10
Ethical, Legal, and Social Implications

Earlier in this report, the committee addressed the challenges involved in identifying how individual human genes interact with other genes and with social and behavioral factors over time to affect human health. Research that elucidates how social, behavioral, and genetic influences interact to impact health may reveal findings that demonstrate beneficial effects on individuals and their health while other findings on interactions may show harmful effects. This lack of consistency may lead to differing perceptions of the value of research on interactions, which in turn may affect the willingness of researchers to do this work; funders to support it; care providers to act on existing evidence; and the population to embrace the findings. At its best, such findings could ensure that public health practice and medical care are attuned to the complex of factors that are affecting a patient, or an individual might be able to use such information as motivation for his/her own health-promoting behavior. On the other hand, such findings could lead to stigmatization and could have negative effects on the ability of individuals or groups to receive appropriate health care and insurance coverage. Consequently, it is important that transdisciplinary research on the impact on health of interactions among social, behavioral, and genetic factors also encompasses investigations that improve our understanding of how individuals make use of this information and how policymakers and the public interpret such research.

Efforts to address the implications of this type of knowledge are not new. For example, environmental regulation is focused to a large degree on the protection of health. Some of the more difficult issues in that arena



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10 Ethical, Legal, and Social Implications Earlier in this report, the committee addressed the challenges involved in identifying how individual human genes interact with other genes and with social and behavioral factors over time to affect human health. Re- search that elucidates how social, behavioral, and genetic influences inter- act to impact health may reveal findings that demonstrate beneficial effects on individuals and their health while other findings on interactions may show harmful effects. This lack of consistency may lead to differing percep- tions of the value of research on interactions, which in turn may affect the willingness of researchers to do this work; funders to support it; care pro- viders to act on existing evidence; and the population to embrace the find- ings. At its best, such findings could ensure that public health practice and medical care are attuned to the complex of factors that are affecting a patient, or an individual might be able to use such information as motiva- tion for his/her own health-promoting behavior. On the other hand, such findings could lead to stigmatization and could have negative effects on the ability of individuals or groups to receive appropriate health care and insur- ance coverage. Consequently, it is important that transdisciplinary research on the impact on health of interactions among social, behavioral, and genetic factors also encompasses investigations that improve our under- standing of how individuals make use of this information and how policymakers and the public interpret such research. Efforts to address the implications of this type of knowledge are not new. For example, environmental regulation is focused to a large degree on the protection of health. Some of the more difficult issues in that arena 202

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203 ETHICAL, LEGAL, AND SOCIAL IMPLICATIONS concern whose health is to be protected—that of the average person in the population of interest and/or the health of high-risk individuals—as well as how and at what cost. Over the last two decades, much attention has been paid to the social and ethical implications of genetic and genomic informa- tion (Murray et al., 1996; Walters and Palmer, 1997; Rothstein, 1997; Rothstein, 2003; Mehlman, 2003). Indeed, the Human Genome Project occa- sioned the first decision by an institute of the National Institutes of Health (NIH) to designate specific funds to explore the social implications of a project. In this arena, the focus has been broader, ranging from effects on health to discrimination in work and insurance to notions of personal respon- sibility, including health and criminal law. More recently, these areas of inquiry have begun to merge in consideration of environmental genomics1 and pharmacogenomics2 (Need et al., 2005), both of which are concerned explicitly with interactions. Discussion in the following section builds upon all these discourses, with an emphasis on the implications of the interactions between genetic susceptibility and social and behavioral factors. Another very important area in the ethical, legal, and social implica- tions realm is that of the granting and licensing of intellectual property rights on discoveries related to genetics. A recent National Research Coun- cil report (NRC, 2006) explores this issue in depth, concluding that “the patent landscape, which is already becoming complicated in areas such as gene expression and protein-protein interactions, could become consider- ably more complex and burdensome over time.” For a thorough and de- tailed examination of the very complex issues in this area, the committee refers readers to the NRC report entitled Reaping the Benefits of Genomic and Proteomic Research: Intellectual Property Rights and Innovation in Public Health. CONVEYING COMPLEX SCIENTIFIC FINDINGS ACCURATELY The picture that emerges from the study of the impact of the interac- tions among social, behavioral, and genetic factors on health is one of complexity. Even single gene disorders such as familial hypercholester- olemia (Austin et al., 2004a; Austin et al., 2004b) are anything but simple. Such disorders may involve hundreds of different mutations, most with 1Environmental genomics is defined as understanding how individuals differ in their sus- ceptibility to environmental agents and how these susceptibilities change over time. Environ- mental genomics includes both the ways in which environmental factors cause genetic damage as well as the ways in which genetic variation affects responses to environmental exposures. 2Pharmacogenetics is the “branch of genetics that studies the ways in which genetically determined variations affect responses to drugs in humans or laboratory organisms” (Wordnet 2.0, 2003).

