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2.5. Ethical challenges of conducting the Hap Map Genetics project in Japan

- Eiko SUDA and Darryl MACER
Eubios Ethics Institute,
P.O. Box 125 Tsukuba Science City, 305-8691 Japan
<http://eubios.info/index.html>
Email: hapmap@hotmail.com, asianbioethics@yahoo.co.nz

1. HapMap Project

The Haplotype Map Project (HapMap) is an international collaborative project collecting blood samples from people from various parts of the world. This paper considers some of Ethical Challenges in the Japanese HapMap Genetics Project, which shows some aspects of the Japanese situation to conduct the international genetics studies.

The HapMap project, is a US NIH initiated international genetic study. The HapMap project was officially launched on 29 October, 2002 at NIH, as a joint project involving financial contributions from USA, Japan, UK, China, and Canada. The goal is to develop a human Haplotype Map, based firstly on analysis of about 270 DNA samples from 4 populations (90 Yoruban from Nigeria, 45 Japanese/45 Han Chinese and 90 CEPH in U.S. residents of Northern and Western European ancestry). The genetic data will be on-line in a free public database for study of human genetic variation. There will be a repository of cell lines accessible for researchers around the world, held at Corriell Repository, in the USA. In this project, only the information about which area the sample came from will be attached to each sample. It will not collect names or health information, and researchers will only know what group each sample came from.

Eventually the project may collect samples from around 100 people from each of about 10 major racial, ethnic, or geographic groups. The project raises ethical issues in the way that the samples are collected, the way the samples are sent to a central repository and then stored as cell lines for access by researchers around the world. While elaborate procedures have been considered to protect the participants who donate samples, there are concerns that the samples may be used to label broad ethnic groups in the future. These concerns are reminiscent of concerns about the Human Genome Population Diversity Project (HGDP)in the 1990s (Lock, 1994; Chee et al., 1995; Macer, 1997). In future studies, researchers may find that certain genetic variations show up more often in people from one group than in people from other groups, and that these variations are more common in people with a certain disease. When these findings become public, some people could think less of a particular group, or more of another group.

2. Development of research protocols in Japan

The Japanese HapMap project is been conducted under the chief investigator, Prof. Yusuke Nakamura in Human Genome Center, University of Tokyo. The establishment of cell lines from blood samples is being done inside Japan by Prof. Yoshimitsu Fukushima in Shinshu University. An independent working group for ELSI issues and sample collection process was established in each country where samples will be collected including Prof. Ichiro Matsuda (President, Japan Society of Human Genetics), Darryl Macer and Eiko Suda.

Protocols were developed with good cooperation inside the ELSI group in Japan, and with the chair of the HapMap ELSI group, Dr. Ellen Wright Clayton, and the NIH ELSI co-director, Dr. Jean McEwen. An English translation of the protocol and informed consent form approved by University of Tokyo IRB are in the Appendix to this paper. The ELSI team in Japan, in particular Suda and Macer talked about the project and plans, receiving suggestions, at conferences in Taiwan, Canada, South Korea, and Brazil, and at 6 public meetings/lectures in Japan. As individuals the ELSI team members also talked to numerous persons about the project. The term public consultation was adopted over community engagement, as more suitable in Japan.

The HapMap will involve making comparisons between population groups, as the fundamental unit of analysis. So individuals may be affected by this research even if they do not donate samples. So the mission of ELSI group is to develop community engagement to discuss about the project with a wide range of people in the society to better understand societal concerns, and to provide an opportunity for broad public input. The main approach to initiate and maintain community engagement consists of two groups, focus group meetings and a later community advisory group. The project also involves creating a community advisory group (CAG) in each area, which will be available for ongoing consultation after the samples have been collected and used for research. The ethical issues faced when conducting this project in Japan will be considered, with lessons for genetic sampling projects in the future. There will be no benefit to the donors, except the future promise of medical research results.

We have also held public forums to talk about this project. To organize focus groups, we attempted to recruit participants by a snowball sampling method. We planned to start with a small number of initiators from various sectors of Japanese society, discuss about the project with them, and then ask to them to share the information and discussions with their acquaintances to recruit the next members. The purpose of this group is the mutual discussion about the project between public and science. The results will be fully reported at the completion of the project, but lack of resources, and lack of people's willingness to join these groups, and to donate, were important issues that led to modification of the research protocol in June 2003 to target people with medical interest in larger venues. Some of the ethical issues of the overall HapMap process are discussed by Macer (2003).

In order to maintain community engagement, an ongoing community advisory group, CAG will be set up after the samples are taken. CAG will be organized by involvement of ordinary people including sample donors. The idea of CAG is ordinary people's involvement in the continual discussion about the project, even if the research is going on after finishing sampling. CAG will be also reported about the progress of the project from researchers and to monitor about the usage of Japanese samples in the cell bank.

