medical Genetics and Genomics 
(ACMG) recommendations for reporting secondary findings \1\ to assess 
the proposed tests and their potential for yielding clinically 
significant findings. Investigators must verify that the proposed tests 
do not produce variants (e.g., single-nucleotide polymorphisms,

[[Page 41130]]

translocation and inversions, copy number variations) on specific genes 
listed by the most recent ACMG recommendations as reportable secondary 
findings and describe how potential secondary findings results will be 
handled.
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    \1\ See ``Guidelines for Returning Individual Results from 
Genome Research Using Population-Based Banked Specimens'' (https://nap.nationalacademies.org/catalog/18829/issues-in-returning-individual-results-from-genome-research-using-population-based-banked-specimens-with-a-focus-on-the-national-health-and-nutrition-examination-survey), convened by the National Academies of Science 
Committee on National Statistics in 2014 at the request of NCHS's 
Board of Scientific Counselors.
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    4. Upon receipt of the specimen and after conducting the approved 
testing, investigators must provide a copy of the resulting data 
obtained from DNA testing to the Division of Health and Nutrition 
Examination Survey (DHANES)/NCHS for quality control assessment.
    5. After DHANES/NCHS has completed the initial quality control 
assessment of submitted data, investigators will be given up to six 
months to conduct a comprehensive quality assurance review. At this 
review's completion, the resulting data's availability will be publicly 
announced 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. 
Analysis and linkage of the resulting data are conducted in the NCHS 
RDC via a separate proposal unless otherwise determined by the NHANES 
Project Officer (see ``APPROVED PROPOSALS: Post-Testing Procedures'' 
section).

Proposals Testing DNA Specimens Already Obtained From Previous 
Solicitations

    Investigators who have obtained NHANES DNA specimens 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 as further provided herein. The investigator must pay an 
additional cost (see ``COST SCHEDULE'' section) per each additional 
proposal).

Proposal Evaluation

    All proposals for the use of NHANES DNA specimens will be evaluated 
by the NHANES Project Officer, a Technical Panel, the NCHS 
Confidentiality Officer, the NCHS Human Subjects Contact, and the NCHS 
Ethics Review Board (ERB). Applications will have a Scientific Review 
by the NHANES Project Officer and the Technical Panel. The Technical 
Panel comprises two members with subject matter expertise: one from CDC 
staff and one external to CDC, i.e., from other federal agencies, 
academia, or industry. Only technical panel members with no conflict of 
interest and no previous knowledge of the research project will be 
asked to review the proposal. The members review each proposal for 
scientific and technical merit and ensure that the proposed project 
does not go beyond the general purpose of collecting the blood 
specimens for DNA in NHANES (see ``PROCEDURES FOR PROPOSALS'' section).
    After the proposal is approved by the NHANES Project Officer and 
the Technical Panel, it will be submitted for Institutional Review. All 
proposals will undergo Institutional Review by the NCHS Human Subjects 
Contact and the NCHS 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 NCHS ERB will review the proposal even if the 
investigators have received approval from their institutional review 
panel. The proposal, if approved, will become an amendment to the 
current NHANES ERB Protocol (i.e., the NHANES ERB Protocol that is in 
effect at the time of the investigator's proposal approval).
    If a proposal is approved, the author's title, specific aims, name, 
and phone number will be maintained by NCHS and released if requested 
by the public. NCHS will not maintain unapproved proposals.

Procedures for Proposals

    All investigators (including CDC investigators) must submit a 
proposal for the use of NHANES DNA specimens and follow the 
instructions as set forth herein, including following the outline set 
out below. Proposals should be a maximum of 20 1.5-spaced typed pages, 
excluding figures and tables, using at least size 10 font. The cover of 
the proposal (which is not included in the 20-page limit) should 
include the title of the proposal, the name, address, phone number, and 
email address of the principal investigator (PI), and the name of the 
institution where the laboratory analysis will be done. The name, 
address, phone number, and email address of all additional 
investigators should also be included on the cover. Office of Human 
Research Protections assurance numbers for the institutions in the 
proposed project should be included. CDC investigators must include the 
expiration date of their Collaborative Institutional Training 
Initiative (CITI) training. All proposals should be submitted via email 
to [email protected]. Note: If the investigator would like to 
propose a subsample of the complete set, please contact the NHANES 
Project Officer to discuss feasibility.
    The following criteria will be used for technical evaluation of 
proposals:
    (1) Abstract: Please limit the abstract to 300 words.
    (2) Specific Aims: List the broad objectives; describe concisely 
and realistically what the proposed project is intended to accomplish 
and state the specific hypotheses to be tested.
    (3) Background and Public Health Significance:
    (A) Describe the public health significance of the proposed study.
    (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 the general purpose of collecting the blood specimens for DNA in 
the survey or the specific stated goals of the proposal.
    (4) Design, Method, and Analytic Plan: The appropriateness and 
adequacy of the methodology proposed to reach the specific 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) Study Design and Methods: Include a detailed description of the 
laboratory methods. The characteristics of the laboratory assay, such 
as reliability, and validity, should be included with appropriate 
references. The laboratory must demonstrate expertise in the proposed 
test, including the capability to handle the workload requested in the 
proposal. The potential difficulties and limitations of the proposed 
procedures should also be discussed. Address methods to ensure adequate 
handling and storage of DNA specimens. Proposals must specify variants 
or the commercial assay(s) 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. Note: A 
standard assay is a commercially available assay for a curated set of 
variants or biological markers. Investigators who submit successful 
proposals will be provided with quality control specimens at no 
additional cost. Approved projects must run these quality control 
specimens and submit these results along with the results from the 
NHANES DNA specimens unless the NHANES Project Officer has approved an 
alternative quality control review plan. The proposal should address 
any additional quality control procedures the laboratory will use to 
assure the validity of the test results and address methods to ensure 
adequate handling and storage of specimens.