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204 GENES, BEHAVIOR, AND THE SOCIAL ENVIRONMENT reduced penetrance. Many have pleiotropic effects. Sickle cell disease, which is caused by a single mutation but has many manifestations, is an even starker example of complexity in the face of apparent simplicity. Furthermore, the “common disease, common variant” hypothesis (Zondervan and Cardon, 2004) suggests that the most common variants in the genome have only modest effects on disease susceptibility (relative risks of 1.5 to 2), so that interactions among social, behavioral, and genetic factors may have major effects on health only for specific subgroups. Moreover, to date, the over- whelming majority of reported genetic associations have not been replicated in subsequent studies (Hirschhorn et al., 2002). Social and behavioral factors are even more difficult to measure than genetic variation. Nor are phenotypic effects readily predictable simply by characterizing the relevant genetic se- quences, behaviors, and social environments, either together or individu- ally. Network theory teaches that living systems are remarkably resistant to change and that the perturbation of one part tends to lead to a countervailing response by another in order to promote stability (Barabasi, 2002). In contrast to this complexity, claims about scientific findings are at times simplistic and even exaggerated. The reasons for this tendency are many. The language of science plays a role. Terms such as “the gene for disease X” obscure distinctions between normal gene function—the normal variation in most genes that is present in the population—and the role of specific deleterious mutations that can cause abnormal function and disease predisposition. Furthermore, the scientific method itself is reductionist, seek- ing to isolate the impact of a particular factor on an outcome of interest. Finally, scientists face economic and social pressures to emphasize the sig- nificance of their findings in easily understandable terms that may have the effect of distorting the subtleties and uncertainties of the results (Holtzman et al., 2005). These difficulties are compounded by those outside the scientific com- munity who often are ill equipped to challenge what are perhaps overstated scientific claims. The media understandably prefers straightforward mes- sages, while concepts of relative risk are notoriously difficult to understand. The legal system continues to struggle, in both regulatory settings and the courtroom, with the enormous disjunction between its methods of truth finding and those of science (Rothstein, 1999). Failures to convey the limitations and complexity of scientific findings are significant because beliefs about the causation of health and disease affect the allocation of responsibility and resources, and this has ethical and social implications. Given the consequences of identifying clear causal ex- planations, the drive for simplification is strong. People generally seek simple explanations for events in their lives. Tort law is premised to a large degree on the notion that no more than a few factors can be held legally “responsible” for injuries to people and property. The attraction of reduc-

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205 ETHICAL, LEGAL, AND SOCIAL IMPLICATIONS tionism and the search for a limited number of causes also contribute to the prominence of determinism—the idea that once a particular factor is known, biological and even social consequences follow more or less inexorably. The trend toward deterministic thinking has been particularly prominent regarding genetics, dating back at least to the eugenics movement of the nineteenth and early twentieth centuries (Kevles, 1985; Duster, 1990), but it extends throughout science and society. The history of how biological information has been used to put people at a disadvantage still looms large in the public’s mind. The first step to countering the resulting fear of science is conveying accurately scientific findings and the difficulties involved in predicting the responses of complex systems. POLICY DOES NOT INEXORABLY FOLLOW FROM SCIENTIFIC DISCOVERIES Greater understanding of the influence of interactions among social factors, behavior, and genetic variation on health and disease pulls us in two directions (Shostak, 2003). Focusing on a person’s unique physiologi- cal and genetic makeup focuses attention on the individual and his/her unique susceptibilities. Acknowledging the role of behavior and social loca- tion, however, directs attention to the situation in which the individual lives, including the social factors that influence and constrain that person’s situation and his/her health-related behaviors. The question is whether and how to intervene to improve health, given this complexity. For the purposes of this discussion, it is assumed that it will not be possible to alter particular gene sequences in an individual, at least not in the near future. Thus, any efforts to improve health and well-being in the population as a whole will necessarily depend on using pharmacologic and other medical interventions as well as on changing the social environments and individual health behaviors. Opportunities to alter these nongenetic factors in useful ways may exist at many levels, from the individual, to the family and community, to larger—even global—approaches. However, the array of realistic possibilities is constrained by a host of factors, such as the individual’s personal and financial assets and cultural beliefs; the availabil- ity of resources; legal rules; and concerns about issues such as discrimina- tion. The goals of intervention may vary because notions of health change over time and differ by cultural settings. Moreover, health-promoting ac- tions can complement or compete with other goods at both the personal and societal levels, including individual priorities and values as well as commercial interests. Indeed, the matrix of factors that affect the applica- tion of scientific knowledge about social, behavioral, and genetic interac- tions and the values at stake is every bit as complex as the science that we seek to understand.

