The Views of Participants in DNA Biobanks

Kelly E. Ormond,I Maureen E. Smith,II & Wendy A. WolfIII

Abstract Biobanks are generally created with the long-term goal of establishing genotype-phenotype correlations. These resources collect and link DNA with health information for use in future genetic research studies. The biobanking process can vary with regard to specific characteristics in study design. Biobanks may extract DNA by using DNA from leftover samples or obtaining new DNA samples specifically for the biobank. Biobanks also vary in whether they use an opt- in or opt-out informed consent process. Some biobanks collect health information at a single point in time, while others “re-access” such information at designated points in the future to categorize subjects accurately into affected/unaffected status. These study design differences can influence the perception of participants and affect their willingness to participate. This paper will address the following three key issues: (1) why people decide to participate in DNA biobanks, (2) what enrollees understand about their participation in DNA biobanks, and (3) how participants feel about the possibility that biobanks will re-contact them, either to obtain new information for future studies or to share potential study results. Finally, we will suggest how information related to these three key issues ought to inform future study design for biobanks.

I. INTRODUCTION...... 81 II. WHY DO PEOPLE DECIDE TO PARTICIPATE IN DNA BIOBANKS?...... 82 III. WHAT DO ENROLLEES UNDERSTAND ABOUT THEIR PARTICIPATION IN A DNA BIOBANK? ...... 83 IV. HOW DO PARTICIPANTS FEEL ABOUT BIOBANK RE-CONTACT, AND HOW SHOULD THIS INFORMATION INFORM STUDY DESIGN?...... 84 V. CONCLUSION...... 87

I Stanford University, Department of Genetics, Stanford, CA. II Northwestern University, Center for Genetic Medicine, Chicago, IL. III Northwestern University, Center for Genetic Medicine, Chicago, IL. 81 STANFORD JOURNAL OF LAW, SCIENCE & POLICY Vol. 1

I. INTRODUCTION

DNA biobanks are created with the long-term goal of establishing genotype-phenotype correlations through collecting and linking DNA with health information. Researchers can use these correlations in research studies that are typically not yet conceived when the biobanks are created. These biobanks may utilize the stored DNA for discovery research, which may include targeted genomic tests, genome-wide association studies,1 and potentially whole genome sequencing studies in the future. The ethical issues that surround DNA biobanks depend largely on the study design and methods utilized by each biobank, and it is therefore important to understand the variety of ways that biobanks can differ in study design and methods. First, biobanks may extract DNA from leftover clinical samples2 or obtain new samples specifically intended for usage in a specific biobank.3 Second, biobanks may use different subject recruitment processes; biobanks can be population-based, narrowly focused on specific medical conditions with a “control” population, or broadly focused on a range of disorders varying in frequency, treatability, severity and social stigma.4 The subject recruitment process may either request subjects to “opt in” (so that a potential subject makes an active decision to participate subsequent to an informed consent process), or to “opt out” (so that a potential subject is assumed to enroll unless the subject actively declines). The “opt out” option is characteristic of a “presumed consent” model, where participants are presumed to enroll in biobanks after obtaining healthcare in certain settings.5 Finally, the last study method where biobanks differ is in their timing for collecting health information; they may collect health information at a single point in time or may “re-access” such information at designated points in the future to categorize subjects accurately as affected or unaffected. Some biobanks choose to have re-contact options so that they can follow up with participants with results from past studies or with requests to obtain consent for future specific studies.6 The health informatics required for these options may require varying levels of de- identification. Coded samples typically involve the efforts of biobank investigators to link the sample with a code rather than with personally identifiable information, such as a name or social security number. (However, investigators may maintain some links to participants in order to re- deposit genomic information and to re-contact participants in the future). Researchers who

