[Federal Register Volume 64, Number 104 (Tuesday, June 1, 1999)]
[Notices]
[Pages 29321-29325]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-13740]
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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 Anonymized Samples and
Proposed Cost Schedule
ACTION: Notice and request for comments.
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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 health and nutritional status of the
United States civilian non-institutionalized population. To add to the
large amount of information collected for the purpose of describing the
health of the population in the most recent survey, white cells were
collected in NHANES III in anticipation of advances in genetic
research.
The cells have been stored and maintained at the Division of
Environmental Health Laboratory Sciences (DEHLS) at the National Center
for Environmental Health (NCEH), CDC. The collection of white cells was
begun because of the significant advances in the rapidly evolving field
of molecular biology that were occurring during the planning phase of
this survey.
Technical advances now make it possible to use these samples for
genetic analysis. NCHS and NCEH, CDC are making anonymized DNA samples
from these specimens available to the research community for such
analyses. No cell lines will be made available.
The purpose of this notice is to request comments on this program
and cost schedule. After consideration of comments submitted, CDC plans
to
[[Page 29322]]
finalize the cost schedule and solicit letters of intent and proposals
for use of the NHANES III anonymized DNA samples. Please contact Ms.
Burwell or go to www.cdc.gov/nchswww/about/major/nhanes/nhanes.htm for
final proposal guidelines and request for letters of intent.
All interested researchers are encouraged to submit letters of
intent. No funding is provided as part of this solicitation. DNA
samples will not be provided to those projects requiring funding until
the project has received funds. Approved projects that do not obtain
funding will be canceled. A more complete description of this program
follows.
DATES:
Comment Receipt Date: June 30, 1999
Invitation to submit Letters of Intent: July 14, 1999
Letter of Intent Receipt Date: September 1, 1999
Invitation to Submit Proposals: September 22, 1999
Application Receipt Date: November 3, 1999.
Scientific Review Date: December 1999.
Institutional Review Date: January 1999.
Notification of approval: January 1999.
Anticipated distribution of samples: February-March 2000.
TO SEND COMMENTS AND FOR INFORMATION: Audrey L. Burwell, MS, Health
Research Administrator, National Center for Health Statistics, Centers
for Disease Control and Prevention, 6525 Belcrest Road, Room 1100,
Hyattsville, MD 20782, Phone: 301-436-7062, 127, FAX: 301-436-4233, E-
Mail: azb2@cdc.gov, Internet: www.cdc.gov/nchswww/about/major/nhanes/
nhanes.htm.
SUPPLEMENTARY INFORMATION: The goals of NHANES are: To estimate the
number and percent of persons in the U.S. population and designated
subgroups with selected diseases and risk factors; to monitor trends in
the prevalence, awareness, treatment and control of selected diseases;
to monitor trends in risk behaviors and environmental exposures; to
analyze risk factors for selected diseases; to study the relationship
between diet, nutrition and health; to explore emerging public health
issues and new technologies; and, 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. The
survey data were collected, and can be analyzed, in 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 301-436-8500 or from
the Internet at www.cdc.gov/nchswww/products/catalogs/subjects/nhanes3/
nhanes3.htm.
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 DEHLS, NCEH at the CDC,
Atlanta GA. DNA is available primarily from cell lines of Phase II
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. Given the
scientific importance of this resource, the NHANES Institutional Review
Board (IRB) approved making anonymized samples of DNA available to the
research community for genetic research. For this purpose, an
anonymized sample is defined as a sample for which no one, including
CDC staff, are able to link the results of the genetic tests back to
the survey participant (2). NCHS and NCEH will anonymize the samples
for each request.
All proposals for testing of anonymized NHANES III DNA samples will
be evaluated by a Genetics Technical Panel (composed of 8-10
scientists; 40 percent from CDC; 30 percent from other Federal agencies
and 30 percent non-government scientists) for scientific merit and by
the NHANES IRB to assure that anonymity will be maintained, as well as
for other human subjects concerns. The NHANES IRB review will be
conducted, even though the investigator may have received review by
their home institution. The NHANES IRB must review all projects because
determination of anonymity required by this proposal review process can
only be accomplished by the NHANES staff who have access to
confidential records. Projects recommended for approval by the Genetics
Technical Panel and the IRB will be submitted to the Director of NCHS
for verification that all appropriate reviews have been conducted.