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206 GENES, BEHAVIOR, AND THE SOCIAL ENVIRONMENT An example may be useful here. It is known that individuals who have one copy of certain mutations in the gene that codes for alpha-1-antitrypsin (A1AT) (i.e., are heterozygous) are more susceptible to lung damage when exposed to certain inhalants, ranging from chemicals typically used and produced in industry to smog and tobacco smoke (Ranes and Stoller, 2005). On its face, it seems obvious that such individuals should not experience these potential harmful exposures. But questions about how to achieve this goal quickly arise. One might think that people with mutations in A1AT would simply choose to avoid being in harmful environments. However, a great deal of evidence demonstrates that knowledge of risk does not lead inexorably to health-promoting behavior change (Marteau and Lerman, 2001), and at times it may lead to harmful responses. The possible explanations for these apparently suboptimal outcomes are many. In some cases, susceptible indi- viduals simply choose to ignore the risk of toxic exposures. Some argue that protecting susceptible individuals by providing health care if they become ill or by cleaning the environment creates “moral hazard”—the possibility that predisposed people would engage in socially undesirable, unhealthy activities because they are insulated from the consequences. The argument in this case would be that people with mutations in A1AT do not avoid exposing themselves to risk because they know they will receive treatment if they become ill. Some decisions not to avoid potentially harmful exposures, however, result from trade-offs that are made with other goals. Some people with these mutations may find that they can earn a living wage only if they live in a smoggy city or work in sites with harmful fumes. They can be faced with choosing between optimizing their health and meeting their immediate needs and those of their families. Also, the personal protective equipment that could ameliorate some of the risk to such susceptible individuals can be onerous and expensive. However, no matter what the reason for lack of avoidance, it does seem likely that most people do not choose ill health as a matter of preference. Moreover, relatively little research has been done to show how to increase health-promoting behavior in these type of situations. Nor is it clear that protecting only those who have greater risk is necessarily the best policy. Exposures to smoke and toxic fumes are po- tentially harmful to a large part of the population, not just to those who are particularly susceptible. Reducing such exposures, then, could im- prove the health of the public generally, not just those members of the public with mutations in A1AT or other susceptibilities. As a result, envi- ronmental regulation has taken a variety of approaches, sometimes re- quiring individual protective measures, but frequently trying to reduce exposures for everyone. This has led to noticeable improvements in air and water quality over the past 50 years, with benefits going beyond good