1 These studies may include, for example, the assessment of assessing low penetrance genes for common diseases or the search for modifier genes that impact phenotype. 2 See Dan Roden et al., Development of a Large-Scale De-Identified DNA Biobank to Enable Personalized Medicine, 84 CLINICAL PHARMACOLOGY AND THERAPEUTICS 362, 364, 367 (2008) (discussing how a majority of the samples was collected from leftover blood samples). 3 See Catherine A. McCarty et al., Marshfield Clinic Personalized Medicine Research Project (PMRP): Design, Methods and Recruitment for a Large Population-Based Biobank, 2 PERSONALIZED MED. 49, 52 (2005) (discussing how DNA was extracted from each patient). 4 See Lyle J. Palmer, UK Biobank: Bank on It, 369 THE LANCET 1980 (2007); Greta Lee Splansky et al., The Third Generation Cohort of the National Heart, Lung, and Blood Institute’s Framingham Heart Study: Design, Recruitment, and Initial Examination, 165 AM. J. EPIDEMIOLOGY 1328 (2007). 5 See Melissa A. Austin et al., Genebanks: A Comparison of Eight Proposed International Genetic Databases, 6 COMMUNITY GENETICS 37, 39 (2003) (describing presumed consent and the opt-out option in Icelandic Health Center Database); Roden et al., supra note 2, at 365–66 (describing the advantages and limits of opt-out study design). 6 Kelly E. Ormond et al., Assessing the Understanding of Biobank Participants, 149 AM. J. MED. GENETICS 188, 189–90 (2009). 2010 THE VIEW OF PARTICIPANTS IN DNA BIOBANKS 82 utilize the samples typically receive only the coded samples and do not have access to the identification links. De-identified data sets include none of the eighteen HIPAA protected data points, while limited data sets may include either dates, geographic data, or both. Samples that have no link to identifiable information preclude biobanks from updating participants with results or re-contacting again to discover further health information. All of these different study methods influence the ethical issues related to biobank participation. This paper will focus on three key issues relevant to biobanks and their related ethical considerations: (1) why people decide to participate in DNA biobanks, (2) what enrollees understand about their participation in a DNA biobank, and (3) how participants feel about biobank re-contact, whether to give new information for future studies or to receive aggregate or individual study results. After addressing these concerns, we will conclude by proposing how information about these issues should inform study design for DNA biobanks.

II. WHY DO PEOPLE DECIDE TO PARTICIPATE IN DNA BIOBANKS?

Several studies have addressed the reasons why enrollees do or would participate in DNA biobanks7 or other genetic research studies.8 One important stated reason is altruism;9 participants report that they feel good “helping mankind” or want to give back after facing illness in themselves or family members. Less frequently, participants express that they want to contribute to the general knowledge for science, medicine, and genetics, or that they want to assist researchers with building a database that will aid the discovery of specific disease genes or genotype/phenotype correlations and subsequent research on treatments or cures. Other factors that appear to influence participation in DNA biobanks include general interest in science, genetics, or research participation, trust in the sponsoring institution,10 ease of participation (especially if no additional blood sample or time is required), and the perceived low risk of having a blood test. Finally, as will be discussed later in the paper, some participants report that they chose to participate because of the potential to gain personal or family benefits, such as improved testing or treatment.11 Several studies suggest that a majority of potential enrollees are comfortable with the study concepts and purposes12 and would consider participation in a DNA biobank.13 With that said, actual enrollment in biobanks varies significantly based on each biobank’s study design and

