Let me start by thanking the committee for inviting me and giving you a little background on myself. I am a human geneticist and statistician by training and I currently conduct epidemiological research on the genetics of cardiovascular disease, hypertension, diabetes, dementia, drug response, and nicotine dependence. My specialty area is in understanding the context-dependent effects of genes – both gene-environment and gene-gene interactions. I am the Director of the Public Health Genetics Program at the University of Michigan (U-M), as well as Co-Director with Toby Citrin of the U-M Life Sciences and Society Program and Center for Genomics and Public Health. I am also currently serving on two National Academy of Science committees – one on toxicogenomics and the other on assessing the interaction among social, behavioral, and genetic factors. These professional experiences have led me to a broad understanding of both the social and policy issues surrounding genetic research and their implications which I am honored to share. From my point of view, a large population study of both genetic and environment factors carries multiple advantages and disadvantages. Although it is not to my personal benefit to focus on the disadvantages, at this time I feel that there are a number of critical social and regulatory policy issues that make such a project premature. For example, the current lack of genetic literacy in the public makes true informed consent and public acceptance for this type of research a major issue. Recently, I had the opportunity to talk to community leaders from one of our university’s community-based participatory research projects in regards to a genetics research project I would like to conduct with them. The overwhelming feedback from this first meeting was one of concern and causation. Concerns about discrimination, race-based medicine, and insecurity about how that information will be used were the first things the community members voiced. Although they unanimously decided to continue pursuing conversations on the topic, the resounding tones of concern was a deep indication to me that the general public is fearful of genetics and not clear on what the real benefit would be for themselves or their families. In my professional opinion, it will take a significant effort to turn the tide of misinformation and mistrust by the public. Unless the public is engaged as a partner, not just as participants, I cannot see how such a large project will avoid exacerbating these issues. In addition, the lack of a federal genetic anti- discrimination law makes it a liability for the public to participate. Anti-discrimination laws at the state level will not protect most of the public because most Americans are insured through group policies that are under federal jurisdiction. With such a big study, involving hundreds of investigators and clinicians, the public is going to be concerned about the extent to which real privacy and confidentiality can be maintained. There is a great deal of fear on the part of the public as to what researchers, doctors, insurance companies, employers, and government agencies will do with biobanks and genetic information. Another issue involving genetic literacy – namely, health care professional education - is also of concern. The vast majority of physicians, health care providers, and public health professionals have no formal training in genetics. They do not know basic genetic concepts, such as Mendel’s Laws, which are essential to accurate risk assessment and medical or public health genetic decision making. They do not understand concepts of mutation or genotype-phenotype relationships. Given the power of genetic information, we need well researched and well executed policies around the duty to warn research subjects or their families of genetic research results as well as how this should be done in conjunction with counseling and support services. I raise this point because much of the health education and health behavior research on genetic risk communication illustrates that the public and health care professionals do not understand concepts of genetic risk. Many do not even know where their genes are located or why a genetic test might be predictive. For example, studies have shown that subjects receiving genetic information on early onset colorectal cancer risk may ignore their negative test results and continue to get yearly screening because the “blood test” is not relevant in their minds when compared to the clinical examination of where the disease will manifest – that is, their colons. Similar types of misinterpretation have also been documented for subjects receiving information about increased genetic risk of disease. There is also evidence that many health care providers do not accurately interpret the genetic information provided to them from genetic testing companies. We need to adequately invest in the social infrastructure need to utilize genetic information before we can responsibly embark on such a large national study. Another class of concerns I have comes from the way we are currently conducting genetic science. Specifically, most genetics research is still focused on identifying single causative factors and has not matured to complex models of genetic causation. This simple single gene focus means that scientists themselves end up promoting naive biological deterministic interpretations of complex disorders which are likely to lead to misinterpretation and misuse of genetic explanations in public policy, in courts, in health and life insurance policies, as well as medical practices. We know that common chronic diseases with the greatest burden on the public’s health have complex genetic etiologies but we have not embraced nor incorporated this complexity in our study methods. The Burlington Northern Sante Fe Railroad decision to secretly test workers for a mutation associated with carpal tunnel syndrome is just one example of how this type of information can be misused. In this case, it appears that the company wanted to avoid financial responsibility for providing workers compensation for their worker’s on-the-job injuries so they secretly tested workers for a rare mutation to see if people had a “pre-existing” genetic susceptibility. In general, we do not have the necessary experience, institutional infrastructure, or scientific culture in which to responsibly carry out such a large and important interdisciplinary study. Genetic science of common complex disorders is simply not mature enough. We are still using the single gene paradigm of the previous century and do not understand the real roots of why genetic effects are