[Federal Register Volume 67, Number 153 (Thursday, August 8, 2002)]
[Notices]
[Pages 51585-51589]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-20038]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Centers for Disease Control and Prevention
National Health and Nutrition Examination Survey III (NHANES) DNA
Specimens: Guidelines for Proposals to Use Samples and Proposed Cost
Schedule
ACTION: Notice.
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SUMMARY: The National Health and Nutrition Examination Survey (NHANES)
is a program of periodic surveys conducted by the National Center for
Health Statistics (NCHS) of the Centers for Disease Control and
Prevention (CDC). 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. To add to the large
amount of information collected for the purpose of describing the
health of the population, blood lymphocytes were collected in NHANES
III in anticipation of advances in genetic research.
The lymphocytes have been stored and maintained at the Division of
Laboratory Sciences (DLS) at the National Center for Environmental
Health (NCEH), CDC. The collection of lymphocytes was begun in the
second phase of the survey (1991-1994) because of the significant
advances in the rapidly evolving field of molecular biology that were
occurring during the planning phase of this survey. CDC is making DNA
samples from these specimens available to the research community for
such analyses. Specimens are available from approximately 7,300
participants in the second phase of NHANES III. No cell lines will be
made available.
This program has been previously announced (Tuesday, June 1, 1999
(64 FR 29321)). The purpose of this notice is to announce a third
category for proposals for use of these specimens and a new cost
schedule. For final proposal guidelines and request for letters of
intent, please contact Ms. Oraegbu or go to http://www.cdc.gov/nchs/
about/major/nhanes/dnafnlgm2.htm.
All interested researchers are encouraged to submit letters of
intent. Approximately twenty proposals for a full set of specimens
(~7,300 samples) and a limited number of proposals (less than five,
depending on the number of specimens requested) for smaller sets of
samples can be awarded in this solicitation. No funding is provided as
part of this solicitation. Proposals will be reviewed by a technical
panel. Approved projects that do not obtain funding on their own will
be canceled. A more complete description of this program follows.
Dates
Letter of Intent Receipt: September 9, 2002
Submission of Proposals: October 7, 2002
Application Receipt: November 18, 2002
Scientific Review: January, 2003
Institutional Review: February, 2003
Notification of approval: March 2003
Anticipated distribution of samples: July-August 2003
ADDRESSES: To send comments and for information, contact:
Ms. Kika Oraegbu, Division of Health Examination Statistics,
National Center for Health Statistics, Centers for Disease Control and
Prevention, 6525 Belcrest Road, Room 1000, Hyattsville, MD 20782,
Phone: 301-458-4367, FAX: 301-458-4028, E-Mail: [email protected], Internet:
http://www.cdc.gov/nchs/about/major/nhanes/dnafnlgm2.htm.
SUPPLEMENTARY INFORMATION:
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; (7) to establish and
maintain a national probability sample of baseline information on
health and nutrition status.
The Third National Health and Nutrition Examination Survey (NHANES
III) began in the Fall of 1988 and ended in the Fall of 1994. Survey
data were collected and can be analyzed from two phases: Phase I was
conducted from October 1988 to October 1991, and Phase II was conducted
from October 1991 to October 1994. Both phases are nationally
representative samples. For details of the sampling design see the Plan
and Operation of NHANES III (1). This information can be obtained by
contacting the Data Dissemination Branch, NCHS, at 301-458-4636 or from
the Internet at http://www.cdc.gov/nchs/about/major/nhanes/nh3data.htm.
[[Page 51586]]
Blood specimens were collected from participants as a part of
NHANES III. Lymphocytes were isolated from the blood collected from
participants aged 12 years and older and stored frozen in liquid
nitrogen or as cell cultures immortalized with Epstein-Barr virus and
frozen at the Molecular Biology Branch of DLS, NCEH, CDC, Atlanta, GA.
DNA is available from cell lines of Phase II (1991-1994) participants.