7 See Laura M. Beskow & Elizabeth Dean, Informed Consent for Biorepositories: Assessing Prospective Participants’ Understanding and Opinions, 17 CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION 1440 (2008); Catherine A. McCarty et al., Informed Consent and Subject Motivation to Participate in a Large, Population-Based Genomics Study: The Marshfield Clinic Personalized Medicine Research Project, 10 COMMUNITY GENETICS 2 (2007); Ormond et al., supra note 6, at 191. 8 See Donald J. Willison et al., Patient Consent Preferences for Research Uses of Information in Electronic Medical Records: Interview and Survey Data, 326 BRIT. MED. J. 373 (2003). 9 Ormond et al., supra note 6, at 191; Willison et al., supra note 8, at 374. 10 See Beskow, supra note 7, at 1442; Ormond et al., supra note 6, at 191. 11 See Beskow, supra note 7, at 1444; Ormond et al., supra note 6, at 193 tbl.2, 195; Mary Dixon-Woods et al., Beyond “Misunderstanding”: Written Information and Decisions About Taking Part in a Genetic Epidemiology Study, 65 SOC. SCI. MED. 2212, 2218 (2007). 12 Gill Haddow et al., Generation Scotland: Consulting Publics and Specialists at an Early Stage in a Genetic Database’s Development, 18 CRITICAL PUB. HEALTH 139, 142 (2008); Informed Consent, supra note 7, at 6–7; Ormond et al., supra note 6, at 191, 195. 13 See Beskow, supra note 7, at 1440, 1447; Jill M. Pulley et al., Attitudes and Perceptions of Patients Towards Methods of Establishing a DNA Biobank, 9 CELL TISSUE BANKING 55, 58 (2008). 83 STANFORD JOURNAL OF LAW, SCIENCE & POLICY Vol. 1 recruitment practices. In one study, when the biobank used “cold call recruitment” by a study recruiter, 15% of the potential population chose to enroll.14 In contrast, if a trusted care provider, such as a primary care physician or specialist physician, encourages enrollment, a much higher percentage of the potential population appears to enroll.15 Projects that enlist already involved study populations to further participate in a biobank have greater success in gaining participation.16 The extent of community involvement in the biobank design and governance may also have an effect on participation rates.17 In projects where there is an “opt out” recruitment model, the decline rate may be less than 1 in 1600 and as high as 2 to 3%.18 This suggests that in a setting where there is perceived approval from a trusted care provider (by inclusion on standard forms, for example) and low “risk” or inconvenience, most people are willing to consider enrolling in a DNA biobank. These varying rates of participation suggest that trust in the health care provider, investigator, or institution play a large role in biobank participation.19 Also, offering future receipt of results or compensation has also been found to increase participation.20 In countries outside the United States, legislation in support of establishing biobanks and providing data- sharing protections has often preceded the onset of recruitment.21

III. WHAT DO ENROLLEES UNDERSTAND ABOUT THEIR PARTICIPATION IN A DNA BIOBANK?

There are a number of potential challenges to achieving informed consent for participants in biobanks. These challenges include how to describe the nature of the research (when researchers obtaining consent for future research may not yet know what may be done in the course of the future research); what to communicate to participants about the possible commercialization of the research through patents; and how to address the risks of potential discrimination and the related fears that participants may have about discrimination. Another potential challenge is how to decide what type of confidentiality protections to enforce. Greater privacy protection for participants would enable researchers to acquire more non-identifiable study data, but such data would preclude potential acquisition of longitudinal health information and the possibility of re-contacting participants. Last but not least, researchers must consider

