 I'll begin with a little bit of a story, and the story began roughly seven and a half years ago when a local business publication called the Boston Business Journal ran an article about a new for-profit entity that was starting up called Framingham Genomic Medicine, and that for-profit entity was designed to take data from the Framingham Heart Study and commercialize it. It resulted in a community uproar of some study participants, certainly an uproar of some study investigators, and a great deal of controversy and the need to deal with this situation. So I'll begin with that story, and it was a 50-year promise under attack. They're not selling my data. Evelyn Langley was adamant. In the spring of 2000, she again became a study activist. She was dead set against the undertaking she read about in a letter to participants and a newspaper report. A university had formed a for-profit company called Framingham Genomic Medicine to distribute a half century of data and genetic information for Framingham Heart Study participants. After attending her 26 voluntary appointments over the course of more than a half century, Langley was livid. When she was young, she had walked the streets of Framingham, urging her neighbors to volunteer, and all those years ago, she gave them her word of honor that their privacy would be protected at the same time that the information gleaned from their volunteerism would be available free of charge to scientists. Langley believed that none of the original 5000 participants or their descendants had ever expected their efforts to enrich medical entrepreneurs. Now she was reading and hearing speculation that their personal medical information would be sold and that a private for-profit company stood to make money off her and her neighbors altruism. So this occurred in recent times and it created a controversy. There were a number of Framingham study participants who called for a boycott of the Framingham Heart Study and threatened to discontinue their 50 plus years of participation in the project. It called for NHLBI to become involved. It resulted in bringing in a well-known ethicist, Art Kaplan from University of Pennsylvania, who in fact was born in the town of Framingham, just a short walk from the site of the Framingham Heart Study, and the need to get together with study participants for NHLBI to send representatives to Framingham, including Terry Minolia, who's here today and I'm sure remembers this event quite vividly, and a reconsideration of the very consent form, ultimately coming to the conclusion that the consent did not provide for the type of for-profit enterprise that was initiated. So let's talk briefly about the way we are doing genetic research today, the steps required to make this effective, including community participation, and the informed consent procedures related to this. We heard in Jim Ostell's presentation a reference to the Framingham Genome-wide Association Study that we now call the SHARE Study, and that stands for SNP Health Association Resource. The Framingham Heart Study has three generations of study participants, an original cohort dating back to 1948, consisting of over 5,000 men and women, 30 to 60 years of age, who've been examined for 29 consecutive examination cycles, and of the original 5,000 participants, about 375 are still alive today and still examined. In 1971, we started the recruitment of a second generation of study participants, we call it the Framingham Offspring Study, and right now they're in the midst of their eighth cycle of examinations, it too was about 5,000 individuals. The third generation of the Framingham Study began recruitment in 2002, and that recruitment was completed in 2005, and that third generation, literally the children of the offspring, the grandchildren of the original study population turned out to be about 4,095 men and women, a mean age of about 40. We have genetic materials, completely representing the third generation, representing the overwhelming majority of individuals in the offspring generation, and in about 12 to 1,500 people in the original study cohort. The SHARE Study, again the SNP Health Association Resource, is a genome-wide association study that will include 9,500 participants who provided DNA and consent across all three Framingham generations. It will involve the genotyping of 5,500 SNPs using a combination of athymetrics chips, and the entire genetics database will represent over 5 billion genotypes. As we were preparing to move forward with the concept for this genome-wide association study, we met with a group of study participants and asked them what questions they had before we should move forward with such an investigation, and they had quite a few questions, and I've summarized a few of the key questions on this slide, and I'll address each one of them at least briefly in the course of my brief talk. The first is, how will participant privacy and confidentiality be ensured, and that's the same as the question we had just a moment ago. How will participants be involved in planning for this type of project? The third is what ethical oversight will take place? Fourth, how will DNA be used in relation to consent? And fifth, how will this resource be shared with the scientific community? So let's go through these questions. How will participant privacy and confidentiality be ensured? There's a delicate balance between ensuring that we create a resource that is fully used for scientific purposes, which is what our study participants want, and at the same time protecting privacy and confidentiality. The more we restrict access, the more we can ensure privacy, but at the same time, the less available the resource and the less good will come from it. Well, in the course of the SHARE project, we're attempting to protect privacy and confidentiality in several different ways. First and obviously, data and samples will be de-identified. They'll be given an ID number that does not match up with the ID number that individuals have in the regular Framingham dataset. Data, and in some cases samples will be