Development of the study protocol necessitated numerous procedural decisions regarding return of results to participants. Over the course of several months, our multidisciplinary team of investigators met to consider various options for disclosure and to craft a protocol that would offer genetic test results and assess their impact on participants. In this section, we provide a detailed review of the process we underwent in developing and implementing the study protocol. presents the study flowchart.
We provide an overview of the parent study from which results were derived, describe our justification for the decision to offer results to participants, and discuss the various challenges and decisions faced when designing and enacting study procedures. Although a detailed description of study results will appear in a separate and forthcoming paper, we provide some preliminary results as they pertain to topics addressed in our protocol.
Overview of Parent Study
Participants were originally enrolled as part of the Genes, Environment and Melanoma (GEM) Study, an international population-based study to improve the understanding of genetic susceptibility to melanoma, a type of skin cancer. Methodological details of the GEM Study are extensively described elsewhere (Begg et al., 2005
). In brief, the GEM Study utilized a case-control design to identify rare but highly penetrant disease-causing variants by defining controls as individuals with a first invasive primary melanoma and cases as those diagnosed with a second or higher order invasive or in situ
melanoma (Begg et al., 2006
). A main study aim was to estimate the relative risk of CDKN2A
mutations in the general population (Berwick et al., 2006
). Coordinated at the Memorial Sloan-Kettering Cancer Center (MSKCC), the GEM Study population consisted of incident cases of melanoma identified through cancer registries in New South Wales (Australia); Tasmania (Australia); British Columbia (Canada); Ontario (Canada); Turin (Italy); California (USA); New Jersey (USA); and North Carolina (USA). It also included incident cases of melanoma identified at the University of Michigan Comprehensive Cancer Center (UMCCC), which evaluates approximately 50% of the melanomas diagnosed in the state of Michigan. This Michigan population provided participants for our study.
All GEM participants at the Michigan site had a melanoma identified between January 1, 2000 and August 31, 2003. Participants provided either blood samples or buccal swabs for DNA analysis. GEM participants also completed a comprehensive phone interview and written questionnaire on melanoma risk factors. The individual research results of interest were genotypes of the cyclin-dependent kinase inhibitor type 2A (CDKN2A), in which mutations were hypothesized to be risk factors for melanoma, as well as pancreatic cancer in some cohorts. The senior author of this paper (SBG) served as the Principal Investigator of the study site for the entirety of the GEM project.
Decision to Disclose CDKN2A Genotype Status
Communicating requested individual research results is typically appropriate as long as (a) the significance of results (or lack thereof) is communicated accurately and understandably, and (b) disclosure poses no significant known harms, including the compromising of a participant’s or third party’s safety, or the study’s scientific validity (Shalowitz & Miller, 2005
). We considered our results analytically valid; that is, we believed the GEM Study’s genetic testing procedures were sufficiently rigorous such that research results could be trusted as the participant’s actual genotype. Furthermore, we considered our results to be clinically valid, in that the association of CDKN2A
with increased incidence of melanoma is supported by a substantial body of literature published since the completion of the GEM Study (Udayakumar & Tsao, 2009
), and the relative risk for a subsequent melanoma among GEM Study participants has been calculated at approximately 4.3 (95% CI: 2.3–7.7) (Berwick et al., 2006
Many commentators also recommend that communicated individual research results have clinical utility for participants. The scope of this utility is much debated, however, with some referring only to medically actionable information, and others incorporating a broader range of meaningful information, including any data relevant to reproductive decision-making or career or financial plans, as in the case of late-onset disease (National Bioethics Advisory Commission, 1999
; Ravitsky & Wilfond, 2006
). For the GEM population, individual and aggregate results were of uncertain clinical significance. All participants had already been advised by their physician to undergo periodic skin surveillance and avoid sun exposure as part of their melanoma follow-up. Although the presence of a CDKN2A
mutation is associated with increased risk of a new primary or recurrent melanoma, recommended prevention and surveillance strategies would not change for this group. Nevertheless, knowledge of increased risk could conceivably affect risk behaviors (e.g., avoidance of sun exposure) or individualized screening strategies to be determined by participants and their primary physicians. Knowledge of genetic status could also potentially affect participants’ life decisions beyond medical care and prompt the notification of blood relatives who might also be at risk. We could not prospectively assess the extent to which CDKN2A
results would have personal meaning to GEM participants; however, offering
individual results allowed participants to make their own judgments.