3. Concerns about donation of blood to a database

Descriptive bioethics approaches include surveys to investigate people's attitudes to the dilemma in question (Macer, 1994). Although questions about the privacy concerns of people have been asked in previous surveys in Japan (Maekawa & Macer, 1998), there have not been questions more directly relating to this project. Several questions were asked in the larger survey on biotechnology conducted by Inaba and Macer (2003) with other laboratory colleagues to examine this question. The data from this public opinion survey of 380 ordinary people, directly related to collection of DNA in databases is available. The full results will be reported later (Suda et al.), but in this paper we present preliminary results of the analysis of open comments from 320 persons.

In response to the question, "Would you be willing to give blood from which DNA would be extracted to be put anonymously into a DNA bank so that researchers could study human genetic variation. This research would not personally help you because the sample is anonymous but would be useful for medical research in general.". We asked to choose from these answers, "Yes" in general, "Yes" only for a temporary bank, "Yes" for permanent bank, "No", or "Don't know". We also asked the reasons for their answers. 44% said "Yes" to blood donation for a DNA bank. 26% were negative to donate and 28% answered they "don't know". One third of the "Yes" group allowed to donate their blood only for temporary storage (Figure 2). To analyze the reasons of their attitude toward blood donation for DNA bank, we classified their comments into 20 categories. Figure 2 shows the 20 categories placed into 5 groups, with the number of comments in each group.

More than half of comments from the "Yes" group people were support for science and medicine. Some particular comments in the "Yes" group were categorized into the help others group, especially among people who accepted to donate their sample for permanent or not specified DNA bank. For example:

If it will be useful for the medical science research.
If it will be helpful for someone else.
If my blood will be used effectively for the science.
It is also necessary to apply to health care in future.
It is useful for the development of humankind.
I'm very keen to make contribution for the medical research. Actually now I'm donating my blood for the research. (the opinion from a genetic disease patient)
It will be my pleasure to contribute to academic research.

2.5 Figure 1
Figure 1:Willingness to donate DNA to a database (N=380)

The comments, which were categorized into "conditionally", could be found in all groups, but especially in the negative group, this category was the second most common. Many of comments mentioned that since they can't understand about the research itself or the significance of the research, they couldn't decide easily to say "Yes". Fort example:

If the research group is sufficiently trustworthy, I can agree with donation because it is meaningful.
I am willing to donate my blood if it is not so painful and I can be paid some money (if possible).
I want to contribute to the medical research. But I'm not sure whether I can donate my blood or not when I exactly face to such situation.
If it will be used effectively, I will donate because I can understand it is necessary that the bank have sufficient number of samples. But I will donate on the premise of that the sample will go to the public institutes. I never donate my blood to any private companies.
If it will be utilized exactly only for research purpose, I will agree to donate my blood.
If it will help someone, I want to do. But my privacy should be exactly protected.
If the privacy of individuals is secured by making samples anonymous, it is meaningful to contribute to the progress in medical science.

Also there were several comments that mentioned about personal benefit. We found some wishes of ordinary people for example, the results would be utilized for themselves, would like to know their own genetic information, and certain compensation for donation. For example:

If the result will be utilized for myself, I will donate my blood. For that case, I'm not sure whether I can accept or not to use samples and data which would be kept by researchers for other purposes.

2.5 Figure 2
Figure 2: Reasons given over donation of DNA

Among comments categorized into "negative reasons" we could find just fear or a bad feeling for their own DNA to be utilized for unknown research without any notification to them. Also there was distrust to researchers or private companies, and simply just a burden, being unclear about the significance of such research. For example:

Although I want to contribute for the research progress, I can't trust entire researchers. Even if it will be made anonymous, I can't help feeling scared thinking if it is abused, so I can't donate.
I don't want anything to remain that came from me.
Even if the sample will be made anonymous, I can't help feeling scared that my genetic information might be utilized anyhow and anywhere. Especially recently the information outflow is very common issue in Japan.
I don't feel such donation necessary because I'm exactly satisfied with my current life.
This is emotional issue for me. I don't like my genetic information to be utilized without any notifications to me in somewhere I don't know.
I feel scared what kind of research my blood will be used for. It is very horrific for me to imagine like that a cloned human being of me might be born in somewhere and be utilized as research material.
My genetic information is exactly the part of myself. I don't like it to be utilized without any notifications to me.
I don't know how it is significant for the medical research. I don't know how to utilize and manage my blood.
It is a trust problem. I can't trust.

Figure 3 shows the results of another question about the consideration of anonymity versus the benefit to know individually useful genetic information. The question is "Would you prefer to learn any genetic information that might help you lower your risk of death, although the sample could not then be anonymous? Assuming researchers still protected your privacy.". People who answered "Yes" toward donation for a DNA bank tended to show a positive attitude to know their genetic information if that is useful for their welfare, even if the sample comes to be not anonymous. While people who answered "No" to donation showed a more negative tendency to know the genetic information than the "Yes" group people for the DNA bank. From the comments they made for the previous question, it is speculated that they feel bad for their DNA to be utilized for research because of fear of harm or distrust.