shared after several different steps have been taken. There will be an application process with review and approval by a Data Access Committee. Jim referred to this in his presentation. We will require IRB approval from the user's institution, and there will be assigned data distribution agreement as well to ensure that certain conditions are met, that data are not redistributed, there's no attempt to identify participants, and the data are housed on a secure computer. The second question was, how will participants be involved in planning for this type of research? Well, we've taken several steps to ensure participant involvement in this Brave New World experiment. Over a course of several years, we communicated with study participants. We had a focus group of study participants in late 2005 to discuss this concept of a genome-wide association study. We communicated that information to participants in a newsletter in 2006. There was a press release about the study in 2006, a town meeting to answer participant questions held just shortly after that, and a notification of the general scientific community that followed only after the study participants were informed. They had the opportunity to provide feedback. They had the opportunity to ask questions and have those questions answered. So this process of involving study participants in this kind of project to identify concerns, to respond to those concerns is not a one-time situation. It's an iterative process, and importantly for everyone involved in population study genetics research, something that we must keep in mind as an important aspect for the success and future of these studies. The third question was, what ethical oversight will take place? I can tell you that I've been with the Framingham Heart Study next month will be 23 years, and we didn't have an ethical oversight committee until just a few years ago. In fact, I'm hard-pressed to think of ethical questions that came up in the course of my first 17 or 18 years working with the Framingham Heart Study, but those questions did begin to come up, in particular with regard to the Framingham Genomic Venture. And so we impaneled a group of ethicists to serve as an advisory panel. It was a one-time panel in April of 2003 to ask them about questions that we had and how to deal with our need for the future to be prepared for dealing with ethical questions as they arise, in particular with regard to genetics research. And that panel recommended that we form a more formal ethics advisory board to address these questions, and that this board include study participants, local clergy, physicians, genetic counselors, and a real ethicist. So we sent out a newsletter to the study participants shortly after that panel meeting to let them know that we had a panel that made recommendations, that we agreed with those recommendations, that we would form an ethics advisory board, that we would publish in our regular newsletters summaries of ethics advisory board discussions of matters that would be of interest to the study participants, and invited study participants to bring up to us through, as the Schindler who's basically a study participant liaison, any questions they had that they wanted the ethics advisory board to consider. So this type of mechanism of addressing participant questions and concerns was put into implementation. And so the ethics advisory board was established and it was charged with several responsibilities to consider complex questions posed by study participants and investigators, to provide a viewpoint of study participants and the community, and to generate written responses to questions that will be summarized in newsletters and shared with all study participants. On November 9th of 2005, the Ethics Advisory Board met and reviewed a proposal for a Framingham Genomewide Association Study. They approved in concept that Genomewide Association Study, and we followed that up in late 2005 with a newsletter informing the participants that a team of researchers would be using new genetic approaches to identify disease-causing genes. At that point, our earliest foray anti-genomewide association used a 100K-aphometrics approach. The participants were notified in that newsletter about this. And again, this was simply a mechanism of keeping them in the loop and allowing them the opportunity to ask us any questions if they had them. The fourth question that came up from our community focus group was, how will DNA be used in relation to consent, and how can we ensure that it is only used as indicated by participant preferences? Well, informed consent has certain aspects that are really mandatory, almost a cookbook recipe for what an informed consent form should look like. The consent form should tell us something about the purpose of the study. It should describe what participants will go through in the case of Framingham, what the clinical exam visit will be like. It tells participants about their rights. It describes the benefits, risks, and costs of participating in human subjects research. In general, there are no benefits from participating in such research. It describes the genetics aims of participating in Framingham research and specific aims regarding specific genetic aspects of the study. And it allows for determination of participant preferences with regard to many different aspects of potential research. And I'll give you some specifics of the exact language in our consent form. For example, the consent form tells participants you may choose to withdraw your blood samples at a future date and your samples will be destroyed at that time. The coded samples will be stored securely, separated from files which link your name to the code numbers. You will be kept informed through periodic publications from the Framingham Heart Study of any new findings about genetics, cardiovascular disease, or other health conditions generated from the DNA analysis. And then we got into a number of check boxes that allowed participants to literally voice their particular preferences, their likes or dislikes regarding particular