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207 ETHICAL, LEGAL, AND SOCIAL IMPLICATIONS health to those as simple as the pleasure of having blue skies and clean water (Grodsky, 2005). Policies regarding who should bear the costs of behavioral choices and environmental exposures are mixed as well. In the individual health insur- ance market, people who smoke or who work in hazardous jobs pay higher premiums. At the same time, both the federal and many state governments regulate the extent to which insurers can use some types of information, particularly information about genetic predispositions, in their underwrit- ing. Employers are concerned with health care costs because they pay higher premiums if their workers have large claims. Over the last 20 years, the ability of employers to exclude workers who may have high health care costs has been limited by laws such as the Americans with Disabilities Act (ADA) (42 U.S.C.A. §§ 12101 et seq. (2006)), which forbids discrimination against workers with disabilities so long as they can fulfill the essential elements of the job with reasonable accommodation, and cases such as Automobile Workers v. Johnson Controls (499 U.S. 187 111 S.Ct. 1196, 113 L.Ed.2d 158 (1991)), which held that Johnson Controls could not exclude women from the potentially fetotoxic workplace. Thus, Terri Seargent, who was essentially asymptomatic, successfully claimed that she was fired because of the costs of enzyme replacement for her A1AT defi- ciency (Clayton, 2001). This body of law, however, recently has been undercut by cases such as Chevron v. Echazabal (536 U.S. 73, 122 S.Ct. 2045, 153 L.Ed.2d 82 (2002)), in which the Supreme Court upheld regulations issued under the ADA that permitted employers to refuse to hire workers whose underly- ing medical conditions make them more likely to be made ill by the toxic workplace. Finally, although society often tries to encourage its members to avoid risky behavior, it has chosen not to require people to bear all of the consequences of their actions. Instead, reflecting a belief that a civil society should provide basic care for its citizens, our health care system provides a substantial, if spotty, safety net against catastrophic illness for many of its members, even when those diseases result in part from per- sonal behaviors. Expressed another way, risks to individual health of whatever sort— genetic, behavioral, or social—raise a set of common questions, as illus- trated below. For these purposes, we assume that a threshold level of scien- tific validity has been met demonstrating that a particular factor influences disease risk.3 3What this level might be can itself be contested. Does the likelihood of the truth of a particular scientific outcome need to be more probable than not, clear and convincing, be- yond a reasonable doubt, or have a probably of less than 0.05?

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208 GENES, BEHAVIOR, AND THE SOCIAL ENVIRONMENT • Who decides whether it is known that a particular individual has a specific risk factor, whether social, behavioral, or genetic, or a combination thereof? Does the individual have the exclusive right to make decisions about whether to find out about his/her risk status, or can third parties require testing or make testing a condition for receiving employment or other goods? • People may have more control over access to some sorts of personal risk information than to others. For example, the fact that an individual smokes cigarettes is difficult to hide, while whether that person has a ge- netic variant that affects the metabolism of that smoke may not be apparent without a specific test. • If the fact that a person has a particular risk factor is known, who should be able to obtain access to this knowledge? Options include the individual, the government, and private entities such as employers or insurers. • If the fact that a person has a particular risk is known, who gets to act upon that information? Can a third party force the individual to amelio- rate the risk, perhaps by denying employment to the person or requiring him/her to use special protective equipment? Can an insurer permissibly charge higher premiums? • What are the costs of acting on the risk information, and who will bear those costs? The answers to this inquiry can be complex. For example, excluding particular individuals from certain opportunities or social goods may benefit some entities, such as employers, while arguably harming the individual as well as impinging on social norms of equality. It also is impor- tant to recognize that most costs are shared, albeit to varying degrees, and all, in the final analysis, are borne by the citizenry. In some ways, traits such as the A1AT deficiency present a relatively simple case in the United States, because these mutations are present prima- rily in Caucasians and cause disorders—emphysema and liver damage— that are not particularly stigmatizing. Questions about appropriate inter- ventions almost certainly will become more vexing as more is learned about the impact of interactions among social, behavioral, and genetic variation on behavioral itself. For example, it was recently reported that individuals with low levels of monoamine oxidase A (MAOA) who were subjected to severe child abuse are more likely to engage in a variety of antisocial behav- iors (Caspi et al., 2002). These results could raise a host of questions, ranging from whether these children need special protection during child- hood to whether they should be monitored for antisocial behavior more closely as adults, all of which have serious implications for civil liberties. Even assuming that the findings of Caspi et al. will be replicated in the future, any intervention would be overly broad, because the majority of

