key: cord-0009554-t892pi75
authors: Waltz, Margaret; Meagher, Karen M; Henderson, Gail E; Goddard, Katrina AB; Muessig, Kristin; Berg, Jonathan S; Weck, Karen E; Cadigan, R Jean
title: Assessing the implications of positive genomic screening results
date: 2020-03-03
journal: nan
DOI: 10.2217/pme-2019-0067
sha: 9405881300d700380f74e152a7bb33a02201e838
doc_id: 9554
cord_uid: t892pi75

AIM: Before population screening of ‘healthy’ individuals is widely adopted, it is important to consider the harms and benefits of receiving positive results and how harms and benefits may differ by age. SUBJECTS & METHODS: Participants in a preventive genomic screening study were screened for 17 genes associated with 11 conditions. We interviewed 11 participants who received positive results. RESULTS: Interviewees expressed little concern about their positive results in light of their older age, the risk condition for which they tested positive, or other pressing health concerns. CONCLUSION: Researchers and clinicians should recognize that returning positive results may not have the impact they presume given the diversity of the conditions screened and those who choose to undergo screening.

As genomic technology advances, population screening of healthy individuals for pathogenic variants associated with medically actionable conditions is becoming more feasible [1] [2] [3] [4] [5] [6] . Before the screening of 'healthy' individuals is widely adopted, the potential harms and benefits need to be assessed [7] . One important programmatic and scientific question is whether to target screening toward certain age groups, and/or to include an upper age limit on population screening programs since the benefits and harms of screening may not be consistent throughout the lifespan [4, 8] . Reducing morbidity and mortality risks and increasing lifespan may not be realized to the same degree among older individuals because of competing causes of death [8, 9] . Risks of recommended interventions for those who screen positive may differ, such as increased risk for perforation of the colon during colonoscopy among individuals over 75 [10, 11] . However, risks for insurance or employment discrimination may lessen for individuals over 65 who are more likely to be retired and are eligible for Medicare [12] . Likewise, older participants may perceive less personal benefit from learning genomic information, while perceiving greater familial benefit since children or grandchildren could gain from cascade testing [4, 13, 14] .

We examine the issue of older age as it relates to the potential harms and benefits of screening through a preventive genomic study, GeneScreen, in which 262 adults across a broad age range received screening for 17 genes related to 11 diverse, medically actionable conditions [2, 15] , ranging from cancer syndromes (e.g., hereditary breast and ovarian cancer, Lynch syndrome) to cardiovascular conditions (e.g., long QT, familial hypercholesterolemia). Previously, we examined participants' perceptions of age eligibility criteria prior to receiving screening results [9] and found that participants of all ages perceived the same benefits of screening, including the potential for prevention and treatment, gaining peace of mind, sharing information with family, advancing science/research and helping others. Those who noted risks, including worry and discrimination, did not differ by age. Here, we report on the reactions of participants in GeneScreen who received positive results. 

Most interviewees expressed little concern about their positive genomic screening results. One reason for this was age. As depicted in Table 2 , this was an older group of individuals whose mean age was 64, reflecting the average age of the GeneScreen participants, which was 60. Those in their 60s and 70s noted that they would have worried more about the results if they were younger. For instance, when a participant with a positive result indicating a possible increased risk of long QT syndrome was asked if the result had changed anything in her routine, she replied, "Well, I'm 74 so, you know, it's not like I was 20 and found out about this and worried about would I be able to live long enough to have children or not" (Participant 10). Older participants also reasoned that symptoms would have already appeared if they were going to develop. For example, someone with a positive result indicating increased risk of hemochromatosis said he was not worried about his result since he is "already 63 and [has] never experienced a problem with it" (Participant 8). For these reasons, older participants noted that the results were more helpful to their families than to themselves. Another reason interviewees expressed little concern about their positive genomic screening results was the type of condition. As shown in Table 1 , half the participants tested positive for genetic variants in the HFE gene associated with increased risk of hemochromatosis, arguably the most benign condition on the panel and the one with the lowest penetrance. The 63 year old mentioned above stated that "if you have to have [a genetic anomaly], this seems to be a pretty good one to have. It's not a high-risk problem" (Participant 8). The type of result, along with his age, made him less concerned. Others with hemochromatosis genomic screening results were dealing with more pressing health concerns, including one woman recently diagnosed with breast cancer (Participant 5).

For some, the result was not a surprise. Three people who were interviewed already knew their results from previous genetic testing, tempering concern about their result. One 60 year old with a BRCA2 result said she threw out the result report since she already knew the information (Participant 1). Two participants received HFE hemochromatosis results for a second time. One, a 76 year old, said she was relieved she did not screen positive for genes related to cancer (Participant 4). The other, a 77 year old, said he tends to forget about his risk of hemochromatosis, so the result made him 'more aware of it again' (Participant 3). He planned to talk to his primary care physician about follow-up care, but when asked if the result would change any future plans, he commented, "No, I'm going to be 78 and, at this age, there are so many other things that could go wrong." This again highlights the role of older age in interpretation of the significance of results, especially for conditions in which the penetrance or risk of developing clinical disease is very low.