14 Ormond et al., supra note 6, at 189. The authors learned about this information regarding cold call recruitment through Wendy Wolf’s role as the director of the NUgene study at Northwestern University, a study that has not yet been published. 15 Ormond et al., supra note 6, at 189. The authors also learned about this information from Wolf’s role as the director of the NUgene study. 16 Splansky et al., supra note 4, at 1331, 1334. 17 See Béatrice Godard et al., Strategies for Consulting with the Community: The Cases of Four Large-scale Genetic Databases, 10 SCI. & ENGINEERING ETHICS 457, 457 (2004); Catherine McCarty et al., Community Consultation and Communication for a Population-Based DNA Biobank: The Marshfield Clinic Personalized Medicine Research Project, 146A AM. J. MED. GENET. 3026–33 (2008). 18 Linus Johnsson et al., Patients’ Refusal to Consent to Storage and Use of Samples in Swedish Biobanks: Cross Sectional Study, 337 BRIT. MED. J. a345 (2008); Roden et al., supra note 2, at 363. 19 See Gail Henderson et al., Great Expectations: Views of Genetic Research Participants Regarding Current and Future Genetic Studies, 10 GENETICS IN MED. 193 (2008); Nancy E. Kass et al., Trust: The Fragile Foundation of Contemporary Biomedical Research, 26 THE HASTINGS CENTER REP. 25, 26–28 (1996); Ormond et al., supra note 6, at 191, 196. 20 David Kaufman et al., Subjects Matter: A Survey of Public Opinions About a Large Genetic Cohort Study, 10 GENETICS IN MED. 831, 835 (2008). 21 Godard et al., supra note 17, at 462. 2010 THE VIEW OF PARTICIPANTS IN DNA BIOBANKS 84 how to communicate with participants about results from genetic research, when there may be great controversy about what those results actually imply. Each of these challenges are factors that may influence the overall enrollment and diversity of study population samples, as well as the ability of participants to comprehend the complex nature of biobanking and genomic research. Only a few studies have addressed the understanding of current DNA biobank participants.22 These studies show that participants generally have a good understanding of the nature and purpose of the biobank, but have far less understanding of confidentiality and potential risks from participating in the study. More specifically, in both of these studies, most participants recognized confidentiality as an issue of potential concern, but they felt that they were at low or no risk for any breach of confidentiality, assuming that the study design and privacy protections were adequate. Few participants in either study specifically mentioned concerns regarding employer or insurance discrimination, and a percentage of those who did also discounted those concerns on the basis of age or prior illness. These studies were completed prior to full implementation of the data sharing standards for federally funded genome-wide association studies.23 Further evaluation of participants’ concerns about privacy and use of genetic data will need to be assessed following implementation of this policy. In the next few years, it will also be important to assess whether potential biobank participants have concerns about the confidentiality of their genetic information, both as federal laws such as the Genetic Information Nondiscrimination Act of 2008 (GINA) are more fully enacted and as genetic testing for conditions that may be viewed as stigmatizing, such as psychiatric conditions and neurodegenerative conditions such as dementia, become more common.

IV. HOW DO PARTICIPANTS FEEL ABOUT BIOBANK RE-CONTACT, AND HOW SHOULD THIS INFORMATION INFORM STUDY DESIGN?

Various approaches to re-contact and re-consent include: (1) no option for re-contact or re-consent; (2) the ability for participants to opt out of specific types of future studies; (3) re- contact if future studies need more information or meet certain IRB criteria; or (4) a requirement for re-contacting participants and obtaining new consents for any future study. With respect to the “re-consent” issue, most current literature suggests that only a small percentage of research participants withdraw their samples from future research studies.24 Research also suggests that participants do not want to be re-contacted separately for all future studies25 but are willing to be contacted to provide information for future studies.26 Factors that suggest that participants would want to be re-contacted for future uses of their sample or data are whether the samples are clinically obtained or personally identifiable, and whether the samples were obtained for research

22 McCarty et al., supra note 7, at 2–7; Ormond et al., supra note 6, at 188–98. 23 The National Institutes of Health implemented the data sharing standards for federally funded genome-wide association studies. NAT’L INSTS. OF HEALTH, NOT-OD-07-088, POLICY FOR SHARING OF DATA OBTAINED IN NIH SUPPORTED OR CONDUCTED GENOME-WIDE ASSOCIATION STUDIES (GWAS) (2008), available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-088.html. 24 Johnsson et al., supra note 18; Birgitta Stegmayr & Kjell Asplund, Informed Consent for Genetic Research on Blood Stored for More than a Decade: a Population Based Study, 325 BRIT. MED. J. 634, 634–635 (2002). 25 See Stegmayr & Asplund, supra note 24, at 634 (discussing how 22.3% of participants wanted to be informed about and give new consent for each new genetic project). 26 McCarty et al., supra note 3, at 55 (“Only 142 participants (0.81%) opted out on the consent form for contact for future studies.”); Ormond et al., supra note 6, at 190. 85 STANFORD JOURNAL OF LAW, SCIENCE & POLICY Vol. 1 on a specific disease rather than as part of a biobank.27 In one further recent study, 85% of its interviewees stated that they would consent to having their DNA stored indefinitely for future research.28 These studies suggest that if participants in a de-identified biobank are given appropriate information that a variety of genetic tests will be performed, it seems unlikely that re-consent for each individual study would be beneficial or desired by most participants. Questions of re-contact will only become more significant with the advent of technologies. Genome-wide association studies and whole genome sequencing may lead to unanticipated uses of samples and obligatory data-sharing, which may eventually identify specific disease risks for individuals, particularly for rare or unusual disorders. New technological advances also raise the question of re-contact for return of results, particularly when this was not in the original study design.29 Regarding the potential disclosure of research results, there has been growing support in recent years for “participant rights to research data,” as well as a sense that researchers are obligated to disclose results out of respect for participants.30 As some of these papers suggest, this raises two critical questions: (1) how does one define “clinically relevant” or “significant” findings?; and (2) how does one maintain records for re-contact in a manner that minimizes risks to confidentiality? Regarding the current literature on this topic, one key reference is a position paper by the National Bioethics Advisory Commission.31 NBAC suggests that disclosure of genetic research results should occur only in exceptional circumstances and that the informed consent process should describe when and why such disclosure may occur and include a plan for management, appropriate referrals, and medical advice. NBAC also specifies that such results should be scientifically valid and confirmed, that the results should pose significant health concerns, and “a course of action to ameliorate or treat these concerns is readily available.”32 While this may appear to be a straightforward guideline for researchers, our own experience suggests that more than ninety percent of patients will opt for potential re-contact with research results,33 and that providing such an option can lead study participants to expect to receive such results in the future.34 Two sample quotations from papers include:

