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Report of the Workshop on Population-Based Samples for the NIGMS Human Genetic Cell Repository

July 20, 1999


Introduction

The scientific community considers the samples from the identified human populations currently in the NIGMS Human Genetic Cell Repository to be of substantial value and has asked that this collection be expanded to include samples from additional populations as well as a greater number of samples per population. Like the samples from identified populations that currently exist in the collection, the proposed additional samples would be from unrelated individuals about whom no phenotypic information would be provided. The individual samples would be anonymous or anonymized, although the population that the sample came from would be known, as discussed below.

Enlarging this collection raises scientific as well as ethical, legal, and social (ELSI) questions. On the scientific side, the questions include a determination of the characteristics of populations that would be of most value for researchers and of the appropriate number of samples from each population. On the ELSI side, the current human subjects regulations (45 CFR Part 46) are focused on the protection of individuals and do not extend to groups to which the individuals may belong. In recent years there has been discussion about the potential consequences for specific populations of genetic studies that are conducted on individuals who are members of these populations. Thus, expanding the collection of samples from identified human populations raises important questions, including whether appropriate protections can be put in place to reduce the possibility of negative impacts on populations if the Repository acquires population-based samples.

A workshop was held on July 20, 1999 to consider the scientific benefits and the risks to populations of expanding the collection of human population-based samples and to develop recommendations about whether, and under what conditions, the Repository should acquire these samples. To assure a diversity of views, participants in the workshop included individuals with expertise in population genetics, physical and cultural anthropology, bioethics, medicine, psychology, and patient advocacy.

The meeting agenda began with several brief presentations that set the stage for the extensive discussion that followed. Dr. Anne Spence summarized the research purposes for which the type of population-based samples described above are of value. Samples from distinct populations are useful: (1) for identifying genes in both rare and common disorders; (2) for demonstrating gene function by distinguishing between a disease-causing mutation and a normal polymorphism; and (3) for answering fundamental questions related to an understanding of population structure, which is essential for interpreting data from the first application.

Dr. Andrew Clark provided evidence for the power of grouping individuals by population, as opposed to pooling them, in the discovery of an association between DNA variation and disease-causing genes, particularly for complex disorders.

While the scientific value of samples from identified populations was acknowledged, so too were the potential risks and harms to populations. Dr. Marvin Natowicz described some of the risks. These include stereotyping and stigmatizing, by the use or misuse of information derived from a study as well as by the very act of identifying a group; discrimination in access to various social benefits; conflict with the group's cultural beliefs; and, under certain circumstances, loss of potential property rights. Further discussion led to the identification of additional risks to populations, which include internal self-stigmatization by members of the population itself and community disruption.

Dr. Jeanne Beck presented data on the Human Variation Collections currently in the Repository. These include 142 samples from 18 populations in the Yale-Stanford Collection and 11 Human Variation panels (of 10-100 samples), which were assembled from materials already in the Repository. (The samples in the DNA Polymorphism Discovery Resource have no ethnic identifiers. As a result, these samples cannot be associated with any population, and therefore are not at issue here.) Since 1991, shipments of samples from the Yale-Stanford Collection have represented 2.4 percent of all shipments from the Repository. From December 1, 1997 to July 1, 1999, 263 Human Variation panels have been shipped. Thus, the demand for this material is high. Based on information derived from the statement of research intent required to place an order, investigators use these samples to identify single nucleotide polymorphisms (SNPs), to determine allele frequencies, to characterize polymorphisms, to compare interspecies variations, and to study evolutionary history.


Recommendations: Scientific Issues

Extensive discussion at the workshop yielded a set of recommendations that were then refined and elaborated upon by the workshop participants via an e-mail distribution list discussion over the course of several weeks. That process culminated with the development of consensus recommendations. The first group of recommendations relates to scientific issues.