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209 ETHICAL, LEGAL, AND SOCIAL IMPLICATIONS children in the high-risk group (low MAOA + abuse) in that study exhibited no behavior problems, which often is the cause for complex phenotypes. At times, particular genetic alleles are more frequent in individuals of a certain geographic or historical origin. For example, mutations that cause cystic fibrosis are more common in populations of Northern European ancestry than in those of Asian or African origin (Nussbaum et al., 2004). Similarly, behaviors and social environments and practices vary among cultural groups. Because it often is difficult to ascertain these variables for any particular person, it can be tempting to use more readily available social groupings, such as race or ethnicity, as proxies for variations in all these domains. (See Chapter 5 for a more detailed discussion of race/ ethnicity and sex/gender.) Using categories such as race as a proxy, how- ever, can have adverse effects. For example, in the late 1980s and early 1990s, after it became clear that penicillin prophylaxis could be lifesaving for children with sickle cell disease, a number of states decided to screen only non-Caucasian newborns for hemoglobinopathies, with the reasoning that focused screening would be more cost-effective because these muta- tions are most prevalent in populations that arose in equatorial areas. Most states subsequently abandoned this strategy for several reasons, not the least of which is that some affected children were missed. One reason for incomplete ascertainment is that hemoglobinopathies occur in many populations in this country. More generally, states have faced difficulties in defining which children were to be tested. Different strategies were used, including visual determination of the race of the mother and/or the child or asking the mothers to identify their race. No matter what was tried, affected children were missed, including some whose ances- try meant that they were more likely to have inherited these mutations. It also has become increasingly clear that race is not a stable category, but rather is a social construct whose definition changes over time. The prob- lems with targeted newborn screening for hemoglobinopathies were all the more challenging because they occurred in the context of the longstanding history of race discrimination in this country and the more recent history in the 1970s of discrimination against those with sickle cell trait (Reilly, 1977). The memories of these events never have been too far from the surface. This example, while focusing on genetic variation, illustrates some of the difficulties that can be presented by interventions targeted at groups of people. Risk factors, be they social, behavioral, or genetic, can be both overinclusive and underinclusive—some individuals will be singled out for further attention who would never have become ill, while others who are actually at risk will not receive beneficial assistance. These problems of over- and underinclusiveness are exacerbated when the criteria for targeting are not fully concordant proxies for the actual risk factors. For example, even though more men than women ride motorcycles, it would make little

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210 GENES, BEHAVIOR, AND THE SOCIAL ENVIRONMENT sense to teach only men about the importance of wearing helmets, because most men do not ride, while some women do. Moreover, the use of histori- cally disfavored groups as proxies for genetic variation, behavior, or social environment creates the risk of reinforcing old prejudices and stereotypes. Targeted intervention may well be appropriate at times, but such programs should be undertaken only after careful consideration of the social conse- quences and after weighing other alternatives. It is beyond the scope of this report to make recommendations regard- ing the application of knowledge of social, behavioral, and genetic interac- tions in forming policy. However, the array of factors that must be consid- ered in deciding how to use this knowledge is very broad and extends far beyond the science itself. Often, a variety of social responses are ethically and socially acceptable. Thus, the idea that social policy follows inexorably from scientific discovery is every bit as misplaced as the notion of scientific determinism itself. To address difficulties in how individuals and groups understand complex scientific findings, as well as the potential impact such findings could have on policy development, the committee makes the following recommendations: Recommendation 11: Communicate with Policymakers and the Public. Researchers should (1) be mindful of public and policy- makers’ concerns, (2) develop mechanisms to involve and inform these constituencies, (3) avoid overstating their scientific findings, and (4) give careful consideration to the appropriate level of com- munity involvement and the level of community oversight needed for such studies. Recommendation 12: Expand the Research Focus. The NIH should develop RFAs for research that elucidate how best to encourage people to engage in health-promoting behaviors that are informed by a greater understanding of these interactions, how best to effectively communicate research results to the public and other stakeholders, and how best to inform research participants about the nature of the investigation (gene-environment interactions) and the uses of data following the study. ETHICAL IMPLICATIONS FOR RESEARCH Institutional Review Boards (IRBs) perform several roles in overseeing research regarding interactions, but it is important at the outset to identify one area in which they may not act. Although they are required to weigh the risks and benefits of research protocols for research participants, they