“I believe I will [get results back] if there is any reason for me to. According to the consent form, it said that if there were anything that they learned as a result that affected some condition that they would pass that on to me . . .”35

27 See Stegmayr & Asplund, supra note 24; Dave Wendler & Ezekiel Emanuel, The Debate Over Research on Stored Biological Samples: What Do Sources Think?, 162 ARCHIVES OF INTERNAL MED. 1457, 1461 (2002). 28 See Beskow & Dean, supra note 7, at 1446 (“Most (85%) interviewees said that, if asked, they would allow their blood and information to be stored indefinitely at the Biorepository for use in future research”). 29 Susan M. Wolf et al., Managing Incidental Findings in Human Subjects Research: Analysis and Recommendations, 36 J. OF LAW MED. & ETHICS 219, 239 (2008); See Timothy Caulfield et al., Research Ethics Recommendations for Whole-Genome Research: Consensus Statement, 6 PLOS BIOLOGY 430, 431 (2008). 30 Conrad V. Fernandez & Charles Weijer, Obligations in Offering to Disclose Genetic Research Results, 6 AM. J. BIOETHICS 44, 44–46 (2006); Fiona A. Miller et al., Duty to Disclose What? Querying the Putative Obligation to Return Research Results to Participants, 34 J. MED. ETHICS 210, 210–13 (2008); David Shalowitz & Franklin Miller, The Search for Clarity in Communicating Research Results to Study Participants, 34 J. MED. ETHICS (2008). 31 NAT’L BIOETHICS ADVISORY COMMISSION, RESEARCH INVOLVING HUMAN BIOLOGICAL MATERIALS: ETHICAL ISSUES AND POLICY GUIDANCE 1 (1999). 32 Id. at 72. 33 Ormond et al., supra note 6, at 195. 34 Beskow & Dean, supra note 7, at 1443–45; Dixon-Woods et al., supra note 11, at 2217–2218. 35 Ormond et al., supra note 6, at 195. 2010 THE VIEW OF PARTICIPANTS IN DNA BIOBANKS 86

“I think [the statement that you should not expect to get individual results] is practical . . . . However, I would hope that if there were something wrong with me, and . . . there was an easy fix, that somehow there should be a way for that information to get back to my doctors.”36