The GEM Study informed consent document indicated that participants would not receive individual test results, although they could obtain a summary of aggregate study results upon request. Some investigators may believe they are bound to the disclosure policy stipulated in the parent study’s informed consent document. However, the presence of such a statement does not necessarily preclude investigators from offering individual results if it becomes clear that access to such information is ethically justifiable (Banks, 2000
; Emanuel, Wendler, & Grady, 2000
). While recognizing that there were some reasons not
to disclose CDKN2A
results, our approach was to offer access to these results via participation in a separate research protocol to which participants affirmatively consented. We therefore provided individual CDKN2A
genotype results to a subsample of GEM Study participants as part of a research protocol approved by the Institutional Review Board of the University of Michigan Medical School.
Format for Disclosing Results
The standard of care in clinical practice for disclosure of genetic test results is an in-person session with a certified genetic counselor or other clinical genetics specialist. However, it is unclear whether disclosure of genetic research results would necessarily have to be communicated per usual clinical protocol. Given that traditional genetic counseling procedures for adult-onset disorders (e.g., Huntington disease) are time-intensive and that there are limited numbers of genetic counselors, there has been a move in clinical research to develop more feasible models of genetic education and counseling (Schwartz et al., 2005
). For example, ancillary education tools (e.g., CD-ROM) have been shown to reduce face-to-face time with clinicians in genetic counseling for hereditary breast and ovarian cancer (Wang et al., 2005
), and telephone disclosure protocols have also shown comparable safety and efficacy in this context (Baumanis et al., 2009
; Klemp et al., 2005
Furthermore, there is evidence that many research participants would prefer to receive research results via written communication rather than in person (Shalowitz & Miller, 2008
). However, there are very few data specifically addressing the preferences of participants to receive individual genetic
results. One study found that participants in this situation are “relatively open with regard to how they would prefer to be recontacted” (Ormond et al., 2004
). Another study suggested that people considering genetic testing are more likely to decline the service if offered in only one format (e.g., telephone vs. in person) rather than having a choice (Sangha, Dircks, & Langlois, 2003
). We allowed interested participants to choose whether they would receive their results by telephone or via an in-person session at the Cancer Genetics Clinic of the University of Michigan. Providing this option was reinforced by the large catchment area of the study, as 36% of identified recruits lived 75 miles or more from our site. In either format, a certified genetic counselor with cancer genetics experience would deliver the information and related counseling and education. Ultimately, all participants in our study opted for results disclosure by telephone.
Decision on Retesting of Research Samples
U.S. investigators and research administrators may be concerned that the Clinical Laboratory Improvement Amendments of 1988 (CLIA) prevents disclosure of research results if the data were obtained in a research laboratory that is not CLIA certified. Whether retesting of research samples in a CLIA-certified laboratory is required before any
type of disclosure is an unsettled question of law. We contend that such retesting, while often preferable and required, is not necessarily mandated in all situations. CLIA delineates quality control standards for laboratories performing tests for the purpose of “providing information for the diagnosis, prevention, or treatment of any disease or impairment of, or the assessment of the health of, human beings,” thereby enhancing the analytic validity of clinical laboratory results (Centers for Medicare and Medicaid Services, 2003
). If the decision to communicate research results is because of their potential clinical significance, retesting should occur in a CLIA-certified laboratory (if the original research laboratory was not CLIA certified). If, however, results are communicated because of non-clinical value, such as personal meaning (or, in our case, because response to research results was what was being assessed in our study), CLIA certification is not necessarily required. Investigators should consider their potential responsibilities in communicating clinically significant individual results in developing study protocols and ensure appropriate laboratory quality standards are in place.