The Genetics Technical Panel will evaluate the public health
significance and scientific merit of the proposed research. Scientific
merit will be judged as to 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. See Criteria for Technical Evaluation of Proposals
below. The proposer should outline how the results from the DNA
analysis will be used. Because NHANES is a complex, multistage
probability sample of the national population, the appropriateness of
the NHANES sample to address the goals of the proposal will be an
important aspect of scientific merit. The Genetics Technical Panel will
assure 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 of the specific
stated goals of the proposal. The Panel will also review an evaluation
by the NCHS staff as to whether anonymity can be assured for the
proposed project.
Investigators are encouraged to obtain the NHANES III Reference
Manuals and Reports and NHANES III Public Use Data (on CD-ROM) These
can be obtained by contacting the Data Dissemination Branch, NCHS at
301-436-8500 or from the Internet at www.cdc.gov/nchswww/products/
catalogs/subject/nhanes3/nhanes3.htm.
Because of the complex nature of this Survey, sampling weights are
used to make national estimates of frequencies. The use of weights,
sampling frame and methods of assessment of variables included in the
data tape are likely to affect the proposed research. The Genetics
Technical Panel will review the analysis plan and evaluate whether the
proposal is an appropriate use of the NHANES III population.
Due to the design of NHANES III, the DNA samples are not suitable
for family studies. On average, NHANES III sampled 2 individuals from
each household in Phase II. The relationship
[[Page 29323]]
between individuals is not available on the data file. If the
investigator requires strict assurance that only one subject per
household is included among the samples, the investigator should
request only one subject per household, and estimate statistical cell
sizes by dividing the results from cross tabulations by 2 (see Special
Studies procedures below). In this instance, the NCHS staff can use the
confidential household code (not available on public use tapes) to
select one subject per household for approved projects.
The provided samples will consist of DNA suitable for use in the
polymerase chain reaction or other justifiable genetic assessments. No
cell lines will be made available. Unique, randomized IDs will be
assigned to each set of DNA samples.
Two types of proposals will be evaluated: (a) Those that aim to
describe allele frequencies which require only basic demographic
information (age, race, and gender) linked to the samples or (b) those
where additional co-variates from the NHANES data base are required
(special studies).
Age-Race-Gender Studies
To facilitate proposal preparation of allele frequency research,
NCHS will make available the following data 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. These proposals, therefore, do not need to provide an
analysis of NHANES III data to support the 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 review will be limited to those
requesting samples from within these domains for the identification of
the frequency of the genes in the population. These proposals must
address all criteria except for the verification that anonymization can
be achieved. Because of the limited data associated with the genetic
result, a shortened (2-3 pages) proposal is acceptable as long as each
of the criteria below are addressed.
Special Studies (Requests for Additional Variables)
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 DNA 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 DNA samples with participant data on the NHANES III
public use data set. Investigators should obtain the NHANES III Public
Use Data and should verify prior to submission that anonymity is
achievable with the requested set of variables. To obtain the NHANES
III Public Use Data contact the Data Dissemination Branch, NCHS at 301-
436-8500 or from the Internet at www.cdc.gov/nchswww/products/catalogs/
subject/nhanes3/nhanes3.htm.
Recoding is required for continuous variables and may be required
for integral variables to assure anonymity. A cross tabulation of all
requested variables must be provided, with demonstration that there are
at least five individuals in each statistical cell of that cross
tabulation. Because the DNA specimens are primarily available on phase
II subjects, these analyses should be run using phase II subjects only
(SDPPHASE=2). (Household codes are confidential data. Therefore, if
only 1 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 1
individual per household is requested, the minimum statistical cell
size of the cross tabulation should be 10 subjects.) From each
statistical cell, either 2 subjects or 20 percent of the subjects of
the cell, whichever is larger, will be deleted from the pool of samples
sent to the investigator. The DNA samples which are sent to the
investigator will be selected by the NCHS staff at random from the
domain.
All protocols, either for the age-race-gender studies or the
special studies, will be reviewed by NCHS staff for anonymity and must
be approved by the Genetics Technical Panel and the NHANES IRB. The
anonymity of all sample requests, when linked with demographic and
clinical data, will be verified prior to release to the investigator.
Applicants may request a project period of up to 3 years. At the
end of the project period, any unused samples must be returned to the
Bank in accordance with instructions that will be provided. Extensions
to the period of performance may be requested.
