Research
Ethical Issues in Genetics
Summary: This project examines a broad range of clinical- and research-related issues in genetics, including: 1) the justifications used for the introduction of new genetic tests into clinical practice, using newborn screening as a paradigm case study; 2) providing the results of genetic research to study participants; and 3) recruitment of family members into genetic research.
| Section: | Ethics and Genetics | ||||||||||
| Principal Investigator: | Sara Hull, Ph.D. | ||||||||||
| Collaborators: |
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Background
Newborn Screening: Newborn screening is one of the oldest approaches to genetic testing and is often heralded as a public health success because of its impact on the prevention of severe consequences of rare pediatric diseases. However, in the last decade there has been a rapid expansion of newborn screening for a much wider range of diseases, stimulated by enthusiasm from patient advocacy groups, commercial laboratories, and clinicians. Perhaps they misunderstood Bob Dylan, and though that he said, “everyone must get screened.” The main thrust of this project has been to explore the implications of expanding newborn screening beyond the traditional diseases such as phenylketonuria (PKU) and congenital hypothyroidism. This will be come more important as, in short order, it may be possible to screen for an infinite number of conditions during infancy.
Providing Research Results: There has been significant controversy about the responsibility of investigators to communicate individual research results to study participants. Although some have argued that routine disclosure is appropriate based upon the principle of respect for participants, others have argued that disclosure should be limited with an emphasis on the balance of benefits and harms of such disclosure. The Common Rule does not provide clear guidance on this question.
Family Recruitment: A significant amount of health-related genetic research requires not only the participation of persons with a medical condition (“probands”) but also their family members. Access to family members often can be gained only through information reported by probands themselves, including relationship and disease status of multiple family members. A standard approach involves researchers contacting family members after receiving names and contact information from probands. Alternatively, some have argued that the initial contact should be made by someone who has an existing relationship to the recruitee such as the proband. Researchers and IRBs are routinely faced with questions of how to balance the effectiveness of recruitment approaches with minimizing unwelcome intrusions and undue influences upon patients and family members who are potential subjects of research.
Departmental Research Initiative
Newborn Screening: Recommendations for empirical research prior to newborn screening have been articulated since the 1970’s after the unexpected complexity of PKU screening was appreciated. The first and only randomized controlled trial of NBS was conducted between 1985–1994 in Wisconsin for cystic fibrosis. However, this trial has been criticized as unethical. The two main concerns were that it was unethical to have an unscreened group in the trial, and second that it was wrong to not inform families about the trial. In our response, we argued that design of the trial was appropriate because the benefits and risks of NBS were not known, so it was not even clear which group was potentially disadvantaged (Taylor and Wilfond, 2005). While parents were informed about the study through an added paragraph in the standard Wisconsin NBS brochure, we argued that additional modest steps could have been taken to increase awareness. However, we rejected the recommendation that such research can only be conducted with each parent signing a consent form.
In a related paper, we argue that it is necessary to conduct research about new screening programs that do not have the usual standard of protections including extensive informed consent and genetic counseling because these are not as likely to be provided in the clinical setting. Therefore is it necessary to learn how people respond to testing an such a natural setting, to better assess the benefits and risks important for subsequent policy decisions (Freund, Clayton, Wilfond, 2003).
We wrote a series of papers that focused on the clinical introduction of cystic fibrosis newborn screening. An empirical paper based on interviews with state health department officials documented the variability in screening approaches, including laboratory methodologies and cut offs for false positive and false negative results, communication about results interpretation, and availability of genetic counseling. This paper concluded that these different approaches could have an impact on the benefit/risk evaluation of the programs (Gollust and Wilfond, 2005). This paper showed that some approaches had as many 10 to 20 false positive infants who needed a sweat test and turned out to be CF carriers for each child identified with CF. A subsequent analysis pointed out because the benefits of CF newborn screening were generally not life saving, that it might be appropriate to design a screening program that accepted a lower sensitivity in order to reduce the number of false positives (Wilfond, Parad, Fost 2005).
We realized that the issues that occurred for CF newborn screening relating to the balance of benefits and risks had implications for future genetic testing programs. In 2005, the American College of Medical Genetics (ACMG) released a report that recommended that all states expand their newborn screening programs to include metabolic screening using tandem mass spectroscopy that has the potential of identifying close to 50 conditions. For some of these conditions, it is not clear if any interventions are necessary and for others it is not clear if interventions will be helpful. The report argued that screening should expand beyond diseases for which screening was clearly beneficial for the child because of the potential benefit to the family of knowing that there child had a condition. In response, with colleagues from the CDC, we stipulated that such an expansion from screening as a public health service rather than a public health emergency would have specific policy implications. These include consideration of balancing false positives and negatives rather than maximizing detection, reopening the debate about informed consent for newborn screening, and explicating making decisions about resource priorities in deciding whether to adopt new tests (Groose). These issues had not been addressed by the Report.