Health information collected in the NHANES III 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 or the establishment in accordance with section 308(d)
of the Public Health Service Act (42 U.S.C. 242m). Although the consent
form was signed by participants in the survey, and participants
consented to storing specimens of their blood for future research,
specific mention of genetic research was not included. Nevertheless,
given the scientific importance of this resource, the CDC/NCHS
Institutional Review Board (IRB) approved making anonymized samples of
DNA available to the genetic research community.
The anonymization requirements proved to be restrictive and
difficult to implement, therefore, in August, 2001 the CDC/NCHS IRB
approved a revised plan for using these specimens based on the
guidelines in the August, 1999 National Bioethics Advisory Commission
(NBAC) report on the use of stored biological materials for research.
This revised plan includes a process that gives researchers the ability
to obtain more information associated with specimens for protocols that
are determined by the IRB to have minimal risk for harm to the
participant. For those protocols that cannot be conducted under
unlinked (or anonymous) conditions, but have been determined to involve
minimal risk, the revised plan allows for linking the genetic
laboratory results to the NHANES data through the NCHS Research Data
Center. This process would ensure that confidentiality of the subjects'
identity is maintained, and would reduce the possibility that linking
genetic information to the NHANES III data files might identify an
individual or cause group harm.
Potential Research Proposals
Category (A): Special studies using the NCHS Research Data Center:
Complete set of samples in deep-well format (96 specimens/per plate)
~7,300 samples. Studies which request DNA samples linked to previously
collected NHANES III public use data without the restriction of
anonymization. Data analyses must be done within the NCHS Research Data
Center.
Category (B): Age-race-sex studies using anonymized samples: A
limited number of subsets may be distributed in 50uL cryovials. Subsets
based on the selection criteria proposed by investigators. Studies of
allele frequencies which require only basic demographic information
(age, race/ethnicity, and sex) to be linked to the samples.
Category (C): Special anonymized studies: A limited number of
subsets may be distributed in 50uL cryovials. Subsets based on the
selection criteria proposed by investigators. Studies in which
additional co-variates from the NHANES III public use database are
required, but the re-coding maintains anonymization (minimum of 5
individuals in each statistical cell) of the samples.
These latter two research designs do not differ from the previous
Plan for distributing NHANES III DNA samples to researchers.
Category (A): Special studies using the NCHS Research Data Center--
Distribution of the complete set of samples in deep-well format (96
specimens/per plate) ~7,300 samples. The investigator will specify the
genetic analyses to be conducted on the samples. The investigator will
also include in the research protocol application a list of demographic
and clinical variables that would be used for the data analyses. Data
analyses that combine the genetic analyses with NHANES III data must be
conducted in the NCHS Research Data Center (RDC). The researcher will
conduct the genetic laboratory analyses on the samples that are labeled
with a unique random ID and are, therefore, anonymous to the
researcher. To perform the data analyses, the researcher will then
provide the results of the genetic laboratory tests with the random
identification numbers to the Division of Health Examination Statistics
(DHES). The random identification numbers are also anonymous to all
staff, except the one person who has the crosswalk file. These results
will be matched to the NHANES III data by that person. The resulting
data file will be provided to the RDC. These analyses will be subject
to all the confidentiality restrictions of the RDC (http://www.cdc.gov/nchs/r&d/rdc.htm). Because all the data analyses will be completed in
the NCHS RDC, which charges for computer time and for RDC support time,
it is recommended that the investigator develop the project proposal in
conjunction with the NHANES Staff and Research Data Center staff. The
investigator should perform preliminary analyses using NHANES public
use data to determine whether the proposed research is feasible.
Approval of these protocols by the RDC is required after approval by
the Genetics Technical Panel. The RDC uses the following criteria for
approval: risk of disclosure, consistency with the mission of NCHS,
availability of RDC resources, and the feasibility of the project.