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211 ETHICAL, LEGAL, AND SOCIAL IMPLICATIONS are specifically precluded from considering “possible long-range effects of applying knowledge gained in the research (for example, the possible effects of the research on public policy) as among those research risks that fall within the purview of its responsibility” (45 CFR § 46.111(a)(2) (2006)). (For an in-depth analysis of issues regarding protection of research partici- pants, please see the report Responsible Research: A Systems Approach to Protecting Research Participants [IOM, 2003].) Such factors, which we have seen can be implicated by research regarding the effect of interactions among social, behavioral, and genetic factors on health, must be considered elsewhere, if at all. Privacy and Security IRBs are responsible for ensuring, where appropriate, the protection of the research participants’ privacy and the protection of the data regarding the participants (45 CFR § 46.111(a)(7) (2006)). Studying interactions among variations in social, behavioral, and genetic factors requires the collection of information about relevant DNA variants as well as clinical or other phenotypic information, which often includes sensitive personal in- formation about behavior and social factors. The risk to research partici- pants, were such information to be accessed by people and institutions outside the study, could be substantial. Indeed, fear that sensitive or stigma- tizing information will be uncovered or revealed is a common reason people give for declining to participate in research (Schwartz et al., 2001). Some protection from disclosure is provided by laws such as the Privacy Rule promulgated under the Health Insurance Portability and Accountability Act of 1996 (HIPAA)(45 CFR Parts 160 and 164 (2006)). However, IRBs should direct investigators to take additional administrative and techno- logical steps to prevent the unwarranted release of data. The first approach in this regard is to provide adequate security for the data, which can involve storing data on computers that are kept in locked facilities with limited access by personnel, allowing no connection to the Internet, and using methods of encryption. The second draws upon the model provided by HIPAA. In this approach, investigators who share their data with others must execute data use agreements that ensure that the recipients will com- ply with all the restrictions that apply to the individual or institution that collected the information initially. The third approach is to obtain addi- tional legal protections against disclosure. The most important of these protections are the still relatively underutilized Certificates of Confidential- ity, which can be obtained from the U.S. Department of Health and Human Services (Cooper et al., 2004; Office of Extramural Research, 2005). Several different methods, which vary in their impact on the utility of the data, may be taken to secure data. Irretrievably removing identifiers

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212 GENES, BEHAVIOR, AND THE SOCIAL ENVIRONMENT provides the greatest security, but if this is done correctly, it may require eliminating many variables. Furthermore, this method precludes following study participants prospectively for disease incidence by adding new clini- cal data. A different strategy may be to adopt one-way encryption so that neither investigators nor database managers can identify individual research participants, even though new clinical information can be added. It also may be possible to code the information and maintain a key that makes it possible to go back to particular individuals in order to obtain additional specific data pertinent to new hypotheses, to invite them to participate in new research projects, perhaps exploring preventive or thera- peutic interventions, or even to provide them with clinically meaningful research findings. Retaining a key, however, presents additional challenges. Strict limits on access to the key would be necessary to avoid seriously compromising security. Criteria and a process of review need to be devel- oped to justify recontacting individuals for more information or to invite further research participation. Despite individuals’ concerns about their privacy, pressure is mounting from many quarters to increase the availability of data. Pharmaceutical companies are being asked to report details of all their clinical trials (Herxheimer, 2004). Investigators and funding agencies around the world are proposing expanded data sharing policies (Arzberger et al., 2004). Coun- tries and funders are creating new, very large datasets with genomic and phenotypic data to be made broadly available. The Data Quality Act en- ables entities that dislike particular regulatory decisions to question the science on which they are based (Rosenstock, 2006). To date, no clear consensus has emerged about exactly what data need to be shared or how individual privacy is to be protected, although at least some writers have recognized that the latter is an issue. Given this uncertainty and the power of datasets that include rich phenotypic, genomic, and environmental infor- mation, it is particularly important that IRBs attend to questions of how fully data can be encrypted or de-identified and what research participants need to be told about the research. Disclosure of Results One of the most contentious issues posed by maintaining a mechanism for personal contact involves the question of whether research participants should receive individual results. Although some argue that this informa- tion should be offered as a matter of right (Council for International Orga- nizations of Medical Sciences, 2002; Shalowitz and Miller, 2005), strong arguments have been made that it is better to reveal individual research results, if at all, only under very limited circumstances. Routine disclosure

