Psychological reactions to predictive genetic testing for Huntington’s disease: A qualitative study

There is a lack of qualitative research investigating the experience of individuals at risk for Huntington's disease (HD) during the period prior to undergoing predictive testing, as well as their reaction to the test result. This secondary analysis study aimed to explore the experiences during the predictive testing process of individuals who had been or who were at risk for HD. For the primary study, in‐depth semi‐structured interviews were conducted, and data were analyzed using inductive thematic analysis. We employed the explorative qualitative design for this study, which involved 33 individuals who had been or who were at risk for HD. Results indicate that many had been anticipating the onset of the disease even before they knew their mutation status. Their choice of whether to get tested or not was influenced by personal, social, and practical factors. Whether the test result was positive or negative, coping with the test result was reported to be difficult. Participants with a mutation‐negative result felt a need for more follow‐up consultations than what they had received. Findings indicate that the decision to undergo predictive testing for HD was not only a personal choice, but was also influenced by both proximal and distant factors. Similar to individuals who tested positive for the mutation, individuals who tested negative for the mutation may need comprehensive follow‐up to adapt to the reality of the test result.

Predictive genetic testing is available to all adult individuals at risk of inheriting the mutation for HD. The Norwegian Biotechnology Act mandates the inclusion of genetic counseling as component of predictive genetic test. A predictive test for genetic disorders without prevention or treatment options can only be performed on individuals of 16 years or older. However, it has been recommended that those who are at least 18 years old may undergo the test (MacLeod et al., 2013).
In Norway, the HD test protocol applied in practice includes a pre-test genetic counseling, an evaluation by a healthcare professional with an expertise in psychology, a second genetic consultation with blood sampling, and a genetic consultation on the result, as recommended by the European Huntington's Disease Network (MacLeod et al., 2013). A follow-up consultation is automatically scheduled for those who tested positive for the HD mutation. Genetic consultation services are provided by a clinical geneticist and a genetic counselor, who thus play a key role in the predictive genetic testing process.
Studies indicate that more than 80% of those at risk for HD choose not to undergo a predictive genetic test, suggesting that arriving at a decision whether or not to get tested is quite complex (Baig et al., 2016). People's motivation to undergo predictive testing may include the need to eliminate uncertainty, to plan their life and career, and to determine the risk of their children (Ibisler et al., 2017). Individuals who decide to undergo predictive genetic testing may experience a range of psychologically challenging dilemmas prior to the test and after receiving the test result. Research shows that genetic testing indeed may have an adverse psychological impact on those at risk for HD (Crozier, Robertson, & Dale, 2015). Factors that may aggravate psychological distress among individuals who tested positive for the HD mutation include their inability to predict the onset of disease symptoms or the progression of their disease, as well as the fact that a cure for their disease is currently non-existent. Also, the disease can be stigmatizing for the affected individual and/or for his/her family (Crozier et al., 2015).
Many individuals have experienced stress and anxiety when they first learn that they carry the HD mutation (Gargiulo et al., 2009); such a test result has been shown to negatively impact one's life decisions, particularly their long-term plans (Broadstock, Michie, & Marteau, 2000;Gong, Fanos, Korty, Siskind, & Hanson-Kahn, 2016).
Interestingly, some individuals describe positive changes after learning that they have the HD mutation; for instance, they become more purposeful toward their future, and therefore, they reach milestones early, and they make active choices for their future in terms of education, career, romantic relationships, and family planning (Gong et al., 2016). Ambivalent or mixed emotional reactions have been reported both by individuals who tested positive and by those who tested negative for HD mutation. Studies show that the mental health and quality of life of those who have and those who do not have the mutation do not significantly differ (Crozier et al., 2015;Licklederer, Wolff, & Barth, 2008). Clinical experience and some studies suggest that prior to getting tested, some people may have spent years believing and living as if they had the mutation; therefore, they may experience a struggle adapting to a future not having the disease (Mand, Gillam, Duncan, & Delatycki, 2013). Accepting the choices they made based on the perceived certainty of developing HD in the future may therefore constitute an emotional burden. Some people may also experience ambivalence over their own status as being not at risk for developing HD; they are relieved and happy that they cannot pass the mutation on but worried at the same time knowing that other family members may be at risk or have developed HD (Codori & Brandt, 1994).