Decisions & changes since receiving the results During their first interview, most reported following up with their physicians after receiving their results. Importantly, they all had health insurance. By the second interview, most reported that their lives had not changed much.

For example, during her first interview, the 74 year old with a possible increased risk of long QT (Participant 10) reported she had followed her physician's recommendation that she stop taking two medications and have an electrocardiogram, the results of which were normal. In the second interview, she said that knowing about the positive genomic result was not terribly helpful and that her doctor did not even mention long QT at her recent appointment, reinforcing her belief that the positive result was not particularly important. The 63 year old with increased risk of hemochromatosis (Participant 8) said at the first interview that he had an iron panel done and will continue to have one every few years, per physician recommendation. In his second interview, he said he will keep up with the iron tests but that the results did not weigh on his mind because he had other health concerns, including Type II diabetes and a history of cancer. Finally, a 47 year old who had RYR1 variants indicating possible risk of malignant hyperthermia (Participant 14) said he was going to get a medical ID bracelet at his first interview. At the second interview, he had not yet gotten the bracelet and reported that the result is not something he worries about.

For those who did not previously know their results, they had not yet developed signs or symptoms, nor did the results explain any symptoms that previously had no identified cause. One exception was an individual (Participant 13) who received a positive result for a pathogenic variant in the RET gene associated with multiple endocrine neoplasia type 2A. Even though she had no symptoms, the management of her case included prophylactic thyroid surgery due to a positive family history.

During the first interview, most recipients of positive results discussed intentions to tell family members about their result and recommend genetic testing. Several participants had already told family members at the time of the first interview. By the second interview, four participants said they did not think any family members had pursued testing. Three participants reported that at least one first degree relative was tested.

In the context of returning medically actionable genomic results to research participants, especially anticipating the translational potential in population screening, these findings support continued attention to how older age frames participant perceptions of its relative harms and benefits. These findings also point to challenges when an array of conditions is screened for together.

These results provide evidence supporting the likelihood that voluntary programs without an upper age limit will include interested older adults [9] who will interpret the implications of their positive genetic findings through the lens of age. Given that the average age for all participants was 60, it is not surprising that those who received positive results were also older. Their assessments generally reflect a relatively low level of concern. This aligns with prior research that learning positive genetic results does not lead to significant psychological harm [21] [22] [23] . Additionally, revelations of genetic risk later in life are less worrisome, in part because much time has passed without any development of symptoms. The two participants with increased risk of long QT syndrome acknowledged that learning about this at a younger age could have yielded beneficial early interventions. At the same time, our older participants' absence of any long QT arrhythmia symptoms, despite having a positive result, is exemplary of the concern that population genomic screening could lead to overdiagnosis and unnecessary monitoring or interventions [24, 25] .

The study also revealed the difficulty of assessing harms and benefits of genetic screening for a diverse panel of 11 medically actionable conditions. For instance, the implications of receiving a long QT positive risk result are different at age 70 than at age 20, and are different than receiving a hemochromatosis risk result at any age. Diverse conditions on a panel (or, moreover, in genome sequencing) can also temper participants' interpretation of and reaction to their results, as evidenced by a participant who noted his positive hemochromatosis risk result was relatively 'good' in comparison to other results he could have received. In addition, participants' current and past health status mattered. Some recipients of positive results were dealing with health conditions they deemed of great urgency or import. Other participants already knew about their positive results, making the other negative results from the panel potentially more meaningful than the positive results. These findings remind us that context matters in how people respond to receiving screening results, and that in population screening programs, the information people already know when they undergo the screening cannot be controlled.

Arguably, the biggest potential benefit of population genomic screening of the sort anticipated by GeneScreen is the prevention or early treatment of disease in those with positive results. Thus, adherence to recommended follow-up care is crucial. Most people we interviewed did pursue some or all of the care recommended to them by the time of their first interview, including iron tests for those with hemochromatosis risk results and EKGs future science group www.futuremedicine.com for those with long QT risk. However, by the second interview, almost no one had done anything further. This may have been consistent with clinical recommendations within 8 weeks of result receipt; that is, initial test results may have indicated that no further testing was needed. However, it is also possible that the importance of the result and interest in follow-up care faded for both participants and providers, given the type of result received or the lack of symptoms. Results from prior research on the relationship between receipt of genetic test results and adherence to prevention behavior has been mixed. Some studies show an increase in adherence [22, 26] . Others report that screening results have little impact on prevention behavior [27, 28] , including a study examining followup care-seeking behavior among asymptomatic individuals after receiving positive genetic results through direct to consumer testing [29] . Our study further reveals the complexity of predicting behavioral responses to genetic screening results over time when considering the age of those screened and the type of conditions included on the panel. We found initial interest or intent to act upon the result, but further research is needed on the potential disconnect between these temporal motivations and subsequent healthcare utilization within genomic screening contexts.