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213 ETHICAL, LEGAL, AND SOCIAL IMPLICATIONS fuels the therapeutic misconception (Appelbaum et al., 1982)—the mis- taken belief that research is directed toward the same goal as clinical care, namely the best interest of the patient. The purpose of research, instead, is to create generalizable knowledge. The research process typically proceeds by fits and starts. Because many initial findings cannot be replicated, par- ticularly in areas as complex as the impact of interactions among social, behavioral, and genetic factors on health, a practice of routine disclosure often would provide misplaced reassurance or create unwarranted fear. On a more practical level, most research is conducted in laboratories that are not approved under the Clinical Laboratory Improvement Amendments and their regulations (42 USCA § 263a (2006) and 42 CFR Part 493(2006)). Therefore, research laboratories may not use the rigorous sample handling and tracking procedures used in clinical laboratories. This increases the risk that results would be attributed to the wrong person or be incorrectly reported. Finally, some people may not welcome this information. Numer- ous studies demonstrate that while many people express interest in learning about individual risks, fewer actually pursue testing once it is available (Bowen et al., 1999). As a result of these problems, most commentators favor limits on the disclosure of individual research results. The National Bioethics Advisory Commission, for example, proposed that individual research results could ethically be revealed only if an ethics committee or other review body concluded that “a) the findings are scientifically valid and confirmed, b) the findings have significant implications for the subject’s health concerns, and c) a course of action to ameliorate or treat these concerns is readily avail- able” (National Bioethics Advisory Commission, 1999). The availability of effective prevention also may suffice to justify disclosure. This threshold rarely would be met in research involving the impact of interactions among social, behavioral, and genetic factors on health because the relative risks are almost always relatively modest, and because behavioral and social factors can be difficult to quantify. In any event, it is critical that investiga- tors and IRBs define the criteria for the disclosure of individual results at the outset of the project. Even when individual research results are not revealed to participants, it often is desirable to inform them periodically about general research findings. This can be accomplished by routine mailings, by presentations at meetings of patient organizations, or by creating websites, which may or may not be password protected, that participants can visit. Informing re- search participants about the progress of the project will enable them to talk more effectively with their clinicians about seeking testing or other interventions once the research findings become sufficiently robust to be incorporated into clinical care.

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214 GENES, BEHAVIOR, AND THE SOCIAL ENVIRONMENT Community Involvement The desirability and limits of including lay oversight and some level of community involvement in research protocols were recently reviewed in the National Research Council/Institute of Medicine’s report Ethical Consider- ations for Research on Housing-Related Health Hazards Involving Chil- dren (NRC/IOM, 2005). Lay involvement can take many different forms, ranging from membership on IRBs to community-based participatory re- search, in which laypeople and investigators jointly define every aspect of the project. Including participants can improve research by identifying is- sues or risk factors that would not have been considered by investigators, improving recruitment and communication, and increasing transparency. Community advisory groups, which represent an intermediate level of in- volvement, increasingly act as conduits of research to the larger group of research participants (Coriell Institute for Medical Research, 2006). At the same time, greater lay involvement is time intensive for both investigators and laypeople. To date, little data exist regarding its efficacy. In considering what level of lay involvement is appropriate in studies of the impact of interactions among social, behavioral, and genetic factors on health risks of the research, the practicability of inclusion should be taken into account. More active involvement may be desirable, for example, when study results have the potential to stigmatize individuals or groups, as might be the case in studies that explore genetic and environmental influ- ences on antisocial behaviors. It is important to recognize that all types of differences—social, behavioral, and genetic—can be potential sources of stigma, and, where implicated, they may warrant greater lay involvement. The risk to individuals or groups may be even greater when the research participants are in some way vulnerable within the larger society. One of the most vexing problems facing investigators is deciding what to do when research involving samples and clinical information collected for one purpose suggests new hypotheses. For example, researchers may have focused initially on cardiovascular disease risk, but new findings may suggest that the exploration of factors contributing to Alzheimer’s disease also may be fruitful (e.g., the work currently being conducted on apolipoprotein E isoforms). Consultation with the community may provide insight into whether this new direction is consistent with the original intent of the participants. Lay involvement may be more obviously required when defined politi- cal structures exist within the group from which research participants are drawn. The paradigmatic example in the United States is research involving Native Americans because they are members of sovereign nations; however, in that setting, care must be taken to ensure the representativeness of the process and of those who purport to speak on behalf of the participants