  • Samples from unrelated individuals, without phenotypic information, from identifiable populations are of scientific value and should be acquired by the Human Genetic Cell Repository.
  • While recognizing the shortcomings of the approach, inclusion of a sample as part of a population (clustering) should be based on self-identification of the individual as part of that population and, at a minimum, on information about the individual's four grandparents. Information about the grandparents should include both their geographic origin and ethnicity.
  • Although human populations can often be defined by such characteristics as language and geographic origin, subdividing humans into distinct population groups cannot be done with complete accuracy. One way to quantify the degree of relatedness is to score anonymous markers (such as microsatellites) in a homogeneous fashion across the entire set of samples. Therefore, consideration should be given to analyzing markers for up to 100 randomly chosen loci in each population-based sample. These data would be provided along with the samples so that clustering methods could be used to group individuals based on these markers. This information would complement the clustering based on self-identification.
  • For some purposes it will be of greatest value to collect samples from populations that have experienced little recent admixture. Populations from Africa are especially diverse and would provide much information on the spectrum of human genetic variation, which would in turn aid in making inferences about the variation that underlies disease. Extreme care should be taken to avoid the perception that genetics researchers are or will be exploiting such populations, many of whom are poorer and have less social power.
  • There is also value in collecting samples from highly admixed populations such as those in the United States, although many such samples are already available in the Repository and elsewhere. Only by sampling admixed populations, such as European Americans, African Americans, and Hispanic Americans, with awareness of the subpopulations that exist within these populations, can scientists hope to obtain meaningful genetic associations for these populations. Analysis of genetic association in admixed populations requires careful ascertainment and sampling of "parental" populations (those with little admixture as described in the paragraph above). In addition to their scientific value, acquiring samples from admixed populations might lessen the fears of some small, non-admixed populations--many of which are "minority" populations that have experienced past discrimination--about being singled out to serve as sample donors.
  • The number of samples per population that should be collected for the Repository depends on the expected research use to which they would be put. Approximately 200-250 samples would be needed for estimates of linkage disequilibrium, while a smaller number would be sufficient for estimates of allelic variation. The collection of large numbers of samples per population requires such a large commitment of resources that it would preclude acquiring very many different populations. As a practical matter, it might be advisable to obtain a large number of samples from just a few populations (i.e., one or two African populations, one or two Asian populations, one or two populations from the Western Hemisphere, etc.) with smaller numbers of samples from additional populations. The latter would serve for preliminary studies of variation.
  • For each population, the Repository should require that the submitter provide careful documentation about how the population was ascertained and defined, the history of the population, its age, the extent of admixture, what the familial relationship is, if any, among samples in the population, and other characteristics.
  • The information above should be made available to researchers.

Recommendations: Human Subjects Issues

The following recommendations are related to human subjects issues that are raised by the collection of samples from identified populations and the storage and distribution of these samples by the Repository. These recommendations represent a new approach to the protection of populations that complements the protections that are afforded individuals by the current system of Institutional Review Board (IRB) approval and informed consent.

The National Bioethics Advisory Commission (NBAC) recently released its final report,  Research Involving Human Biological Materials: Ethical Issues and Policy Guidance (August 1999). The report provides a thorough analysis of the ethical issues involving groups and contains two recommendations, quoted below, that address potential harms to individuals other than the research subject.

Recommendation 17

Research using stored human biological materials, even when not potentially harmful to individuals from whom the samples are taken, may be potentially harmful to groups associated with the individual. To the extent such potential harms can be anticipated, investigators should to the extent possible plan their research so as to minimize such harm and should consult, when appropriate, representatives of the relevant groups regarding study design. In addition, when research on unlinked samples that poses a significant risk of group harms is otherwise eligible for exemption from IRB review, the exemption should not be granted if IRB review might help the investigator to design the study in such a way as to avoid those harms.

Recommendation 18

If it is anticipated that a specific research protocol poses a risk to a specific group, this risk should be disclosed during any required informed consent process.

Some of the recommendations, below, stemming from the workshop might be considered to afford protections beyond what were recommended in the NBAC report.

  • Samples from identifiable populations should only be acquired by the Repository if their acquisition meets a set of standards, detailed below, in addition to those currently required by the regulations for the protection of human subjects (45 CFR 46).
  • For each population, the Repository should require that the submitter provide careful documentation about the informed consent process for the individual members of the population who are sample donors (including the information given to the individuals by the researcher during the consent process); the process of consultation with, and involvement and participation of, the population, from the early planning of the sample collection through its implementation; and any restrictions promised in the process of individual consent or consultation with the population. This information should also be made available to those investigators who obtain cell lines derived from those samples.
  • A critical aspect of the plan to extend protections to populations is the establishment of special oversight groups (distinct from the IRB) that will evaluate whether the samples were (or will be) acquired consistent with the appropriate protections. The oversight groups should be constituted to include individuals with expertise in relevant scientific and bioethical issues, and representatives who are sensitive to the interests of the population under consideration. In most cases, the latter should be members of the population under consideration and should include non-professionals. The special oversight group would evaluate whether the proposed acquisition of samples meets the following conditions, and others that may arise:
    • That consultation with and appropriate participation by members of the population occur at all stages: in advance; during the course of the collection, acquisition, and distribution of samples by the Repository; and following the generation of research results. The process of consultation with the population will vary depending upon the specific population but is a process that is well known to many anthropologists and other social scientists. This process is often called "involving the stakeholders."
    • That the population is informed about the use of the samples, the benefits, if any, that are promised to the population, the potential harms to the population, and what will be done to minimize those harms. It was acknowledged that direct benefits ("payback") would be uncertain, since the investigators who collect the samples will not know, in more than a general way, what research will be done using the samples.
    • That the informed consent process for the individual sample donor and the consent document signed by the individual also include the information described in the preceding paragraph.
  • As each population is considered as a source of samples, the Human Genetic Cell Repository in consultation with the Project Officer should convene a special oversight group. It is expected that each special oversight group will have a different composition to address issues specific to different populations. However, it would be advantageous to have some members who would participate on all oversight groups to provide consistency and institutional memory.
  • The Repository should publicize to the scientific community its requirements for the protection of populations from harm in the acquisition of population-based samples.
  • The Repository should require that investigators who purchase population-based samples use them only for research that is consistent with the informed consent of the donor and with the recommendations of the special oversight group. Although it would be best if restrictions were not placed on the types of genetic studies to be carried out using samples from particular populations, it might be necessary in some cases to acquire samples with less than blanket consent. That is, a population may stipulate certain categories of genetic research that should not be performed with its samples.
  • The Repository should require that investigators who purchase population-based samples must report research results based on these samples in a manner consistent with the protections provided for the donors of the samples and their populations.
  • Although it is beyond the scope of the Repository to accomplish alone, a greater effort needs to be made to educate the public, as well as the medical establishment, about the benefits and risks of population-based research.