The Study Risks section of our informed consent document—mailed in the Announcement Mailing and reviewed with study personnel during the Recruitment Call—therefore read as follows: “There is an unknown risk regarding the accuracy of your test results. Because genetic testing in the GEM Study was performed for research purposes, your blood sample in that study was not examined at a laboratory regulated by the federal government through the Clinical Laboratory Improvement Amendments (CLIA). CLIA sets standards for laboratories performing clinical testing and ensures laboratories are achieving those standards. While we have no reason to believe your test results are incorrect, they were not obtained from a CLIA-approved lab, a process that would have been followed had the test been conducted as part of your health care. After the study is complete, you have the option of re-testing your sample at a CLIA-approved lab. This confirmation testing is optional, and you are under no obligation to have it performed. The cost of such testing would not be covered by the study but is covered by some insurance companies.” The letter to participants accompanying results disclosure read, “It is important to note that this testing was not completed in a lab certified for clinical use. You have the option of having CDKN2A
testing repeated in a clinical laboratory; this would cost about $3501
and may or may not be covered by your health insurance.” Specific CLIA-approved laboratories were not recommended to participants, but the genetic counselor was available to provide options for those interested. Participants who were found to be mutation carriers were subsequently notified that the costs of their resting could be lower given that retesting to confirm a mutation is typically less expensive than other types. Ultimately, none of our participants pursued retesting during the course of our three-month follow-up period, although one mutation carrier stated an intention to have retesting performed eventually.
Some experts have suggested higher rates of test errors (e.g., sample mix-ups) in research laboratories versus CLIA-approved ones, although we have not seen any published data documenting this discrepancy. Such concerns, while perhaps speculative in nature, are related both to potential false positive and negative results. We would not want participants to make subsequent decisions based on incorrect information, nor would we want them to be erroneously reassured by false negative results. In addition, retesting would enhance our genetic counselors’ confidence in the information we were providing. To address these concerns, we retested samples in a second research laboratory (not CLIA-certified) to gain an appreciation for the likelihood of discordant results in our sample. Three samples were not properly archived and could not be retested. Of the 36 samples retested, we did find one discordant result (3% rate of discordance), although this participant opted not to participate in our recontact protocol. This underscores the need for investigators to be mindful of the potential harms of discordant or otherwise inaccurate results.
Development of Education and Risk Communication Materials
Our planning discussions focused on: (1) the risk information to be disclosed; (2) how to communicate this information; and (3) recommendations, if any, regarding clinical follow-up. Unfortunately, the quantitative risk for melanoma conferred by a CDKN2A
mutation is unclear. Published penetrance estimates through age 80 for CDKN2A
mutations range as high as 67% (95% CI = 31% to 96%) (Bishop et al., 2002
). Researchers in the GEM Study estimated the risk for melanoma among CDKN2A
mutation carriers to be 28% through age 80 (95% CI: 18–40%) (Begg et al., 2005
). Further complicating matters was that these estimates describe risk for a first primary melanoma, whereas the relevant risk for GEM participants would be a recurrence of cancer or the development of a second or higher-order primary melanoma. We decided to combine the point estimates referenced above and counsel participants that CDKN2A
mutations confer a 30–65% risk for melanoma by age 80 and may also increase risk of a new primary melanoma. Although the large range of this estimate was unsatisfying, we believe it reflects the state of current knowledge and addresses the fact that mutations may confer varying levels of melanoma risk. Furthermore, we believed that skilled genetic counselors could help explain this estimate and its caveats. In addition, the cancer genetics literature suggests that test recipients often do not retain specific quantitative estimates but rather a qualitative understanding (i.e., “the gist”) of their risk (Julian-Reynier et al., 2003
A number of studies have also suggested an association between CDKN2A
mutations and pancreatic cancer, but this finding has not been consistently demonstrated among families with no family history of pancreatic cancer (Goldstein, 2004
). Our educational materials thus stated, “Some families with CDKN2A
mutations may also be at increased risk for other cancers, particularly pancreatic cancer. People who have a family history of melanoma and pancreatic cancer should talk with their doctors about whether or not additional screening tests are necessary.” To avoid prompting participants to seek invasive procedures for pancreatic cancer screening given weak evidence, our study clinician proactively discussed CDKN2A
and pancreatic cancer risk in the genetic counseling sessions only if participants had a family history of the condition. However, other participants who were concerned about pancreatic cancer risk were free to raise this issue with the genetic counselor.