uses of their materials or DNA. And so we had a total of nine check boxes on our current consent form. And I'll go through seven of those nine. The first check box, number one, I agree to participate in the Framingham Heart Study examinations described above to study the frequency of and risk factors contributing to heart and blood vessel diseases, lung and blood diseases, stroke, memory loss, and other diseases and health conditions. This is a generic study participation clause that doesn't specify genetics at all. Check box number two, I agree to provide a blood sample from which DNA and other components can be extracted. The DNA will be made available to researchers studying the diseases listed above. Check box number three, creation of a cell line. If a cell line has not already been collected, I agree to allow a cell line to be made from a sample of my blood to provide a renewable supply of DNA. So these are kind of somewhat generic check boxes. We then get into somewhat more specific check boxes that describe particular traits that can be studied. Check box four, I agree to participate in the genetic studies of factors contributing to heart and blood vessel diseases, lung and blood diseases, stroke and memory loss. These are traits that participants who have been in the study know we've been studying for years and years. So these come as no surprise to anyone. Check box number five, I agree to participate in genetic studies of other diseases and health conditions including but not limited to joint disease, bone loss and cancer. In fact, we have Doug Keel today who's one of our investigators looking at osteoporosis and genetics of osteoporosis. And because some participants may not be aware that we're studying genetics of this condition, we included this additional check box. Check box number six deals with sensitive medical conditions that participants may not be aware that we would be studying in a genetic context. I agree to participate in genetic studies of reproductive conditions and mental health conditions such as alcohol use and depressive symptoms. Check box number seven was implemented after the Framingham Genomic Medicine crisis. And here, participants gave their preference. I agree to allow researchers from private companies to have access to my DNA and genetic data which may be used to develop diagnostic lab tests or pharmaceutical therapies that could benefit many people. Here are the results to date for those specific check boxes in over two thousand study participants who are now currently coming in in the offspring cohort for their eighth cycle of exams. Check box one agreed to participate in the physical exam. Twenty two hundred thirty four individuals replied and all said yes. Obviously they said no, we would not have gone past that point. Check box number two basically permitting a collection of DNA for genetic research. There were two refusals of use of DNA, although they agreed to collect blood and participate in the exam for non-genetic purposes. Check box number three, permitting a cell line. There were only four people who refused a creation of a cell line. That's a two tenths of one percent. And similarly low numbers of individuals who refused the study of basic heart lung blood disorders. Only three who refused genetic studies of other non-heart lung blood conditions such as joint disease, bone loss and cancer. Check box number six dealing with potentially sensitive medical conditions such as reproductive health, mental health and alcohol use. Only seven refusals. Again this is a tiny number of individuals, only a fraction of one percent. And the controversial check box as I mentioned implemented after Framingham Genomic Medicine commercial use of data. There were a hundred seventy individuals in the offspring cohort who refused for their data or DNA to be shared with the for-profit entities and this turned out to be around seven percent of the offspring cohort. Ninety-three percent gave consent to sharing their data with for-profit entities. The last question is how will this resource be shared with the scientific community? I'll make this very brief because we heard a little bit about this from Jim Ostell in his presentation. We believe in the rapid sharing of this resource with the scientific community via NCBI. Aggregate data will be posted with no requirement for a special application and will be posted on the DB GAP website that Jim demonstrated so nicely in his talk. Individual participant data though also will be made available to requesting individuals and this requires an application form, an IRB approval, a data distribution agreement and insurance that data are distributed to individual investigators only in accordance with the check boxes that I referred to earlier. So there will be separate distribution, clauses of for-profit entity would not be able to get data on individuals who did not check yes to the box giving permission to distribution to a for-profit. And an exciting aspect of this project is that our launch date for distribution of the data from the five billion genotypings in SHARE and hopefully relatively rapidly, rapid posting of the aggregate association results will begin on October 1st of this year, just a few months from now. I know Jim you're going to be very busy over the summer. I've shared with you a lot of data in a short period of time but let me conclude by saying that genetic research and prospective observational studies must include several important elements. One I believe strongly is participant involvement. A second is multiple consent provisions. It's nice to be able to predict the future. Those check boxes allow us to do our best job doing so. We also must build into such studies a careful ethical oversight and lastly in my belief to be maximally effective and beneficial to the scientific community and to fulfill the wishes of the study participants, the data will be best used when they can be shared with other investigators and planning for that sharing must take place long in advance. Let me stop at this point and thank you very much.