Although researchers sign confidentiality agreements to use the
RDC, strict confidentiality protocols require that researchers with
approved projects must complete their work using the facilities located
within the Research Data Centers (currently only the Hyattsville, MD,
facility is in operation). Two access methods are available for
researchers to accomplish their tasks: onsite and remote. The costs and
restrictions are different for each method. Onsite researchers have the
ability to use the full capabilities of the SAS system with the only
additional requirement being a disclosure review. Individual cells are
suppressed if the minimum requirements for disclosure are not met.
Additional restrictions limit the analysis capabilities of the remote
access system. Under these situations, the printed output is scanned
and screened prior to transmittal to the investigator. Strict minimal
disclosure limits are adhered to and data items are suppressed if the
minimums are not met. For remote access, all statistical cells with
fewer than five observations are suppressed. Under the RDC option
(protocol category A), the researcher may obtain aggregate statistics
from statistical calculations which effectively use smaller statistical
cell sizes for intermediate steps, such as performing regression
analyses on detailed data, as long as the intermediate steps are never
made available separately.
Category (B) Age-race-gender Studies: A limited number of subsets
may be distributed in 50uL cryovials. Subsets based on the selection
criteria proposed by investigators. To facilitate the research proposal
preparation of allele frequency, NCHS will make the following data
available with the DNA sample: age in 10-year age groups, race-
ethnicity (white, black, Mexican-American), gender, mean sample weights
for each demographic group and the average design effect. Thus,
investigators wishing to submit proposals under this research design
type do not need to provide an analysis
[[Page 51587]]
of NHANES III data to support the unlinked (anonymization) scheme
proposed. These data have sufficient sample sizes in each category (the
smallest age, race/ethnicity, gender statistical cell contains 62
persons) to preserve anonymity. To further preserve anonymity, only 80
percent of the subjects in each statistical cell will be used.
Proposals submitted for this category of review are limited to
those requesting samples from within these age, gender, race/ethnicity
cells for identifying the frequency of the alleles in the population.
These proposals must address all criteria except for the verification
that anonymization can be achieved.
Category (C): Special Anonymized Studies (Requests for Additional
Variables)--A limited number of subsets may be distributed in 50uL
aliquots in cryovials. Subsets are based on the selection criteria
proposed by the investigator(s). The investigator will include a list
of demographic and clinical variables and specify recoding schemes, if
appropriate, that the principal investigator would like to have linked
to the samples to meet the objectives of the study. The combined
information on all variables provided to the investigator by CDC must
not constitute a unique set of values that could link the samples with
participant data on the NHANES III public use data set. Investigators
should obtain the NHANES III Public Use Data and should verify that
anonymity can be achieved before submitting the proposal with the
requested set of variables.
A cross tabulation of all requested variables must be provided and
must demonstrate that there are at least five individuals in each
statistical cell of that cross tabulation. Recoding is required for
continuous variables and may be required for integral variables to
ensure anonymity. Because the samples are primarily available from
phase II subjects, these analyses should be run using phase II subjects
only (SDPPHASE=2). (Household codes are confidential data. Therefore,
if only one individual per household is to be included in the protocol,
the investigator can estimate the sample size per statistical cell by
halving the cross tabulation results. For instance, if only one
individual per household is requested, the minimum statistical cell
size of the cross tabulation should be ten subjects.) From each
statistical cell, either 2 or 20 percent of the subjects of the cell,
whichever is larger, will be deleted from the pool of samples sent to
the investigator. In all three proposal designs, the investigators will
receive samples that are coded with a random identifier that is unique
to that proposal.
DNA Samples
For proposals falling into category A, the laboratory will dilute
the stock specimens that are currently in deep-well plates 1:2 and
distribute 50 ul aliquots of diluted lysate. The amount of DNA in each
aliquot will be approximately 180-1,500 nanograms (ng). Aliquots will
be dispensed into deep-well plates for distribution to investigators.
Each well will be bar-coded and labeled with a readable identifier.