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    (B) Analytic Plan: Describe the data analysis and statistical 
methods to be employed. Include power calculations. Resulting data from 
DNA specimens are restricted access data and must be analyzed in the 
NCHS RDC. The proposal should state that the data analysis will be 
conducted in the RDC unless DHANES/NCHS determines otherwise.
    (5) Additional information for NHANES:
    (A) Clinical Significance of Results: The consent document for DNA 
specimen storage and future studies states that individual results will 
not be provided to participants; therefore, no tests that 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 secondary findings to review the 
proposed tests and the potential secondary findings. Investigators must 
verify that the proposed tests do not produce variants on specific 
genes listed by the most recent ACMG recommendations as reportable 
secondary findings and describe how potential secondary test results 
will be handled. The 2021 statement, ``ACMG SF v3.0 list for reporting 
of secondary findings in clinical exome and genome sequencing: a policy 
statement of the American College of Medical Genetics and Genomics 
(ACMG),'' lists 73 genes where specific variants on these genes are 
pathogenic for 34 conditions.
    (B) Data Transfer: Specify the secure method to transfer the 
resulting 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 proposed project period. 
Substantial progress must be made in the first year that specimens have 
been obtained, and the project should be completed within a reasonable 
period of time. Please discuss the approximate time the investigator 
expects this project will take to complete. The NHANES Project Officer 
must be consulted about the disposition of the specimens. At the end of 
the project period, any unused specimens must be returned to the NHANES 
DNA Specimen Repository or destroyed by the investigator.
    (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 specimens (see 
COST SCHEDULE FOR PROVIDING NHANES DNA SPECIMENS and Cost Schedule for 
NHANES DNA Specimens for details).
    (6) Resumes/CV: Please include a two-page CV for each member of the 
study team in the proposal (not as attachments; CVs do not count 
towards page maximum).

Submission of Proposals

    Proposals must be submitted in MS Word format by email to 
[email protected].

Proposal Timeframes

 Submission of Proposals: Can be submitted on an ongoing basis
 Scientific Review: Completed approximately two months after 
proposal submission
 Institutional Review: Completed approximately six weeks after 
completion of scientific review
 Notification of Approval: Approximately 30 days after 
completion of Institutional Review
 Anticipated Distribution of Specimens: Approximately 60 days 
after the following is completed: notification of proposal approval, 
agreements signed (as described below), and payments received (as 
described below)

    Note: Timeframes 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.

Approved Proposals

    Investigators must transfer payment to DHANES/NCHS and sign terms 
and conditions agreements for the use of the DNA specimens with CDC/
NCHS before releasing the NHANES DNA specimens. Investigator(s) must 
agree to: (a) use the specimens 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 project to any other data; (d) 
not use the DNA specimens for commercial purposes, as set forth in a 
legally binding Materials Transfer Agreement (MTA; if non-government 
investigators) or Interagency Agreement (IAA; if government 
investigators); and (e) sign and abide by a Designated Agent Agreement 
(DAA) with CDC/NCHS in accordance with NCHS' confidentiality 
legislation.

Agency Agreements

    A formal signed agreement, embodied in the form of an MTA or an 
IAA, and a DAA with investigators who have projects approved, must be 
completed before the release of the specimens to the investigator. For 
the MTA or IAA, this agreement will contain the conditions for use of 
the specimens as stated in this Federal Register notice and as agreed 
upon by the investigators and CDC. The DAA is the mechanism by which 
CDC/NCHS may authorize the designation of agents to exclusively perform 
activities needed to produce approved data using the Confidential 
Information Protection and Statistical Efficiency Act (CIPSEA; Title V 
of the E-Government Act of 2002 [Pub. L. 107-347])-protected NHANES DNA 
specimens. The DAA must be signed by the investigator taking custody of 
DNA specimens and producing resulting data.