significant in one study but not the next. Especially with a large population study, there will be a desire and a tendency to use all the power of its sample size to promote its findings as “definitive” and make genetic causal statements while ignoring local heterogeneity in environmental and genetic factors that will directly affect the clinical and social utility of the results. Another scientific concern I have is that most geneticists are not well enough versed in the social, behavioral, and environmental causes of disease to lead such a large study that purportedly focuses on gene-environment interactions. True interdisciplinary research that integrates knowledge across the levels from the influence of the genome to the influence of our human ecology are only now in their infancy and currently these two ends of the spectrum – geneticists and social-behavioral scientists - are pitted against each other at the funding tables or in institutions. My own experiences with being a part of our school’s Robert Wood Johnson Health and Society Scholars program have shown me the genuine lack of respect that genetics commands compared to health effects of poverty, racism, and unfair social policies. Through a lot of hard work, we are starting to sit down at the table and trying to work from the bottom up and the top down. Learning each other’s languages, methodologies, and inferential processes is a major endeavor that will take concerted time, effort, and money. It is clear that we need new models and information gathering systems – holistic models or perhaps systems models – that incorporate a person’s lifetime of exposures, their parent’s exposure, their community’s exposure to adequately understand genetic influences on health and disease. In this arena, geneticists are appropriately criticized for our simplistic genocentric analyses, our lack of key social-behavioral measurements, the lack of replicable results, and the lack of clear causative mechanisms. It is very difficult to move from a statistical genetic association to an understanding of the mechanism of action that would suggest new therapies, preventions, or that would withstand evidence-based regulatory decision making. Many genetic testing companies are marketing products without waiting for the results of this arduous task and instead move from association to testing. This last point troubles me the most because it means that genetic findings in complex disorders, especially gene-environment interactions, are difficult to prove and are not likely to pass the muster that would allow regulatory bodies to create policies that adequately protect people. A large definitive study would also significantly decrease the ability of other studies in this arena to be launched to in order to confirm or refute their findings. Although there has been some progress lately in that scientists are at least starting to study gene-environment interactions, such as in toxicogenomic and pharmacogenetic research, the research results themselves have exposed the immense complexity of integrating this type of knowledge into existing policy standards and methods. Traditionally, public health policy has focused on population level solutions – for example, ubiquitious anti-smoking campaigns. In contrast, genetic information is individual-based, family-based, ethnic-group based and would require intense research on the implications of specialized policies and regulations for the protection of vulnerable populations. The work by Barbara Koenig’s group on the ethical implications of smoking through a neurogenomic prism is an excellent example of the wide ranging ethical, legal, and policy issues that could emanate from the findings of a large longitudinal cohort study. Are we ready for this information? More importantly, what would we do with it? What if we found that some people are sensitive to their environments and others were not? Is it the responsibility of the individual to take themselves out of harms way when the rest of society can ignore their vulnerability? The current risk assessment paradigm used by the EPA and FDA does not have a method for setting standards and guidelines for businesses or products based on susceptible genetic subgroups. Furthermore, because there are likely to be many different genetic factors operating simultaneously, defining a vulnerable or susceptible population could be a nightmare in and of itself, especially when it is conjoined with already existing definitions of vulnerable populations that are to date based on age, race, or disability. It is my current understanding that the regulatory agencies such as the FDA, EPA, and FTC do not have the resources to tackle an upheaval of their systems and often have nobody on staff who really understands genetics or genomics. Its not just departments of health and health professionals that are not ready for genetic information - the EPA is not ready, the FDA is not ready, the FTC is not ready, and legislatures are not ready. This is slowly changing but will take time and resources. The last thing we want is a repeat of the sickle cell screening debacle of the 70’s where marriage laws were passed that were supposed to protect people but ended up adding insult to injury. The current lack of oversight on genetic testing coupled with a lack of public education leaves the public very vulnerable. Genetic testing companies can market directly to consumers or to doctors without regulatory oversight. This includes the ability of companies to withhold information demonstrating the utility of their product (i.e. truth in advertising). For example, Best Buy recently released a nutrigenomic DNA testing kit. To the best of my knowledge, our scientific understanding in this arena is quite limited and certainly not ready for prime time. One question I have as the Director of our Public Health Genetic Program is why is this happening? I think that many people have had their interest in genetics peaked by the publicity about the Human Genome Project and daily newspaper articles that overstate research findings. The “news you can use” paradigm in the media is creating a market for these tests and so American businesses are capitalizing on that desire. I think the large US study being proposed will simply add fuel to this fire. Without adequate regulations, genetics could quickly become the snake oil of the twenty-first century. Switching gears to some of the other questions you asked me to address, such as “How much consultation is needed with the broader scientific community to inform a decision about undertaking a US large population study?”, I have to admit some skepticism. Simply asking for comments will