This data suggests that individuals hypothetically desire clinical and genetic research results, but it is unclear whether they understand the potential implications of receiving such information. For example, several studies found that roughly sixty to ninety percent participants in genetic research hope to receive genetic test results for a real or hypothetical condition in them or in their families.37 However, few participants provided any qualifiers; it is unclear whether a particular participant’s desire for testing would change due to the age or family status of the participant, the type of disease being tested, or the treatability of the disease. Additionally, a number of studies addressing highly penetrant mendelian conditions have found that the hypothetical offering of results to “at risk” individuals is not a good predictor of what individuals will do once confronted with the actual opportunity to obtain results. The percentage of individuals who actually take predictive genetic tests is frequently much lower than the percentage of individuals who expressed initial interest in taking such tests.38 This suggests that receiving results is appealing in theory, but in reality, individuals have varied opinions on the desirability of results. Two questions follow from this experience. The more important question, and the more difficult one to answer, is how to define “clinically significant” results. Concepts of clinical validity and clinical utility can be useful starting places,39 but definitions of severity and treatability are highly subjective and may change over time for researchers, clinicians, and study participants. Fernandez and Weijer suggest that participants should be involved in determining whether they view a piece of information as “clinically effective or of personal value.”40 Additionally, study design can critically impact any interpretation of what is “clinically significant,” particularly since most GWAS studies assess low penetrance/high frequency alleles; it may be many years before we understand in detail what prospective risks exist for persons carrying low penetrance/high frequency alleles individually or in combination. Whole genome sequencing studies, however, pose a different challenge, since such testing may detect rare but high penetrance conditions (such as BRCA, HNPCC, and Huntington’s disease), as well as identify persons with autosomal recessive carrier status for a range of conditions. The second question is how researchers can optimally communicate with participants about the results of genetic testing. Genetic testing technologies provide researchers with both

36 Beskow & Dean, supra note 7, at 1445 tbl.4. 37 Ormond et al., supra note 6, at 195 (citing in addition other studies where several biobank participants hope to be re-contacted with results from genetic research); Wendler & Emanuel, supra note 27, at 1459. 38 Christiane Bernhardt et al., Decreasing Uptake of Predictive Testing for Huntington's Disease in a German Centre: 12 Years' Experience (1993-2004), 17 EUR. J. HUM. GENETICS 295, 295–300 (2009); S. Creighton, et al., Predictive, Pre-natal and Diagnostic Genetic Testing for Huntington's Disease: The Experience in Canada from 1987 to 2000, 63 CLINICAL GENETICS 462, 462 (2003); Anneke Maat-Kievit et al., Paradox of a Better Test for Huntington's Disease, 69 J. NEUROLOGY, NEUROSURGERY & PSYCHIATRY 579, 579, 583 (2000). 39 Vardit Ravitsky & Benjamin Wilfond, Disclosing Individual Genetic Results to Research Participants, 6 AM. J. BIOETHICS 8, 10–12 (2006); Centers of Disease Control & Prevention, Genomic Translation: ACCE Model Process for Evaluating Genetic Tests, http://www.cdc.gov/genomics/gtesting/ACCE/index.htm (last visited Dec. 3, 2009). 40 Fernandez & Weijer, supra note 30, at 45. 87 STANFORD JOURNAL OF LAW, SCIENCE & POLICY Vol. 1 clinically useful information and information with no known clinical implications at the time of discovery. Researchers must consider how to communicate all that they know to participants, even when the predictive value of the genetic information is uncertain. In order for researchers to make the right disclosure decisions, deliberation over the return of genetic testing results should involve professionals with the appropriate clinical expertise to evaluate the results and to consider the medical and social impacts on recipients.41 The genetics community, legal community, and general public should continue to discuss what results should be disclosed to patients and the appropriate thresholds at which disclosure should occur, particularly if a clinically validated test is publicly available.

V. CONCLUSION

Based on our experiences, we suggest that researchers and institutional review boards strongly consider the above points when designing DNA biobanks and subsequent studies. Issues to consider must include the subject recruitment process, informed consent process, and whether to provide or offer potential future results to participants. The involvement of various stakeholders, including the public, also substantially affects how each of these issues is handled in the design and governance of the biobank. Since our understanding of these issues is evolving quickly with the progress of genomics, it is reasonable to develop a plan for protocol evaluation and revisions. However, the recruitment and informed consent process must be structured in a way that will convey flexibility to participants without creating a false sense of expectation.

41 Caulfield et al., supra note 29, at 433.