2.5 Figure 3
Figure 3: Consideration of anonymity versus the benefit to know individually useful genetic information (see text)

4. Some reflections on the community engagement process in Japan

Through the approaches we experienced at the beginning of community engagement in Japan, we faced a number of tricky issues. Since our social situation is different compared with, for example, United States, which has so many different populations in the same society, the opportunity to recognize the differences of the population is not so frequent in our daily life. We have the universal health insurance coverage system in Japan, and the types of problems in medical services are also different. There are actually various racial groups in Japanese society, we also have various size of social daily life group like local "Han" in our society, but still, we need to consider about the meaning of "community" and "community engagement" for Japanese.

We also faced difficulties to raise awareness of genetics and regarding issues including ELSI in various groups of society. Contrary to the results of survey that near to half of people were positive to donate for DNA bank and made comments like "contribution for science and medicine" or "to help others", many people we contacted individually were not so interested in the project scientifically and they did not want to participate to focus groups. We need to raise people's awareness by bringing the genetics, science and regarding issues closer to the people. And we also need to motivate people and community to be interested enough to join the process by promoting existing social groups with some attractive things and raising their common critical minds.

In Japan many genetic studies have been done already by Japanese researchers over the last decade, and from 2001, we have very strict guidelines for human genome research issued by the Japanese government (Tsuchiya, 2003). An English translation of these is on the Eubios web site. Following to this guideline, there has been the existing sample collection process established by Japanese experts and learning from the history of Japanese genetic research, and researchers have applied it. So there is a hurdle to introduce a novel concept, "community engagement" newly into this existing process. We need to communicate with Japanese experts also.

According to the guidelines shared by the international coordinators at NIH:

"Community engagement for purposes of collecting samples for the haplotype map project and for future studies of genetic variations should be viewed as a process of actively involving the relevant communities in the project. The purpose of community engagement is to enable the researcher to assess a range of responses within the community to the proposed research. This will enable the researcher to consider whether modifications to the consent process or to other aspects of the sample collection are necessary and can be made, consistent with the project's established scientific goals.

The purpose of community engagement is not necessarily to achieve complete consensus among all segments of the community. Formal consent of the community is not required, except with certain populations such as American Indian tribes--none of which will be involved in the project's current phase.

In the international project, those who will be engaging communities and collecting samples for the project must also follow the Policy for the Responsible Collection, Storage, and Research Use of Samples from Identified Populations for the NIGMS Human Genetic Cell Repository (the repository where all samples collected for this project will be stored. See:
http://locus.umdnj.edu/nigms/comm/submit/collpolicy.html

The basic elements for community engagement were developed specifically for engaging the communities that will be approached for participation in the United States. They still think that, "regardless of where samples are being collected, the goal remains the same: active involvement of the relevant communities--not just "education" and not just getting "buy in" by community leaders. "

To quote the main suggestions in the "Basic Elements":