Before they are implemented, the recommendations will be presented for discussion first within the National Institutes of Health and then with the broader scientific community, the bioethics community, and representatives of various populations. The final recommendations may be modified in the future, as experience with the scientific and ethical issues develops. Any proposed modifications to these recommendations should include a similar process involving these three constituencies.


Roster

Marvin Natowicz, M.D., Ph.D., Co-chair
Division of Medical Genetics
Shriver Center
200 Trapelo Road
Waltham, MA 02254
(781) 642-0176

M. Anne Spence, Ph.D., Co-chair
Department of Pediatrics/
Division of Medical Genetics
University of California Irvine
Medical Center, Building 2
101 The City Drive South
Orange, CA 92868
(714) 456-8385

John Blangero, Ph.D.
Department of Genetics
Southwest Foundation for Medical Research
P.O. Box 28147
San Antonio, TX 78228-0147
(210) 258-9400, ext. 634

Andrew Clark, Ph.D.
Department of Biology
Pennsylvania State University
208 Mueller Lab
University Park, PA 16802-5301
(814) 863-3891

William Freeman, M.D., M.P.H.
Indian Health Service
5300 Homestead Road NE
Albuquerque, NM 87110-1293
(505) 248-4384

Atwood Gaines, M.P.H., Ph.D.
Department of Anthropology
238 Mather Memorial Building
Case Western Reserve University
Cleveland, OH 44106
(216) 368-2257

Lynn B. Jorde, Ph.D.
Human Genetics
Eccles Institute of Genetics
University of Utah School of Medicine
Room 2100, Building 533
Salt Lake City, UT 84112
(801) 581-4566

Eric T. Juengst, Ph.D.
Center for Biomedical Ethics
School of Medicine
Case Western Reserve University
10900 Euclid Avenue
Cleveland, OH 44106-4976
(216) 778-8493

Diana M. Lee
Sickle Cell Community Health
Network of Northern California
509 28th Street
Richmond, CA 94804
(877) 726-2372

Nancy Press, Ph.D.
Department of Public Health
and Preventive Medicine
Oregon Health Sciences University
3181 Southwest Sam Jackson Park Road
CB-669
Portland, OR 97201
(503) 494-2535

Catalina Ramos
Y-ME National Breast Cancer
Organization
212 W. Van Buren Street
Chicago, IL 60607-3908
(312) 986-8338

Leonard J. Tamura, Ph.D.
Clinical Psychologist
7220 W. Jefferson Avenue, Suite 401
Lakewood, CO 80235
(303) 980-9712

Deputy Director, Human Genetic Cell Repository
Jeanne C. Beck, Ph.D.
Coriell Institute for Medical Research
401 Haddon Avenue
Camden, NJ 08103
(800) 752-3805

Project Officer
Judith H. Greenberg, Ph.D.
Director
Division of Genetics and Developmental Biology
NIGMS, NIH
Building 45, Room 2AS-19H
45 Center Drive MSC 6200
Bethesda, MD 20892-6200
(301) 594-0943

Alternate Project Officer
Catherine Lewis, Ph.D.
Branch Chief
Division of Cell Biology and
Biophysics
NIGMS, NIH
Building 45, Room 2AS.13K
45 Center Drive MSC 6200
Bethesda, MD 20892-6200
(301) 594-0828


Agenda

9:00-9:30 Introductions and background to the meeting Judith Greenberg
9:30-9:45 Why study populations? Anne Spence
9:45-10:00 Human variation samples in the Repository Jeanne Beck
10:00-10:15 What are the concerns related to studying identified populations? Marvin Natowicz
10:15-10:30 Break  
10:30-12:00 Discussion Participants
12:00-1:00 Lunch  
1:00-3:00 Discussion, continued Participants
3:00-4:00 Recommendations Participants
4:00 Adjourn  


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