We next turned our attention to conveying the information effectively. An educational brochure was developed based on protocols developed by Peshkin et al. (2008)
for telephone genetic counseling of women considering BRCA1/2
testing. The study’s genetic counselor (JNE) took the lead in developing brochure content, organized by: (1) risk factors for melanoma; (2) melanoma genes; (3) pros and cons of receiving genetic test results; (4) implications of CDKN2A
testing for cancer risk; (5) methods of reducing melanoma risk, and (6) resources for more information (the full brochure is provided as an online Appendix
). Risks were presented using words and numbers, supplemented by pictographic visual aids, which have proven efficacy in enhancing risk comprehension (see ) (Fagerlin et al., 2007
). A study genetic counselor reviewed these materials with participants in the genetic counseling session.
Sample Risk Communication Tool Used in Educational Materials.
Lastly, we felt it important not merely to provide risk information, but also to provide resources for reducing and coping with potential health threats. Because all participants were already melanoma survivors, we asked counselors to reinforce the importance of adhering to indicated melanoma screening and health behaviors. To enhance comprehension of the information provided, we also decided to mail each participant a summary of the main points of the education session. Finally, we provided genotype details to those participants who tested positive for a CDKN2A mutation, to facilitate subsequent confirmatory testing, or sharing with a medical professional or family member.
Identification and Notification of Potential Participants
Our eligible study population consisted of 663 GEM Study participants at its University of Michigan site, seven of whom had identified CDKN2A mutations. We selectively recruited all participants with known CDKN2A mutations due to the potential clinical and personal utility of knowing their carrier status. However, we did not have the resources to enroll all mutation-negative participants into our study. CDKN2A mutation carriers were first identified and matched per GEM Study records by sex, ethnicity, and age (+/− 4 years) with non-carriers. We attempted to enroll three non-carriers to each carrier through sampling with replacement. GEM participants who had indicated they were not interested in taking part in follow-up studies were excluded from consideration. Given time and budget limitations, we ultimately attempted to enroll 32 mutation-free individuals.
As mentioned earlier, the original GEM Study protocol was not designed to offer participants the individual results of their genotyping. As a result, there were several obstacles to enrolling GEM participants in our protocol. First, while some contact had been maintained between participants and investigators through clinical visits and a study newsletter, most participants had not been seen or contacted in years. In many cases, this required updating contact information through review of existing clinical records. In addition, the clinical course of melanoma is severe enough that we felt obligated to screen the medical records of potential participants to identify any who had died since their GEM Study participation; we thereby avoided the potential distress involved in contacting family members of the deceased. Ultimately, we attempted to reach 39 participants overall, but we could not establish contact with ten of these.
Potential participants were informed of a new study regarding communication of research results via a mailing sent from the Michigan site PI of the GEM Study (SBG). The mailing stated that much had been learned about melanoma genetics since their initial enrollment, and that a new study was being conducted to learn whether participants were interested in learning more about melanoma genetic information, including the possibility of learning their individual genetic information. Potential participants were provided the opportunity to decline participation in the study. Those who did not opt out were telephoned by the study coordinator for enrollment after review of the study’s goals and a consent document included in the initial mailing. A second packet of materials was then mailed to interested participants including information about CDKN2A genotype and its implications for cancer risks. Participants were contacted via telephone by genetic counselors to schedule an in-person or telephone genetic counseling session, to review the mailed information, and to discuss any concerns they may have had about the implications of CDKN2A genotyping. Participants were then given a choice as to whether or not to receive their genotype and corresponding risk information, thus satisfying the participant’s right not to know information that they might deem burdensome or otherwise unwelcome. The genetic research result was disclosed either during the same call or a subsequent session, according to the participants’ preferences.