  1. Acquiring Background Knowledge: The researcher must first gain a background understanding of how the community is internally organized. This background can be acquired in a number of ways. Anthropologists generally begin by doing qualitative participant-observation in the community; sociologists might undertake some sort of quantitative survey. Researchers who have had prior interactions with community members can draw upon that history of contact. Whatever method is used, the rationale for obtaining this understanding in the first instance is to then conduct the community engagement as a purposeful process--that is to say, to engage the community in a discussion of the proposed research by approaching the appropriate social actors and groups that the community itself recognizes as composing its primary internal divisions.
  2. Conceptualizing and Approaching the Community: The background knowledge gained in the first step should allow the researcher to conceptualize the community as an internally organized whole. That whole then can be approached in one of two ways. For relatively small communities, each part can be purposefully involved in the process by engaging appropriate representatives or leaders in an ongoing dialogue about the project. For larger, more heterogeneous communities, two different strategies suggest themselves: (1) attempting to contact and involve the leaders of formally organized subgroups that approximate the range of social division within the larger community (i.e., social, religious, fraternal, etc. groups) in an ongoing dialogue about the project; or (2) identifying several local geographic divisions of the larger community that constitute relatively small sub-communities in themselves (e.g., neighborhoods) and engaging them in the same manner. The difficulty with the first approach is that formally organized community groups and their leaders may not provide an accurate reflection of the full range of views within the larger group. The difficulty with the second approach is that views within the larger community may vary significantly from one locality to another. However, both of these difficulties can be overcome by using focus groups and surveys to randomly spot-test the validity of those necessarily limited findings in other segments of the larger community.
  3. Organizing Working Groups: The researcher can ask small groups of community members (8-10 people) to work on specific tasks. These could include: identifying risks and benefits of the proposed project from a community perspective; suggesting modifications to the informed consent agreement (e.g., devising ways to minimize community-specific harms and optimize community-specific benefits of the study); assisting in designing the protocol for recruiting participants from among community members; determining how the community should be named in research publications; identifying research questions of interest to community members that might be addressed in future studies using the community's samples; and assisting in planning follow-up activities, such as the presentation by the researcher of findings back to the community. Working group members will probably be self-selected community activists or leaders who have some self-interest in taking part in this phase of the consultation. For this reason, it is important to validate their findings and work products with other, less activist community members.
  4. Confirming Working Group Conclusions: The findings and products of working group meetings can be validated for larger segments of the community by convening randomly selected focus groups that reflect a demographic cross-section of the larger population or using similar sampling methods in administering an individual survey instrument. There are standard methods for determining how many focus groups or individuals surveyed will constitute an appropriate sample for validation, depending on the size of the larger population.
  5. Holding Public Meetings: A useful means for engaging a community at the start of a consultation, for taking its temperature during that process, and for helping validate the findings of a consultation is a public meeting. There are two ways to think about organizing a public meeting: (1) securing a meeting space in the community and calling a special meeting open to all members just to discuss the project; or (2) securing a place on the agenda of a regularly-scheduled public meeting to discuss the project. The former approach requires some means for motivating attendance and participation that may result in a very self-selected audience (with either or both strong proponents or strong opponents in attendance but with few members who are in the middle). The latter approach may play to an audience that is self-selected for quite different reasons (i.e., the main purpose of the regular meeting) and so not be much engaged in the subject of the proposed project. Thus, public meetings, while useful as supplements to the process outlined above, should not be relied on as the primary means to accomplish community engagement.
  6. Documenting the Process and Establishing a Community Oversight Group: The outcome of the researcher's discussions with the community must be documented and made available to the repository where the samples from the community will be stored. As part of the documentation, the researcher should describe the methods that were used in the engagement (i.e., interviews, forums) and the rationale for the choice of community representatives consulted. The researcher should also provide a summary of the views of the individuals and groups involved in the process. The researcher must also put a plan into place for long-term follow-up with each participating community. The establishment of a Community Advisory Group (CAG) to serve as a liaison between the community and the repository where the samples will be stored is an essential part of the community engagement process and is required with respect to all samples deposited in the NIGMS Human Genetic Cell Repository. Each community's CAG will be responsible for the long-term oversight over the use of the samples collected from that community. The procedures for establishing CAGs for the haplotype map project still need to be worked out by the participating investigators. "

In the community engagement and sample collection process in Japan, there are many important components. Mutual communication between science and the public regarding ELSI issues is still inadequate. For public acceptance of Japanese commitment, there are several issues we have to consider. Concerns about sending samples to a repository abroad, putting Japanese data into public database, compensation for donors, and so on. We would like to consider how we could see those issues from the point of view of the community.

This process was not primarily for getting samples and not for getting Japanese common opinion. Community engagement is not the same as community consent. The purpose of this process is to raise issues in public and construct frameworks for active discussions.

In Japan, some epidemiological genetics studies including Japanese BioBank project are starting. In such studies it's getting more significant to have a public framework to discuss about the projects, consider about the risks, benefit, the relationship between individuals and community, individual duties towards the social good, for example. We would like to initiate such framework people can consider what's the meaning of the projects, asking questions like, how the future will be influenced by the research? How can they expect something by participating the research? It will be related to some more practical issues, like management of databases and cell banks, Japanese policy for genome research, and the research itself. Although there were concerns about the lack of funding given to ELSI issues in genomic research in Japan in the 1990s (Macer, 1992), the situation may not have really improved after a decade (Macer, 2003).

We can ask what kind of genetic studies conducted with what kind of process are ideal in the future in Japan? We need to consider explaining to ordinary people about not only the risks but also benefits or the meaning of participation in such studies. The HapMap study is an important step in the evolution of ELSI studies in Japan.

Appendix A: Procedure of Recruitment for Hap Map in Japan (from IRB document)

A. Recruitment (agents C)

The recruitment of donors will attempt to obtain a Japanese representative sample, including donors from many sectors of society. This process will be involving a series of three small focus group meetings, after recruitment using the attached recruitment form (form A). This aspect of the process will be independent of Tokyo University, organized by Eubios Ethics Institute (responsible persons Mrs. Eiko Suda and Dr. Darryl Macer; agent C).

Agent C will contact initially approximately 15-20 persons. After brief explanation, including the written form, if those persons wish to participate in the small group meetings about HapMap project, they will also be asked to pass 10 copies of the form A to their acquaintances. To achieve community representation this will include members of different social groups, like nursing school, university student, rotary club, volunteer group, etc., including some members of existing focus groups on biotechnology and bioethics organized by agent C. This is called snowball sampling.