The ACMG report received endorsements from the March of Dimes and a Secretary of Health and Human Services Advisory Committee. However, out of concern that the empirical methodology was flawed and the report did not provide a detailed ethical analysis of the issues, we collaborated in writing a critique with a diverse group (Botkin 2006). This critiqued urged that the expansion proceed with caution and pointed out that much of the report was based on “expert opinion” and passionate enthusiasm rather than deliberative policy analysis.
Providing Research Results: Questions about when it is appropriate to provide results from genetic research became tangible for the Department via two separate ethics consults that came through the Clinical Ethics Consultation Service, both of which were ultimately published as case studies. First, a microarray study of hereditary breast cancer gene expression profiles yielded a finding in which it appeared that a woman who was originally thought to have a sporadic case of breast cancer might actually be positive for a BRCA1 mutation (Hedenfalk et al. 2001). The IRB protocol had included a waiver of the requirement to obtain patients' consent to use these samples with the stipulation that investigators would not contact subjects with results. However, because of the potential clinical and scientific value of the outcome, the decision was made to contact the subject through her primary care physician. She agreed to be tested and was found not to have a BRCA1 mutation, which was of both scientific and clinical relevance.
The second case involved questions about providing genetic research results to the family members of a research subject (Loud et al. 2006). The investigators had informed the subject herself of her personal research results (she was BRCA mutation positive); however, she misrepresented these findings to members of her family. Although the investigators recognized their obligation to protect her privacy, they were concerned that her daughters, both in their 20s, might mistakenly believe that they are not at risk for carrying this mutation. The research team ultimately decided to protect the privacy of the research subject but continued to discuss with her the importance of giving truthful results to her children to ensure that they pursued recommended screening.
The handling of such cases would benefit from broader guidance and conceptual analysis. To this end, we participated in an NHLBI working group to develop recommendations regarding if, when, and how genetic information related to the diagnosis, prognonsis, and treatment of specific diseases should be reported to study participants (Bookman et al. 2006). The group concluded that results should be reported when the associated risk for the disease is significant, the disease has important health implications (e.g., premature death or substantial morbidity), and proven therapeutic or preventive interventions are available.
We proposed a similar but more nuanced approach in which the analytic validity and clinical utility of specific genetic research results determine whether they should be offered routinely (Ravitsky and Wilfond, 2006). This analysis took into account the personal meaning that individuals may attach to a result, as well as factors specific to each study such as an investigator's capacity for appropriate disclosure, subjects’ alternative access to the result, and subjects' relationship with investigators. Accordingly, the same research result may require different decisions regarding disclosure in different contexts.
Other members of the Department offered an alternative perspective about returning research results, arguing that the obligation to respect research participants requires researchers to comply with requests for individual research results in most circumstances (Shalowitz and Miller 2005).
Family Recruitment: The Department undertook to examine attitudes of both probands and their family members regarding different approaches to recruitment by surveying people who had participated in the Colon Cancer Risk Counseling (CCRC) study, including both probands and their first-degree relatives. A majority of respondents indicated that they would mind if their names were given to researchers by their family members or doctors without their permission, although most would grant their permission if asked. Respondents also were least willing to give out their relatives' names to a researcher without first asking permission, preferring instead approaches that involved their own initial contact with their relatives.
Impact of Research:
Newborn Screening: As a result of these analyses, we have been asked to speak before state health departments that are considering expanding newborn screening. We participated in a workshop sponsored by the CDC on CF newborn screening that wrote a balanced report about this issue. We have also participated in a Cystic Fibrosis Foundation workshop that offered policy recommendations that were influenced by these analyses. This projects has implications beyond newborn screening and the issues that have been raised, including being clear and realistic about the potential benefits, minimizing risks, and gathering empirical evidence will be important as new genetic tests are developed for pharmacogenomics and for “personalized medicine”.
Current and Future Initiatives:
Newborn Screening: We are currently working an analysis of the ethical and health services implications of offering newborn screening and carrier testing for the same condition. There is only prenatal diagnosis for Tay-Sachs disease and only newborn screening for PKU. Yet for Sickle Cell and Cystic Fibrosis, both programs are offered. Are such programs complementary or contradictory. This project will look at the goals both carrier screening and newborn screening programs and argues that it is necessary for policy makers to be explicit about the goals before they can assessed and prioritized with other pediatric services. We are also working an a manuscript based on a empirical study of obstetricians practices about CF carrier testing that compares practices between states with and without newborn screening. This paper suggests that there may be lower uptake of carrier testing in states with newborn screening.