Assessing the Impact of Disclosure
Little is currently known about the impact of communicating the results of genetic testing for melanoma risk. Available studies suggest that (1) uptake of an offer of testing is high, (2) communication of genetic testing results does not change behaviors related to surveillance, and (3) receipt of results does not cause significant emotional distress (Bergenmar, Hansson, & Brandberg, 2009
; de Snoo et al., 2008
). Although consistent with the broader literature on communication of research results (Shalowitz & Miller, 2008
), these studies are extremely small and methodologically limited.
We therefore sought to compile measures that would be useful to other researchers interested in assessing the impact and costs of returning individual genetic research results. We were aided in this process by one of the authors’ (JSR) experience with assessing the psychological and behavioral effects of genetic susceptibility testing (Green et al., 2009
; Roberts et al., 2005
). Based on existing literature on communication of research results, we were most interested in assessing: (1) psychological impact, (2) recall and comprehension of risk information, (3) perceptions of personal utility and attitudes towards being recontacted, and (4) cost to investigators of implementing disclosure protocols (see for a summary of measures). We plan to publish results from these measures in a forthcoming paper.
One concern about disclosing genetic research results for a serious condition such as cancer is that the information may induce psychological harms. We therefore assessed the psychological impact of receiving individual research results using three validated measures. First, we used a brief 5-item tool to measure general depression and anxiety symptoms (D. M. Berwick et al., 1991
); while more comprehensive measures are available, we chose this instrument both to reduce respondent burden and because prior related work on the impact of genetic testing had not suggested significant adverse psychological effects in response to risk information (Butow et al., 2003
; Douma et al., 2008
). Second, to differentiate the emotional effects of results disclosure in particular from more general distress or worry, we used a measure of event-related distress (Horowitz, Wilner, & Alvarez, 1979
), as well as a validated measure that assesses the emotional impact of cancer risk assessment in particular (Cella et al., 2002
Another concern about disclosure of research results is that participants may not fully understand their meaning, with misconceptions potentially leading to undue concerns, false reassurance about risk status, or regrettable decisions. Recall and comprehension of results disclosed were therefore assessed using measures developed as part of the aforementioned REVEAL Study (Roberts et al., 2005
). Recall was assessed by asking participants to report both their genetic test results and the numerical melanoma risk estimate provided. Comprehension was assessed by asking participants to (1) rate their risk of developing another melanoma compared to the general population and persons with a family history of melanoma, and (2) list possible options for risk reduction and screening.
We also assessed potential benefits of receiving research information. For example, we assessed perceptions of personal utility and attitudes towards being recontacted. For example, participants were asked to indicate agreement with statements such as “genetic testing for melanoma risk should be offered to everyone” and rate the usefulness of the information, explanation, and consultation provided in the study. We additionally asked participants to report changes, if any, in screening and protective behaviors (e.g., skin self-exams; use of sunblock) and to indicate whether they had shared their results with family members or health professionals.
Finally, investigators may not have the capacities in terms of personnel, resources, or finances to implement disclosure protocols even if they are inclined to do so. We therefore assessed the costs associated with returning results by tracking the monetary costs to develop each component of the intervention, including creation and printing of educational and mailing materials, costs of retesting samples, and the fees associated with utilized clinical space. Opportunity costs were also tracked by recording the time needed to complete each component of the protocol, including notification, informed consent, education, and results disclosure.
We recognize that our approach to assessment is not without limitations and that our follow-up period (three months) may not allow us to capture all meaningful responses to research results, such as health behavior changes. Nevertheless, we believe that a systematic approach to assessing the impact of returning individual research results will help answer key questions regarding benefits, harms, and feasibility.