Those persons who want to be potential donors send the form using a prepaid envelope (the second page of the recruitment document) including their "name", "sex", "contact details", "age group (up to 30, middle, over 50)", "wishes about the meeting schedule" and "any other information they want to send to us", addressed to Eiko Suda. We need at least 140 persons initially.

The appropriate balance of these groups will be made, for example gender ratio, and suitability to locations. The focus groups location suggested would be 2 in Tsukuba, 1 in Ushiku, 3 in East Tokyo, 3 in West/Central Tokyo.

In all groups Eiko Suda is to chair discussion. The groups will be held in the two following months after IRB approval. One further Japanese person from the Eubios Ethics Institute will attend the meetings for logistical and secretarial support.

The process of discussion and people's concerns about the project will be written up anonymously as an academic study, preserving the participants privacy. The concerns participants raise in the meetings will be tape recorded and these might be reported anonymously in the academic literature so that scientists might be better able to understand Japanese citizens concerns and hopes for this type of research. This will be a valuable resource to understand ordinary people's concerns about genetics that may help future design of informed consent forms in Japan for genetics research. Any serious group concerns from this process of community engagement will also be given immediately to Prof. Ichiro Matsuda, the chair of the community advisory group.

Focus group meeting 1 (2-3 hours); after 5 minute introduction, get every member's images and concerns, self-introductions, then a fuller introduction of project (15-20 minutes) and distribution of 1) brochure (abridged translation of the Brooks report); 2) informed consent form (without signature page); initial questions from members.

Focus group meeting 2 (2-3 hours - 1 week after meeting 1); answer every member's questions. Discussion. Distribute signature page of informed consent form and any extra information prepared after meeting 1.

Focus group meeting 3 (2-3 hours, 1 week later). Further discussion. At the end of the third meeting the persons who showed the willing to participate the research will be given a random number as an identifier, which will only be known to that person and Eiko Suda (agent C). Mutually acceptable times to donate will be agreed, which will be at the University of Tokyo (Agent C will be presence at the donation).

Blood samples will only be taken from persons who sign the attached informed consent form (form C). It is not obligatory for every donor to attend all 3 focus group meetings, but we would expect them to attend at least 2 of these meetings. These meetings will provide the time needed for proper consideration of willingness to donate. Members of the focus groups are free to drop out. If we are short of donors, we may initiate making a further focus group in the same way as described.

A coding form of the random number and the name of the participant will be held by agent C for up to two months after the receipt of the informed consent form. If a person fails to show up at donation, that person will be contacted one week after that missed date by Mrs. Eiko Suda, asking why they changed their mind, for purely research purposes. If that person says that they do want to donate, they will be given a new time. All information linking names to number will be held on a secure hand written form by agent C and destroyed within one month after the final blood donation for this project.

B. Donation (agent A, B, D)

No information about the donors, including name, will be given to those taking the blood. The blood sample will be sent to Shinshu University only with the random number. This will ensure privacy of donors. Of the approximately 140 blood donors, only about 100 cell lines will be deposited, which will also ensure the privacy of the donors, and also no one will know for sure if their cell is in the cell repository. Prof. Fukushima (agent D) will be responsible for making the set of 100 cell lines and will not report any other details to the agent A or agents C.

The informed consent forms will be sent by agent A to Prof. Ichiro Matsuda (agent B), Chair, Tokyo University Ethics Committee, in a sealed envelope for storage at Tokyo University. Repository manager, Prof. Yoshimitsu Fukushima (agent D), will not see these forms, to ensure privacy of the donors.

When the donors give the blood sample they will receive compensation for their travel, and time, equal to Y5000, plus a travel supplement. This is a small level of compensation compared to their time to attend the focus group meetings. There will be no compensation for those who do not donate, except a verbal thank you.

These persons should be 20 years or older in age. The donors should not be genetically related to each other, but spouses would be acceptable. There is absolutely no commitment to become a donor from joining these discussion groups, and this is clear in form A. After the focus groups and donation there will be no contact of focus group members by the HapMap project except for approximately 4 participants of focus groups who will be asked whether they wish to join the CAG after an interview with agent B.

C. Cell lines Repositories and Shipping (agent D)

Arrangements for shipping between Corriell Repository and Shinshu University are a technical matter up to Prof. Yoshimitsu Fukushima. After Corriell Repository has confirmed receipt of 100 cell lines, and confirmed they meet their requirements, agent D will destroy the surplus blood samples and cell lines. Informed consent forms stay at University of Tokyo with agent B in a sealed envelope that was prepared by agent A.

The use of the samples by researchers will be by application to Corriell Repository, or if in Japan, to the CAG. Approval of the chair of the CAG (agent B) will be needed for the Japanese case.