Continuations

    A brief progress report must be submitted annually to NHANES. This 
report should describe the work completed and the timeline to project 
completion. When five years have elapsed since the initial approval of 
the proposal by the NCHS ERB, the investigator must provide an updated 
project timeline to complete the study for approval by NHANES. If a new 
investigator(s) is added at any time during the project, or the 
Principal Investigator has changed, the NHANES Project Officer must be 
notified.

Approved Proposals: Post-Testing Procedures

    After DNA specimens are received and testing is complete, the 
investigators must send the resulting data back for DHANES/NCHS quality 
control assessment. While DHANES/NCHS quality control assessment is 
underway, the investigator can submit an NCHS RDC proposal (http://www.cdc.gov/rdc) to conduct an additional quality assurance review. The 
vast majority of resulting data from DNA specimens is restricted; 
therefore, the data are available only in the NCHS RDC. Once the 
investigators' quality assurance review is complete and the results are 
returned to DHANES/NCHS, investigators will be given up to six months 
to conduct a comprehensive quality assurance review in the NCHS RDC. 
The quality assurance review timeframe will be negotiated between the 
investigators and the NHANES 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

[[Page 41132]]

available variant data, see: http://www.nhgeneticvariant.com/.
    A minority of resulting data from DNA specimens are not restricted. 
In these cases, the resulting data will undergo disclosure review by 
the NCHS Confidentiality Officer and NCHS Disclosure Review Board or 
designee before the linked data are sent to the investigators for 
quality control review. Once approved by disclosure review and after 
the investigators have signed the Data Sharing Agreement, the linked 
data file will be sent to the investigators for use pursuant to the 
terms of the relevant agreement. The quality control review must take 
place within 60 days or a negotiated length of time, and the return of 
the data to NCHS within the next 30 days so these data may be released 
to the public.

Disposition of Specimens

    The provided DNA specimens 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 
specimens can be shared with others, including other investigators, 
unless specified in the proposal and so approved. Specimens must be 
returned upon completion of the approved project or destroyed. Both 
options require written approval from the NHANES Project Officer.

Cost Schedule for Providing NHANES DNA Specimens

    There is a nominal processing fee of $17.17 for each DNA specimen 
received from an NHANES DNA Repository. The costs include collecting, 
processing, storing, and retrieving the DNA specimens, reviewing 
proposals, and preparing the data files. The costs listed are for the 
recurring laboratory materials to dispense and prepare the DNA 
specimens during collection and shipping. The NHANES DNA Specimen 
repository costs include long-term storage (including inventory 
management and materials and equipment) and accessioning of specimens 
and specimen retrieval for shipment to the investigator. Labor costs 
are based on a proposal administrator to manage the proposal process 
and computer programmers at NCHS who prepare the data files for the 
release of the data along with documentation on the NHANES web page. If 
the investigators request to use the DNA specimens for another proposed 
project after the completion of the initial project, the additional 
cost will be 5 percent of the specimen set cost to handle the 
processing of the data and management of the subsequent proposal 
process. A new proposal must be submitted and go through the approval 
process before any additional use of the DNA specimens.

                                     Cost Schedule for NHANES DNA Specimens
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                                                                    1999-2002,      1999-2002,
                                                                    2007-2008,      2007-2008,
                           Total costs                              2009-2010,      2009-2010,      NHANES III
                                                                     2011-2012       2011-2012     complete set
                                                                   complete sets    partial set
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    Materials and equipment--contractor: plates, reagents,                 $1.72           $5.15           $0.85
     assays, aliquoting and packaging specimens; use of
     equipment..................................................
    Labor--contractor: processing, handling, and shipping; NCHS:            5.66           28.31            2.83
     data quality control.......................................
    Proposal review and administrative expenses--contractor:                3.43            6.87            1.72
     inventory management and reporting; NCHS: management of
     proposal process non-NCHS: technical panel fees............
    Space--contractor: freezer use and maintenance..............            6.36            6.36            3.17
    Cost per specimen...........................................           17.17           46.69            8.58
Cost per new proposal:
    1999-2002...................................................      134,430.92               *
    2007-2008...................................................       79,181.82               *
    2009-2010...................................................       84,006.11               *
    2011-2012...................................................       71,181.89               *
    III.........................................................  ..............  ..............       61,454.85
Cost per additional proposal: **
    1999-2002...................................................        6,721.94             ***
    2007-2008...................................................        4,130.72             ***
    2009-2010...................................................        4,200.08             ***
    2011-2012...................................................        3,559.95             ***
    III.........................................................  ..............  ..............        3,072.17
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* Cost calculated upon request.
** 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.


Angela K. Oliver,
Executive Secretary, Centers for Disease Control and Prevention.
[FR Doc. 2022-14702 Filed 7-8-22; 8:45 am]
BILLING CODE 4163-18-P