Procedures for Letter of Intent
After consideration of comments on the program and the cost
schedule, NCHS plans to make requests for letters of intent. This
request will be announced on the NHANES web site by July 14, 1999:
Internet: www.cdc.gov/nchswww/about/major/nhanes/nhanes.htm. The letter
of intent is required to enable CDC to plan the review more
efficiently, evaluate the number and magnitude of the requests, and to
assess the capacity of the DNA Bank to fulfill requests.
Investigators from both the extramural and the CDC intramural
research communities must submit letters of intent. The letter should
be no more than two pages and include: a descriptive title of the
overall proposed research, the name, address and telephone number of
the Principal Investigator, a list of key investigators and their
institution(s), one paragraph on the background for the proposal, the
genetic assessments proposed, a list of proposed variables, and an
estimate of the number of samples that would be requested. The
background should state concisely the importance of the research in
terms of the broad, long-term objectives and public health relevance.
If the total number of proposals and samples requested from all the
letters of intent exceed the handling capacity of the DNA Specimen
Bank, a determination of priorities will be made by the Genetics
Technical Panel using the letters of intent. Priority will be based on
the public health importance of the proposed research and the
prevalence of the health outcome(s) targeted by the research.
All investigators will be notified as to whether they should submit
a full proposal based on review of the letters of intent.
Letters of intent should be submitted by September 1, 1999, to:
Audrey L. Burwell, MS, Health Research Administrator, National Center
for Health, Statistics, Centers for Disease Control and Prevention 6525
Belcrest Road, Room 1100, Hyattsville, MD 20782, Phone: 301-436-7062,
127, FAX: 301-436-4233, E-Mail: azb2@cdc.gov.
Procedures for Proposals
After notification by NCHS that a proposal for use of samples and
data from the NHANES III DNA-Bank can be submitted, the investigator
should use the following format: Proposals are limited to a maximum of
5 single-spaced typed pages, excluding figures and tables, using 10 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. Unapproved proposals will be returned to the
investigator and will not be maintained
[[Page 29324]]
by NCHS. The cover of the proposal should include the name, address,
and phone number and E-mail address, if available, of the principal
investigator (PI) and the name of the institution where the DNA
analysis will be done. The cover page should be signed by the
responsible institution representative.
The Criteria for Technical Evaluation of Proposals section at the
end of this announcement and the following information should be used
to develop the proposal content.
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.
2. Background and Public Health Significance--Briefly describe in
1-2 pages the background of the proposal, identifying gaps in knowledge
that the project is intended to fill. State concisely the importance of
the research in terms of the broad, long-term objectives and public
health relevance including a discussion of how the results will affect
health policy or further scientific knowledge. The proposal should
include a discussion of the potential clinical significance of the
results and whether there is definitive evidence that results of the
genetic test would provide grounds for medical intervention.
3. Research Design and Methods--Describe the research design and
the procedures to be used. A detailed description of laboratory methods
must be included with references. If non-standard methods will be used,
discuss how the method is more appropriate than current methods or that
there are no standard methods to accomplish the task. Laboratory
quality control should be described. Include a justification for
determination of sample size or a power calculation. A detailed
description and justification of any sample design whether a random
subsample or case control design, must be given. The program will
evaluate the endpoints assessed in these projects to determine whether
the projects are consistent with the mission of the NHANES program.
Further, the program and IRB are concerned with the possible breach of
anonymity due to the determination of a large number of genetic
analyses in individual research studies. The specific concern is that,
when large numbers of genetic findings are available that are
potentially correlated with other NHANES III data, the investigator or
program staff might be able to inadvertently identify specific
subjects. Therefore, if several genetic analyses are proposed, the
investigator must discuss the potential for linking the findings with
NHANES III data on public use tapes that was not requested as part of
the proposal. A list of variables requested should be included. A
crosstabulation demonstrating the recoding and resulting statistical
cell sizes should be included for special studies.
4. Qualification of Investigators--A brief description of the
Principal Investigator's expertise in the proposed area should be
provided, including publications in this area within the last three
years. A representative sample of earlier publications may be listed as
long as this section does not exceed two pages.
5. Funding--The source and status of the funding to perform the
requested laboratory analysis should be included. Investigators will be
responsible for the cost of processing and shipping the samples. At
this time the cost per DNA specimen is $38.00. The basis for the cost
structure is in the last section of this document. Reimbursement for
the samples will be collected before the samples are released.