D. Community Advisory Group (CAG)

About 10 members, chair Ichiro Matsuda (agent B). Members including Eiko Suda (agent C), Yoshimitsu Fukushima (agent D), several media persons, up to 4 ordinary citizens who were focus group participants be selected by agent B and C after the process of focus groups.
The CAG will approve applications for the use of samples from Shinshu University.
The CAG will be the contact point for questions sent by the IRB of Corriell Repository.
The CAG will receive reports about the HapMap project progress by Email, meetings, etc. from agent A in the future.
There will be some sharing of rejected applications from researchers who approach Corriell with the CAG as a monitoring of unusual research applications not related to genetic variation research.

E. Funding

All funding comes from agent A, from the Ministry of Education, Science, Culture and Sports 21st Century Life Sciences Projects.


Attachment A: (Recruitment Form) Would you like to be a donor to the Haplotype Map Project?

An international collaborative team is collecting blood samples from people whose ancestors came from various parts of the world. This team includes the NIH (The National Institutes of Health; the U.S.A.), and the Human Genome Center in University of Tokyo. We will collect samples from around 140 people from each of about 3 groups whose ancestors come from 3 different geographical parts of the world. One of these will be representing Japan. This project will help learn how genes relate to health and disease.

We are seeking people who would be willing to join a series of three meetings to discuss the project in order to decide whether or not they would like to be a donor for the Japanese sample. These persons should have Japanese grandparents and be 20 years or older in age. The donors should not be genetically related to each other. There is absolutely no commitment to become a donor from joining these discussion groups.

If you are interested we will ask you to attend a series of three meetings, over the course of one month. Each meeting will be about 2-3 hours in length with 15-20 members per group. The purpose is to discuss your concerns and receive information about the project. Then if you decide to donate to this project you would sign an informed consent form and be given a card to go to the donation site at a mutually agreeable time to give about 10ml of blood. No information about you will be linked to the Japanese blood sample. Any information you provide in the meetings will not be passed on with your blood samples. The concerns participants raise in the meetings will be tape recorded and these might be reported anonymously in the academic literature so that scientists might be better able to understand Japanese citizens concerns and hopes for this type of research.

If you wish to join please use the reply form by post, fax or e-mail including your name, sex, address (including fax or e-mail if you have this), age group (under 30 years, 30-50 years, 50 years and over), and wishes about the time and place for the meetings you want to take part so that we will contact you about your schedule to arrange for you to join a group meeting at a location and time convenient to you. We also would like to have your ideas or comments for this project in the remarks column. Your privacy will be protected, and no name list of participants will be given out at the meetings. Neither will your names be given to the Human Genome Center.

Thank you. Please reply to: Mrs. Eiko Suda, c/o Prof. Darryl Macer,
Eubios Ethics Institute, P.O. Box 125, Tsukuba Science City, 305-8691, Japan
Fax: 0298-53-6614 Email: hapmap@hotmail.com


Attachment B: Informed Consent Form

The Haplotype Map Project (HapMap) and Other Research on Genetic Variations Please take as much time as you want to read this form, ask questions, and talk about this project with family or friends.

What is this project about?
An international collaborative team is collecting blood samples from people whose ancestors came from various parts of the world. This team is organized with several institutes in the world including the NIH (The National Institutes of Health; the U.S.A.), RIKEN and the Human Genome Center in University of Tokyo. We will collect samples from around 140 people from each of about 3 places around the world. The Human Genome Center in University of Tokyo is asking Japanese people to give samples. We will not collect names or any medical information, and researchers who study the samples will only know which part of the world each sample came from.

Why are we doing this project?
This project is will help learn how genes relate to health and disease. Genes are the basic "instruction book" for people. Genes are made out of DNA. The DNA of a person is about 99.9% the same as the DNA of any other person. But no two people have exactly the same DNA except identical twins. Differences in DNA are called genetic variations. They explain some of the differences among people, like eye colors and blood groups. They also partly explain why some people get diseases like cancer, diabetes, asthma, and depression, while others do not. Diseases such as these are also affected by diet, exercise, smoking, pollution, and other factors, which makes it hard to figure out which genes affect the diseases. Most genetic variations are found in people everywhere. But there are differences among groups in how common some genetic variations are. For example, all the blood types can be found in all groups of people in every part of the world, but there are differences from place to place in how often some blood types appear. By including people from many ethnic and geographic groups, researchers will find most of the genetic variations. This information will make it easier for researchers to find the genes that affect diseases, in other studies using other samples.

To achieve the scientific objective of this project, in Japan we need to collect only samples that are genetically Japanese. Also considering the necessity to be decided on the participation in this project by one's own will, we would like to ask people of eighteen years and over to participate in this project.