Approximately 20-22 sample sets of specimens from 7,300 participants
will be available for proposals. An investigator must purchase the
samples in full sets. For proposals falling into category B or C,
specimens will be distributed in 50 L aliquots in cryovials
rather than deep-well plates. The amount of DNA in each aliquot will be
75 to 650 nanograms. Only a limited number of smaller specialized sets
for category B or C are available. There are only 3 complete sets of
cryovials, so the number of projects that can be filled with these
samples depends on the types of projects proposed.
Proposed Cost Schedule for Providing NHANES III DNA Specimen Bank
A nominal processing fee of $5.00 is charged for each sample
received from the NHANES III DNA Specimen Bank if the full set of
specimens (category A) are requested. If the more limited set of
cryovials is requested, a cost of $38.00/vial is assessed to cover the
manual selection of these samples. Costs are determined both for NCEH
and NCHS and include the physical materials needed to process the
samples at the NCEH laboratory, as well as the materials to process the
requests for samples at NCHS. These costs include salaries of the staff
needed to conduct these activities at each Center. The fee is estimated
to cover the costs of processing, handling, and preparing the samples
in accordance with the detailed requirements of the investigators.
These costs were based on an assumption that NCEH and NCHS will receive
and process 20 proposals in a year, each requesting 7,300 samples as
shown in the table below or 5 subsets of 1000 samples in cryovials.
The materials listed are for the recurring laboratory costs to
dispense and prepare the samples for shipping. Labor costs are based on
the need for microbiologists, a proposal administrator, and computer
programmers for NCHS and NCEH to maintain the data bases and verify
anonymity. Technical panel travel and expenses are based on the panel
meeting twice a year. The space estimate is based on acquiring storage
and sample aliquoting space in the laboratory.
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Per sample for Per sample for
Total costs 7,300 samples in individual
96 well plates cryovials
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Materials....................... $ 0.25............ $ 1.90
Labor........................... 2.90.............. 22.00
Application review and other 0.35.............. 2.69
administrative expenses.
Space........................... 0.13.............. 0.97
Subtotal........................ 3.63.............. 27.56
NCHS overhead (15%)............. 0.54.............. 4.12
Subtotal........................ 4.17.............. 31.68
CDC/FMO overhead (20%).......... 0.83.............. 6.32
Total cost per sample........... 5.00.............. 38.00
Total cost per proposal......... 36,500............ NA
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Shipping costs are not included in the processing fee. These costs
must also be paid by the investigator.
Procedures for Letter of Intent
NCHS will post information about letters of intent on the NHANES
Web site www.cdc.gov/nchs/about/major/nhanes/nhanes.htm, by September
9, 2002. The letter of intent is required to enable CDC to plan the
review more efficiently, evaluate the number of requests, and to assess
the capacity of the DNA Bank to fulfill requests. Only
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20-22 full sets of samples (7,300 specimens) are available for this
round of proposals. A limited set of individual cryovials will be
available for less than the full set of samples. All letters of intent
will be reviewed by Division of Health Examination Statistics staff for
potential major problems related to the feasibility of the project. If
a problem is identified, the Division staff will inform the
investigator so it can be addressed in the proposal.
All potential investigators must submit letters of intent. The
letter should be no more than two pages and include (1) a descriptive
title of the overall proposed research; (2) the name, address and
telephone number of the Principal Investigator (PI); (3) a list of key
investigators and their institution(s); (4) one paragraph on the
background for the proposal and a paragraph briefly addressing each
criterion for technical evaluation of letters of intent and proposals;
(5) the genetic assessments proposed; (6) a list of proposed variables;
and (7) an estimate of the number of samples that would be requested.
The background paragraph should state concisely the importance of the
research in terms of the broad, long-term objectives and public health
relevance and consistency of NCHS's mission to monitor the nations's
health.
Letters of intent should be submitted by September 9, 2002.
Ms. Kika Oraegbu, National Center for Health Statistics, Centers
for Disease Control and Prevention, 6525 Belcrest Road, Room 1000,
Hyattsville, MD 20782, Phone: 301-458-4367, FAX: 301-458-4028, E-Mail:
[email protected].