do nothing but result in a biased sample of outspoken antagonists from social scientists who are worried about the geneticization of disease and the excessive use of resources by geneticists, as well as by the outspoken proponents who want to be a part of such a large funding (i.e. revenue) source for their own operations. When the National Childhood Study started to create working groups to formulate plans for their large population study, I was asked to be in the Gene-Environment Working Group. I participated for about a year before getting fed up with the obvious and I would say natural self-serving interests of the committee members. Science and scientists are is not value free and currently the market-driven value system of science is a major source of bias in our academy. Another key question you asked was “Is there a general awareness among scientists of a potential US large population study?” In my experience the answer is yes and again it is with some skepticism. Many of the genetic epidemiologists I know think that there is some merit to the idea but that this mega-science model will fund a few insiders very, very well and not leave much for the rest of the scientific community. There is also a sense by many genetic epidemiologists who have spent their lives recruiting cohorts that it is an unrealistically large and broad target to accomplish in a high quality manner. There are also questions about why existing longitudinal cohort studies are not being utilized and about what will happen to funding of these programs. I have been fortunate to be a part of the NHLBI’s Family Blood Pressure Program that has collected over 13,000 individuals from five racial/ethnic groups through over a dozen field centers. As the head of the Analysis Committee and one of the Data Coordinating Centers, I can tell you it takes a tremendous amount of effort to agree on what should be measured, how it should be measured, and how it should be analyzed. This group of dozens of investigators does not include social, behavioral, and environmental scientists who I think will also need to be at the table from the very beginning of such a large US cohort study. The question is: How are we going to realistically design and implement such a large study to move to a high quality result rather than migrate to a lowest common denominator? How are we going to adequate measure the environment which is by far more difficult than measuring genome variation? As you can see, it’s my opinion that we have not had enough time or resources to build the necessary scientific experience or infrastructure to support such a large and ambitious project. There are many intermediate steps that need to be taken before we are ready. For example, just getting genetic researchers to work together so that their already existing cohorts can be used to confirm or reject claims of genetic associations would be a step in the right direction. Figuring out more effective ways to understand mechanisms of action would be another. In addition, we have typically not engaged nor utilized the resources of departments of health in genetic research. There are cancer registries, early death registries, environmental health registries, all of which could be used in a first wave of research. These state level holders of registries and knowledge about the key environmental factors influencing the public’s health have yet to be tapped. In addition, from a policy perspective, departments of health need to be more prepared for dealing with genetic information on common disorders and have working staff investigating the implications of state level policies on things like informed consent and setting up mechanisms to handle the public’s needs for genetic education and genetic services like counseling. In Michigan, we are lucky to have one of the most genetically progressive departments of health in the nation. They are invested in genetics training for their workforce and in collaborating with academia on the genetics research as well as the ethical, legal, and social implications of genetics. The Michigan Department of Health is already seeing the influence of genetics at their back door. For example, they recently had to deal with a case where a small town doctor did a diagnostic genetic test, which they think was prompted by a direct to doctor advertising campaign. The doctor didn’t tell the individual that a genetic test was being conducted. To make matters worse, there was no counseling involved when the doctor delivered some incredibly bad news over the phone. This family was left devastated with no information about social supports or how to deal with the information. They also had no legal recourse because the existing laws on the books stated that informed consent and counseling was not necessary. The department of health staff was left scrambling to figure out what to do for this family who now faced the real possibility of employment discrimination, as well as health and life insurance discrimination. Because of grants from the CDC to build genetics infrastructure in the state, they at least had staff able to direct them to genetic counselors and support groups as a first step. This is just one set of examples of how I think departments of health ought to be brought in as partners in this genetics revolution. They are going to be needed as key players in building bridges for the public and ought to brought in during the development and implementation of such a large cohort study because of the local expertise and resources they have to offer and their watchdog role of ensuring the proper use of genetic information for the public’s good. As a genetic epidemiologist I would normally be very excited about the prospects of such a grand endeavor. However, I feel there needs to be a significant investment in the social and policy infrastructure in order to safeguard the public. There also needs to be a greater investment in the scientific collaborative process across disciplines as well as within disciplines. With adequate investment, this large cohort study could be a great asset to the country. Without adequate investment we could be blindly engineering a genetics study that the general public is against, health care providers inappropriately use, businesses take to the bank and policy makers turn into inadequate and inappropriate laws. At this time, it could ultimately be a study that does more harm than good simply because we don’t have adequate infrastructure and resources in hand to launch this project right now. It is a matter of timing. Once these issues are addressed, this could be marvelous opportunity to advance knowledge for the public good.