How will the samples be used?
Over the next three years, researchers will study the samples to find places in the DNA where people vary. For each sample, researchers will make a list of the genetic variations they find. Researchers will also look for the patterns of genetic variations in people's DNA, which are called "haplotypes." Researchers will put all this information in a scientific database on the Internet. For each sample, this will include information on hundreds of thousands (eventually millions) of genetic variations, as well as the ethnic or geographic group and the sex of the person who gave the sample. The database will not include any medical information about anyone who gave a sample. It also will not include any information that could identify who the individual people are.

Researchers will use the genetic variation information in the database to create a genetic map that summarizes the patterns of genetic variation, called a haplotype map or "HapMap." The HapMap will be put on the Internet. The HapMap will not include medical information, but researchers will use it as a tool in future studies to find genes related to many diseases. The HapMap will show researchers where the haplotypes (patterns of genetic variation) are. Then, for a disease, such as diabetes, researchers will study the haplotypes in a group of people who have the disease, and in another group of people who do not. Areas in the DNA where the two groups differ in their haplotypes will be clues that those areas might contain genes that affect the disease. Researchers can then look for those genes and study how they work. This will help them figure out better ways to prevent, diagnose, and treat the disease. They can also learn how to make drugs that work better in more people. Some researchers will also use the HapMap to look for genes that affect traits such as baldness, behaviors like addiction, and long life.

Researchers will compare the genetic variation and haplotype information for people in the same group and in different groups. In the future, researchers will also use the samples to look for differences in the amount and form of the products that genes make, called RNA and proteins, and will put all this information for each sample in the database. The samples, the database, and the HapMap will also be used to study other questions, such as the biology of DNA, how new variations arise, the genetic history of human groups, and how people from different parts of the world are related to each other.

What will happen if I decide to give a sample?
If after participating in the meetings to explain about this project, you decide to donate a blood sample to this project, you should sign this consent form. You will be issued with a card to take to the Human Genome Center in University of Tokyo to donate about 10 ml of your blood. The individual comments you make, and personal information you reveal during the meetings, will be not linked in any way to your sample or put in the database.

When you go to give your blood, about 10 ml of blood will be drawn from your arm.
We will send your blood to researchers at Shinshu University. They will turn the sample into a cell line, which will make an unlimited amount of your DNA and will last for a long time. Of a total of about 140 blood samples, about 100 cell lines will be deposited, at Shinshu University. The same 100 cell lines will also be sent to an International Human Genetic Cell Repository at the Corriell Institute for Medical Research in New Jersey (U.S.A.), which the NIH oversees.

Cell lines kept at Shinshu University will be available for use by Japanese researchers whose projects have been approved by the Institutional Review Board (IRB) of Shinshu University. Corriell will provide the cell lines they have to researchers around the world to create the HapMap and to use in many future genetic studies as described in this form. All studies using the cell lines will have to be approved by the IRB of Corriell. The researchers will have to follow all U.S. and international laws and guidelines that apply to research.

An IRB is a committee similar to the one that approved this project to make sure that your rights were protected. Also, an Advisory Group is being set up for each country that takes part in this project. This group will include about 10 people to represent different sectors of the Japanese population, including some people who participated in the discussion groups. This group will be told about how the international project is going and will work with Corriell to make sure that future studies using your country's samples that are stored in the U.S. are similar to ones described in this form.

Will there be any costs or payments?
It will not cost you anything to be a part of this project. We will give you Y5000 for your time, travel, and inconvenience if you come in to give us a sample.

The Repository does not let anyone sell material from samples or cell lines. However, information from genetics research sometimes helps companies make products to diagnose or treat diseases. If information from your cell line leads to making a product, it would probably contribute only in a very small way. Also, because your cell line will not have your name on it, neither the researchers nor anyone at the Repository would know if your sample was even used. So you will not get any additional payment if you take part in this project.

How will you protect my privacy?
We will protect your privacy in several ways. After your informed consent forms are collected in the small group meetings, they will be stored in a sealed envelope at the secretariat if the Ethics Committee at the Human Genome Center in the University of Tokyo will keep your signed consent form. Nobody will see it, and it is kept only as a sealed record of the Ethics Committee. We will not keep your name with your sample or even give your sample a code number that could identify you. So there is no way anyone at the Repositories, Shinshu University and Corriell, or who studies your sample will know that it came from you. Also, we will collect more samples than we will use. This way nobody, not even you or us, will know if your sample was used or if any information in the database came from you. (Samples that are not used will be disposed of in standard ways.)

What are the benefits of giving a sample?
You probably will not directly benefit from giving a sample, because of the long time this research will take to produce useful results. But researchers will study these samples for many years to learn about health and disease. This research will eventually benefit the health of people around the world.

What are the risks of giving a sample?
Drawing blood has very minor risks as you may know from routine body check. These include brief pain, slight bruising, dizziness or fainting, and (very rarely) infection where the needle goes in.