Procedures for Proposals
The investigator should follow these instructions for preparation
of proposals: Prepare proposals with a maximum of five single-spaced
typed pages, excluding figures and tables, using ten cpi type density.
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. The cover of the
proposal should include the name, address, phone number, and E-mail
address, if available, of the PI, and the name of the institution where
the DNA analysis will be done, and the category of proposal (A, B, C)
that would be submitted. The cover page should be signed by the
responsible institution representative. Proposals will be ranked by the
technical panel on a scale of 1-10 with 10 being the highest rank for
each category.
As there are only 20-22 full sets of samples (7,300 specimens) and
only a limited set of individual cryovials for proposals requiring less
than the full set of samples available for this round of proposals,
proposals will be ranked by the technical panel on a scale of 1-10 with
10 being the highest rank for each category.
The proposal should contain, and will be evaluated according to,
the following elements:
(1) 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. Category A proposals which
request using the full set of specimens will receive priority
consideration. Category B and C proposals will be evaluated together
since they will be competing for the limited set of cryovials.
(2) Background and Public Health Significance: Describe the public
health significance, scientific merit, and practical utility of the
assay. Scientific merit will be judged on the basis of the scientific,
technical, or medical significance of the research; the appropriateness
and adequacy of the experimental approach; and the methodology proposed
to reach the research goals. Convey how the results will be used and
the relation of the results to the data already collected in NHANES
III. Analyses should be consistent with the NHANES mission to assess
the health of the nation. Because NHANES is a complex, multistage
probability sample of the national population, the appropriateness of
using the NHANES sample to address the goals of the proposal will be an
important aspect of determining scientific merit. The Panel will ensure
that the proposed project does not go beyond either the general purpose
for collecting the samples in the survey, i.e., to determine allele
frequencies in subgroups of the population, or, the specific stated
goals of the proposal
(3) Research Design and Methods: Describe the sampling scheme and
number of samples requested if submitting a category C proposal.
Include power calculations for the subsample and a list of variables
requested; provide a cross-tabulation of requested variables for
category C proposals. For all proposal categories, include a detailed
description of the laboratory methods. If a non-standard laboratory
method is to be used, discuss its advantages over using existing
methods. The characteristics of the laboratory assay, such as
reliability, validity, and ``state-of-the-art,'' should be included
with appropriate references. The potential difficulties and limitations
of the proposed procedures should also be discussed. Address adequate
methods for handling and storage of samples. NCHS will verify the
anonymity for category B and C proposals.
(4) Discussion regarding the race/ethnicity variables: If the
sample request is limited to specific race or ethnic groups or if
information about the race or ethnicity of the subjects is requested,
indicate the reason for analyzing race/ethnicity and how the results
will be interpreted. Discuss the potential for group harm.
(5) Clinical relevance of research findings: The specimens under
this Plan are available for genetic research, not genetic testing.
Therefore, it is the intent of the program to approve only those
proposals that would yield meaningful research, but not clinically
relevant information for the participants. Researchers should address
whether or not findings from the proposed research merit disclosure.
(6) Qualifications: Provide a brief description of the requestor's
expertise in the proposed area, including publications in this area
within the last three years.
(7) Anonymity: Final approval is based upon NCHS confirmation that
anonymity can be maintained by the categorization of variables for
category C proposals (proposals requiring anonymity).
(8) 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 Bank in accordance
with instructions from the Division of Environmental Laboratory
Science. Extensions to the period of performance may be requested.
(9) 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.
Currently the cost per DNA specimen is $5.00 for proposals that use the
full set of samples (~7,300) and $38.00 for subsets. Reimbursement for
the samples will be collected before the samples are released.