Another frequently cited benefit of genetic testing, in terms of both population health and cost-effectiveness, is the identification of at-risk family members through cascade testing [30] [31] [32] . In fact, many people who joined GeneScreen, especially older participants, cited this benefit as a reason to join [9] . Our interviews with people who received positive results reveal a mixed picture regarding family testing. Telling family members and encouraging them to be tested was mentioned by many in the first interview, but by the second interview, less than half reported that family members had been tested. Other studies have found that while rates of informing relatives of results may be quite high [33] , rates of cascade testing for eligible first-degree relatives are quite low [34, 35] . What is unclear, however, is whether low rates of cascade testing can be attributed to educational difficulties (e.g., probands who had the benefit of speaking with a genetic counselor about their results may struggle with communicating genetic information to relatives); lack of resources to make testing for family members easily accessible; the nature of the specific finding (e.g., dominant hereditary cancer risk vs recessive hereditary hemochromatosis); or some other combination of factors. Although efforts to implement precision prevention through genetic testing gain momentum, it is important to identify best practices in reaching family members to make testing efforts effective for both cost and health outcomes.

These findings are limited in their generalizability due to the small sample size and the older age of participants. Furthermore, not all participants with positive results agreed to be interviewed, including the two participants who received familial hypercholesterolemia results. Additionally, because this is a research project, these findings cannot be directly equated with clinical population screening. For all these reasons, it is likely that more themes will be revealed in future research about positive genomic screening results, particularly in terms of how participants react to results for conditions not examined in the current study and how younger people interpret the utility of positive results. Given the limited racial and ethnic diversity of the sample, it is also important to continue to investigate these issues in diverse populations as reactions to results can vary by race and ethnicity [36] . Future research should also focus on how people who receive positive results feel about prior decisions to have their results submitted to genetic databases, like dbGaP, and whether a decision to have post-test counseling in person or by phone impacts patients' decisions or follow-up care.

When considering population screening, researchers and clinicians should recognize that receipt of positive results may not have the impact that they presume. Individuals may already know their positive results and be more interested in the negative results also offered by more extensive tests. In fact, it is quite possible that people who have previously received a positive genetic result may be more interested in pursuing other opportunities, such as panel screening or genome sequencing. And age may impact responses to results, as older individuals may perceive themselves to be less at risk of developing the condition than younger individuals. Coupled with the diversity of conditions for which people will potentially be screened, these issues complicate the assessment of harms and benefits of receiving positive results through population screening. of the version to be published, and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

The authors would like to thank J O'Daniel and M Roberts for their contributions to the manuscript. Many thanks also to those who participated in the GeneScreen study.

The support for this article was provided by the National Institutes of Health (NIH) Grant Numbers 2P50HG004488 and 2U01HG006487-05 (for M Waltz). The views expressed are those of the authors alone and do not necessarily reflect views of NIH. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

The authors have obtained appropriate institutional review board approval. Informed consent was obtained from all participants.

• Population screening of healthy individuals for pathogenic variants associated with medically actionable conditions is becoming more feasible, but the potential harms and benefits across a diverse range of ages need to be assessed before the screening of 'healthy' individuals is widely adopted. • We examine the issue of older age as it relates to the potential harms and benefits of screening through a preventive genomic study in which 262 adults across a broad age range received screening for 17 genes related to 11 diverse, medically actionable conditions. • In total, 11 of the 14 participants who screened positive were interviewed approximately 8 weeks after receiving their results and then 9 months after results. • Results reveal that most interviewees expressed little concern about their positive genomic screening results. For some, this was due to their older age, saying that symptoms probably would have appeared already if they were to develop and that the results may have been more helpful earlier in their life. Additionally, a few participants already knew about their positive result from prior genetic testing. Finally, approximately half of the participants screened positive for hemochromatosis and noted that, in comparison to cancer risk conditions, hemochromatosis was fairly innocuous. • Results reveal that initial interest or intent to act upon the positive result faded for most participants by the time of the second interview. By the second interview, less than half of the interviewees reported that family members had been tested for relevant genetic variants. • Older adults are interested in and participate in screening, and they interpret their positive results through the lens of age. • Diverse conditions on a panel complicate the assessment of harms and benefits of population screening, particularly across a diverse age range. • Receipt of results may not have the impact that clinicians and researchers anticipate.

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