Actually there is a 2/3rd chance your sample will be used. If so your genetic information will be in the database, along with the information from the others whose samples are used. Nobody's name will be there. So nobody will know which information came from you. One way people could match any of the information in the database back to you would be if they thought your information might be in the database, got another sample from you, and then tested that new sample to compare the information from that test with the information in the database. Another is if somebody compared the information in the HapMap database with genetic information known to be from you that was in another database and figured out who you were. The risk of either of these things happening is very small, but it may grow in the future. Also, the database itself won't contain any medical information. If somebody really wanted to find out medical information about you, it would be much easier for that person just to get a sample from you and test it directly.

We cannot always predict the results of research, so new risks to you may come up in the future that we can't predict now. Your sample will not be used to make a clone of you.

Are there any risks to people in Japan?
- In the case samples will be used in abroad -
Information on the geographic areas the samples came from will be included with the samples, in the database, and in the HapMap. In future studies, researchers may find that certain genetic variations appear more often in people from Japan than in people from other parts of the world, and that these variations are more common in people with a certain disease. This may make some people look down on Japanese unfairly.

Some people may use the information from the HapMap or from future studies using the HapMap to exaggerate differences between groups for prejudiced or other bad reasons. Others may use the information to downplay differences between groups, to say that all people's genes are about the same, so we don't need to respect the special concerns of different groups. Biology does not provide a reason for prejudice, but discrimination does exist.

We will work to make sure that the ethnic or geographic identity of Japanese donors is described as carefully as possible--in the sample collection, in the database, in the HapMap, and in any articles researchers write about the HapMap.

Can I change my mind after I give a sample?
Giving a sample is completely up to you. You will not lose any benefits if you choose not to give a sample. However, since nobody will know which sample came from you, after you give a sample you cannot take it back or take any information out of the database.

How will I find out what happens with this project?
Because your sample will not have your name on it, we will not be able to give you individual results from this research. However, we will update the Community Advisory Group on how researchers are using the HapMap and the samples from Japan, and what they are learning about health and disease.


The Haplotype Map Project (HapMap) and Other Research on Genetic Variations Consent Form

Who can I talk to if I have questions or problems?
If you have questions about this sample collection, contact:
(PI)_ Yusuke Nakamura______ (phone) ___________.

If you have questions about your rights as part of this research project or about the Community Advisory Group, please contact:
(IRB and Corriell Repository)_____Ichiro Matsuda____ (phone) ___________.

If you have questions about the stored samples in Shinshu University, contact:
(Shinshu Repository) ____Yoshimitsu Fukushima___ (phone) ___________.

Consent and Signature
Please read the paragraph below, think about your choice, and sign if you agree:

I agree to give a blood sample and to have a cell line made that will make an unlimited amount of my DNA, for researchers to use for the HapMap project and in other approved studies of the type described in the form. I have read or listened to the information, I have asked any questions I had, and all my questions were answered. I know that giving a sample is my choice. I understand that after I give a sample, I cannot withdraw my sample from the Repository.

Your Signature ___________________________ Date _____________

Please keep a copy of this form and just return a signed copy of this page.

References

(References are on-line at the Eubios Ethics Institute web site).
Chee, H.L., El-Hamamsi, L., Fleming, J., Fujiki, N., Keyeux, G., Knoppers, B.M. and Macer, D., "Bioethics and human population genetics research", Report of the UNESCO International Bioethics Committee Third Session, 1995, from the subcommittee on bioethics and population genetics <http://eubios.info/PG.html>.
Inaba, M. & Macer, DRJ. (2003) "Attitudes to biotechnology in Japan in 2003", Eubios Journal of Asian and International Bioethics 13: 78-89.
Lock, M., "Interrogating the human diversity genome project", Social Science & Medicine 39: 603-6 (1994).
Macer, Darryl (1992) "The far east of biological ethics", Nature 359, 770.
Macer, Darryl R.J., Bioethics for the People by the People (Christchurch: Eubios Ethics Institute, 1994).
Macer, DRJ. "Bioethics and genetic diversity from the perspective of UNESCO and non-governmental organizations" pp. 265-274 in Knoppers, BM. et al., eds, Human DNA: Law and Policy. International and Comparative Perspectives (The Hague: Kluwer Law International 1997).
Macer, DRJ. (2003) " Ethical considerations in the HapMap project: An insider's personal view", Eubios Journal of Asian and International Bioethics 13:125-7.
Maekawa, F. & Macer, D. (1999) "Japanese concept of familial privacy & genetic information", Eubios Journal of Asian and International Bioethics 9: 66-69.
Tsuchiya, T. (2003) " Provisions For Review of Genetic Research in Japan", Eubios Journal of Asian and International Bioethics 13:127-30.

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