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215 ETHICAL, LEGAL, AND SOCIAL IMPLICATIONS (Council for International Organizations of Medical Sciences, 2002; Sharp and Foster, 2002). Efforts to solicit public involvement in research design and dissemination also may be warranted even when community groupings are less well defined. Strategies will differ in each context, but will typically involve tapping into local social networks within the larger group. Informed Consent The last decade has seen an enormous amount of debate regarding the ethical and legal requirements of informed consent for the use of medical information and human biological materials for research (Clayton et al., 1995; Knoppers, 1997; National Action Plan for Breast Cancer, 1997; National Bioethics Advisory Commission, 1999). Among the issues that are often addressed in current consent forms are the types of research that may be conducted; the risks and benefits, both personal and social, that may result from the research; who is going to hold and have access to these resources; what privacy and security protections are going to be used; under what conditions, if any, individuals may be recontacted either to obtain further consent or to be provided specific health-related results; and the possibility that intellectual property may be developed. Particularly in light of evidence that research participants often are not truly informed, more work needs to be done to learn how to communicate this information effectively. These issues merit particular attention in studies of the interac- tions among social, behavioral, and genetic factors on health in order to ensure that participants truly understand what is at stake in the research. Given the sensitivity of research and its implications involving interac- tions among the factors under discussion, it is of primary importance to address the issues of data sharing and informed consent. Therefore, the committee recommends the following: Recommendation 13: Establish Data-Sharing Policies That Ensure Privacy. IRBs and investigators should establish policies regarding the collection, sharing, and use of data that include information about (1) whether and to what extent data will be shared; (2) the level of security to be provided by all members of the research team as well as the research and administrative process; (3) the use of state-of-the-art security for collected data, including, but not lim- ited to, NIH’s Certificates of Confidentiality; (4) the use of formal criteria for identifying the circumstances under which individual research results will be revealed; and (5) how, before sharing data with others, recipients must agree to use data only in ways that are consistent with those agreed to by the research participants. Fur- thermore, if a mechanism to identify individual research partici-

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216 GENES, BEHAVIOR, AND THE SOCIAL ENVIRONMENT pants is retained in the database, IRBs and investigators should consider whether to contact participants prior to initiating research on new hypotheses or other new research. Recommendation 14: Improve the Informed Consent Process. Re- searchers should ensure that informed consent includes the follow- ing: (1) descriptions of the individual and social risks and benefits of the research; (2) the identification of which individual results participants will and will not receive; (3) the definition of the pro- cedural protections that will be provided, including access policies and scientific and lay oversight; and (4) specific security, privacy, and confidentiality protections for protect the data and samples of research participants. REFERENCES Appelbaum PS, Roth LH, Lidz C. 1982. The therapeutic misconception: Informed consent in psychiatric research. International Journal of Law and Psychiatry 5(3-4):319-329. Arzberger P, Schroeder P, Beaulieu A, Bowker G, Casey K, Laaksonen L, Moorman D, Uhlir P, Wouters P. 2004. Science and government. An international framework to promote access to data. Science 303(5665):1777-1778. Austin MA, Hutter CM, Zimmern RL, Humphries SE. 2004a. Familial hypercholesterolemia and coronary heart disease: A HuGE association review. American Journal of Epidemi- ology 160(5):421-429. Austin MA, Hutter CM, Zimmern RL, Humphries SE. 2004b. Genetic causes of monogenic heterozygous familial hypercholesterolemia: A HuGE prevalence review. American Jour- nal of Epidemiology 160(5):407-420. Barabasi, AL. 2002. Linked: How Everything Is Connected to Everything Else and What It Means. Cambridge, MA: Perseus Publishing. Bowen DJ, Patenaude AF, Vernon SW. 1999. Psychosocial issues in cancer genetics: From the laboratory to the public. Cancer Epidemiology, Biomarkers and Prevention 8(4 Pt 2):326-328. Caspi A, McClay J, Moffitt TE, Mill J, Martin J, Craig IW, Taylor A, Poulton R. 2002. Role of genotype in the cycle of violence in maltreated children. Science 297(5582):851-853. Clayton EW. 2001. Through the lens of the sequence. Genome Research 11(5):659-664. Clayton EW, Steinberg KK, Khoury MJ, Thomson E, Andrews L, Kahn MJ, Kopelman LM, Weiss JO. 1995. Informed consent for genetic research on stored tissue samples. Journal of the American Medical Association 274(22):1786-1792. Cooper ZN, Nelson RM, Ross LF. 2004. Certificates of confidentiality in research: Rationale and usage. Genetic Testing 8(2):214-220. Coriell Institute for Medical Research. 2006. Coriell Cell Repositories. [Online]. Available: locus.umdnj.edu/ccr/ [accessed March 24, 2005]. Council for International Organizations of Medical Sciences. 2002. International Ethical Guidelines for Biomedical Research Involving Human Subjects. Geneva: Council for International Organizations of Medical Sciences. Duster, T. 1990. Backdoor to Eugenics. New York: Routledge. Grodsky JA. 2005. Genetics and environmental law: Redefining public health. California Law Review 93(1):171-270.

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