Providing Research Results: Members of the Department are involved in an ELSI-funded project at the University of Minnesota that seeks to examine unanticipated research findings.
Publications:
Newborn Screening
The Role of Empirical Research in Newborn Policy Development
Wilfond BS, Thomson E. Models of public health genetic policy development in Khoury MJ, Burke W, and Thomson E, eds Genetics and Public Health in the 21st Century: Using genetic information to improve health and prevent disease. Oxford University Press, New York, NY. 2000:61-81.
Freund CL, Clayton EW, Wilfond BS. Natural Settings Trials: Improving the introduction of new clinical genetic tests. Journal of Law Medicine and Ethics. 2004;32:106-110.
Taylor H, Wilfond B. Ethical Issues in Newborn Screening Research: Lessons from the Wisconsin Cystic Fibrosis Trial. J Peds. 2004;145:292-6.
Cystic Fibrosis Newborn Screening: Balancing Benefits and Risks
Wilfond B, Rothenberg LS. Ethical issues in cystic fibrosis newborn screening: from data to public policy. Curr Op Pulm Med. 2002;8:529-534.
Wilfond BS, Gollust SE. Policy issues for expanding newborn screening programs: The cystic fibrosis newborn screening experience in the United States. J Peds. 2005;46:668-74.
Wilfond BS, Parad RB, Fost N. Balancing benefits and risks for cystic fibrosis newborn screening: Implications for policy decisions. J Peds. 2005;147(3S):S109-S113.
Policy Approaches for Expanded Newborn Screening
Grosse SD, Boyle CA, Kenneson A, Khoury MJ, Wilfond BS. From Public Health Emergency to Public Health Service: The Implications of Evolving Criteria for Newborn Screening Panels. Pediatrics. 2006;117:923-9.
Botkin JR, Clayton EW, Fost, NC, Burke W, Murray TH, Baily MA, Wilfond BS, Berg A, Ross L. Newborn Screening Technology: Proceed with Caution. Pediatrics. 2006;17:1793-1799.
Participation in Agency/Organizational Statements Regarding Newborn Screening
American Academy of Pediatrics, Newborn ScreeningTaskforce. Newborn Screening: A Blueprint for the Future. Pediatrics. 2000; 106:389-427.
American Thoracic Society/European Respiratory Society Statement: Standards for the Diagnosis and Management of Individuals with Alpha-1 Antitrypsin Deficiency. Am J Respir Crit Care Med. 2003;168:818-900.
Grosse SD, Boyle CA, Botkin JR, Comeau AM, Kharrazi M, Rosenfeld M, Wilfond BS. (CDC Workshop Writing Group) Newborn Screening for Cystic Fibrosis: Evaluation of Benefits and Risks and Recommendations for State Newborn Screening Programs. MMWR. 2004;53(RR-13):1-35.
Providing Research Results
Ravitsky V, Wilfond BW. Disclosing Individual Genetic Results to Research Participants. AJOB. 2006. (In press)
Bookman EB, Langehorne AA, Eckfeldt JH, Glass KC, Jarvik GP, Glag M, Koski G, Motulsky A, Wilfond BW, Manolio TA, Fabsitz RR, Luepker RV. Reporting genetic results in research studies: summary and recommendations of an NHLBI working group. American Journal of Medical Genetics. 2006;140(10):1033-40.
Loud JT, Weissman NE, Peters JA, Giusti RM, Wilfond BS, Burke W, Greene MH. Deliberate Deceit of Family Members: A Challenge to Providers of Clinical Genetic Services. Journal of Clinical Oncology. 2006;24(10):1643-1646.
Shalowitz DI, Miller FG. Disclosing Individual Results of Clinical Research: Implications of Respect for Participants. JAMA. 2005;294(6):737-740.
Hedenfalk I, Duggan D, Chen Y, Radmacher M, Bittner M, Simon R, Meltzer P, Gusterson B, Esteller M, Raffeld M, Yakhini Z, Ben-Dor A, Dougherty E, Kononen J, Bubendorf L, Fehrle W, Pittaluga D, Gruvberger S, Loman N, Johannsson O, Olsson H, Wilfond B, Gauter G, Kallioniemi, Borg A, Trent J. Gene-Expression Profiles in Hereditary Breast Cancer. New England Journal of Medicine. 2001;344(8):539-548.
Recruitment of Family Members
Hull SC, Glanz K, Steffen A, Wilfond BS. Recruitment Approaches for Family Studies: Attitudes of Index Patients and Their Relatives. IRB. 2004;26(4):12-18.