Proposals will be evaluated by a Genetics Technical Panel and, if
approved, by the CDC/NCHS IRB for human subject concerns. The IRB
review will be conducted, even though investigators' proposals may have
received review by their home institution. The Panel will also review
an NCHS evaluation of whether anonymity can be assured for the
[[Page 51589]]
proposed project for proposals in categories B and C. The samples that
are sent to the investigator will be selected randomly from the domains
by NCHS staff. The Director of NCHS will verify that projects have
received appropriate reviews.
Requirements for the Inclusion of Women and Racial and Ethnic
Minorities in Research
In NHANES III, race/ethnicity was defined by self-report as non-
Hispanic white, non-Hispanic black, or Mexican American. Individuals
who did not self-select into these categories were classified as
``other.'' If the proposal excludes one or more race/ethnic groups or a
gender, this exclusion must be justified.
CDC is also sensitive to the stigmatization of racial/ethnic
specific populations through inappropriate reporting and interpretation
of findings. For all proposals that request information on race/
ethnicity for the samples selected, the investigator should indicate
the reason for analyzing race/ethnicity and how the results will be
interpreted.
Submission of Proposals
Proposals should be submitted by October 7, 2002. All investigators
who submitted letters of intent may submit proposals.
Electronic submission of proposals is encouraged. Please submit
proposals to: Ms. Kika Oraegbu, National Center for Health Statistics,
6525 Belcrest Rd., Rm 1000, Hyattsville MD 20782, Phone: (301) 458-
4367, FAX: (301) 458-4028, E-Mail: [email protected], Attention: NHANES III
Genetic Testing Program.
Approved Proposals
NCHS/NCEH will provide a data file with the requested recoded
variables (for category B and C proposals) and a randomly assigned
unique identification number that is linked to the DNA specimen. No
record connecting the new number with the original identification
number will be kept after the samples have been sent. These samples
cannot be traced to any files maintained by NCHS. For proposals in
category A, the genetic results will be sent back to NCHS so they can
be linked to the NHANES III public use data in the Research Data Center
for analysis.
Agency Agreement
A formal signed agreement in the form of a Materials Transfer
Agreement (MTA) with individuals who have projects approved will be
completed before the release of the samples. This agreement will
contain the conditions for use of the DNA as stated in this document
and as agreed upon by the investigators and CDC. A key component of
this agreement is that no attempt will be made to link the results of
the proposed research to any other data, including, but not limited to,
the NHANES III public use data set. Also, the investigator agrees that
the samples cannot be used for commercial purposes.
Progress Reports
A progress report will be submitted annually. CDC/NCHS IRB
continuation reports are also required annually.
Disposition of Results and Samples
No DNA samples provided can be used for any purpose other than
those specifically requested in the proposal and approved by the
Genetics Technical Panel and the NHANES IRB. No sample can be shared
with others, including other investigators, unless specified in the
proposal and so approved. Any unused samples must be destroyed upon
completion of the approved project. Researchers requesting DNA samples
for age-race-gender studies and special studies will be required to
provide NCHS with the results of all DNA tests performed for each
anonymized sample. These results, once returned to NCHS, will be part
of the public domain. Therefore, ample time will be given to the
investigator to publish results prior to reporting the results to NCHS.
Send Request for Information: Ms. Kika Oraegbu, National Center for
Health Statistics, Centers for Disease Control and Prevention, 6525
Belcrest Road, Room 1000, Hyattsville, MD 20782, Phone: 301-458-4367,
FAX: 301-458-4028, E-Mail: [email protected].
References
1. Plan and Operation of the Third National Health and Nutrition
Examination Survey, 1988-94. National Center for Health Statistics.
Vital Health Stat (32) 1994.
2. Clayton EW, Steinberg KK, Khoury MJ, et al. Informed consent for
genetic research on stored tissue samples. JAMA 1995;274:1786-1792.
Dated: August 2, 2002.
Joseph R. Carter,
Associate Director for Management and Operations, Centers for Disease
Control and Prevention (CDC).
[FR Doc. 02-20038 Filed 8-7-02; 8:45 am]
BILLING CODE 4163-18-P