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.
The 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
Investigators who are invited to submit proposals should send the
original written proposal and 20 copies to: Audrey L. Burwell, MS,
Health Research Administrator, National Center for Health Statistics,
6525 Belcrest Rd., Rm 1100, Hyattsville, MD 20782, Phone: (301) 436-
7062, 127, FAX: (301) 436-4233, E-Mail: azb2@cdc.gov, Attention: NHANES
III Genetic Testing Program.
Criteria for Technical Evaluation of Proposals
The following criteria will be used for technical evaluation of
proposals.
1. Background and Public Health Significance: The public health
significance, scientific merit and practical utility of the assay. The
proposer has conveyed how the results will be used and the relationship
of the results to the data already collected in NHANES III. Proposer
addresses how they will use results of the DNA analyses. The analyses
are consistent with the NHANES mission and the health status variables
will be evaluated appropriately given the methods of data collection in
NHANES III.
2. Research Design and Methods: The sampling scheme must be
described and address its relationship to the NHANES III design. Power
calculations for a subsample must be included. A list of variables
requested with the recoding schemes are included. A cross-tabulation is
provided if the investigator requests a special set of variables. A
detailed description of the laboratory methods is included. If a non-
standard laboratory method is to be used, its advantage over existing
methodology is adequately discussed. The characteristics of the
laboratory assay, such as reliability, validity, and ``state-of-the-
art'', must be included with appropriate references. The potential
difficulties and limitations of the proposed procedures are discussed.
The volume of DNA and the number of samples required are specified.
Adequate methods for handling and storage of samples must be addressed.
The laboratory has demonstrated the capability for handling the
workload requested in the proposal.
3. Discussion regarding the race/ethnicity and gender variables: If
either race/ethnicity or gender are used to restrict the sample, the
proposal gives a clear and compelling rationale for this restriction.
On the other hand, if the race/ethnicity variable is requested, the
proposer indicates the reason for analyzing race/ethnicity and how the
results will be interpreted.
4. Qualifications: A brief description of the requestor's expertise
in the proposed area is provided including publications in this area
within the last three years. A representative sample of earlier
publications may be listed as long as this section does not exceed two
pages.
5. Anonymity: NCHS determination of anonymity has been reviewed and
found to be adequate.
6. Period of performance--The project period should be specified.
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 DEHLS.
[[Page 29325]]
Extensions to the period of performance may be requested.
Approved Proposals
NCHS/NCEH will provide a data file with the requested recoded
variables 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 can not be traced to any files maintained by
NCHS.
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 can not be used for commercial purposes.
Progress Reports
A progress report will be submitted annually. NHANES 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
Genetic 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 returned to the
Bank 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.
Proposed Cost Schedule For Providing NHANES III DNA Specimen Bank
A nominal processing fee of $38.00 is proposed for each sample
received from the NHANES III DNA Specimen Bank. The 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 are
inclusive of the staff needed for 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 15 proposals in a year each
requesting 1000 samples as shown in the table below.
The materials listed are for the recurring laboratory costs to
dispense and prepare the samples for shipping; the computer software
needed for the Web page and advertisements in scientific journals.
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 aliquoting space.
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Total Costs Per Sample if 15 Requests for 1,000 Samples
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Materials.................................................. $1.90
Labor...................................................... 22.00
Panel Travel/Expenses...................................... 2.69
Space...................................................... 0.97
Subtotal................................................... 27.56
NCHS overhead (15%)........................................ 4.12
Subtotal................................................... 31.68
CDC/FMO overhead (20%)..................................... 6.32
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Total.................................................. * 38.00
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* Shipping costs are not included in the $38.00 processing fee. These
costs must also be paid by the investigator.
Comments are solicited on the proposed cost schedule. Comments are
due by June 30, 1999.
Send Comments and for Information
Audrey L. Burwell, MS, Health Research Administrator, National Center
for Health Statistics, Centers for Disease Control and Prevention, 6525
Belcrest Road, Room 1100, Hyattsville, MD 20782, Phone: 301-436-7062,
127, FAX: 301-436-4233, E-Mail: azb2@cdc.gov
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: May 25, 1999.
Joseph R. Carter,
Acting Associate Director for Management And Operation, Centers for
Disease Control and Prevention.
[FR Doc. 99-13740 Filed 5-28-99; 8:45 am]
BILLING CODE 4163-18-P