| Purpose of the study
Indications of complex psychological challenges affecting individuals at risk for HD both prior to and after genetic testing suggest the need for in-depth knowledge about the experiences of these individuals before they decide to get tested; also, knowledge about their reaction to the test result is warranted. Most studies exploring this subject have investigated participants receiving genetic counseling services, that is, those who have already undergone genetic testing; by contrast, the experiences and personal choices of those who have not yet received genetic counseling are less investigated.
Consequently, the reasons affecting one's decision to either get tested or not for HD mutation and the impact of the test results on one's life remain largely unknown. There is a lack of knowledge about how people at risk for HD perceive and/or consider undergoing genetic testing and also which psychological and socio-ecological factors affect their perception of this process. Also, there is a lack of qualitative research investigating the psychological and emotional impacts of the test results in individuals with the HD mutation and in those who do not have the mutation. Therefore, this study aimed to explore the experiences of the predictive genetic testing decisionmaking process in a diverse population of individuals who are or have been at risk of HD.

| Design
Data were extracted from a primary study involving a larger dataset collected through semi-structured interviews; the primary study is a component of a concurring project that investigates childhood experiences in families affected by HD (Kjoelaas, Tillerås, & Feragen, 2020). Given the focus of the original study, inheritance and predictive genetic testing were not covered in the interview guide.
However, all participants shared substantial thoughts on these topics during the interviews; therefore, the interviewers asked them to elaborate their thoughts on these topics. Considering the importance of these topics to the participants, we decided to perform a secondary data analysis (Thorne, 1994). Data were extracted from the original dataset and then qualitatively analyzed separately.

| Study sample and recruitment
By using the convenience and snowball sampling methods, we recruited participants through the National Association for Huntington's Disease in Norway, through the counselors at a National Resource Center for HD in Norway, through the departments of medical genetics in Norway, and through the Internet (websites and social media). To be included, prospective participants should be a member of a family where one of the parents had/has HD (original study), speak Norwegian, and be at least 12 years old. Individuals with communication skills or cognitive function indicative of difficulties in providing informed consent for participating in in-depth interviews were not eligible to participate in the study.
Ethical approval for this study was obtained from the Regional Committee for Medical Research Ethics (Health Region South-East;

Reference No. 2017/1613).
An information sheet about the study and a consent form were sent by post to those who expressed their interest to participate. The information sheet provided details about what their participation in the study would entail, as well as key ethical information, such as confidentiality and their right to withdraw. A total of 42 individuals consented to participate. However, six individuals were eventually excluded as they could not be reached for a discussion on matters regarding interview schedule, leaving us with a sample consisting of 36 participants. Moreover, three individuals were tested prenatally and were also excluded, further reducing the sample size to 33 individuals. Of these, 19 participants had undergone testing, had shared post-test narratives of the test process, and had described their reactions to the test result and to the follow-up they had received.
The demographic characteristics of the participants are presented in Table 1.

| Data collection
An interview guide based on relevant literature and based on feedback coming from clinical experts was created for the primary study. The participants were asked open-ended questions and were prompted to provide more details whenever appropriate. The broad interview topics were as follows: childhood narrative and family situation, relationship to parents, level of understanding or lack of understanding of HD as a child, openness about the disease, and support experiences (interview guide in Norwegian available in Data S1). These interview topics and sample items from the interview guide in English are presented in Table 2. The interviews took place (12/17-09/18) and were conducted face to face or over the telephone by different interviewers who are all qualified and who have been trained in counseling and/or in qualitative methods. On average, the interviews lasted approximately 60 min (range: 27-90 min).
Given the sensitive nature of the research questions, all participants received a follow-up call within two weeks after the interview and were offered additional follow-up from trained professionals, as necessary. As described above, this study is part of a larger study that included a relatively large sample in order to achieve the project's objectives. Saturation was not used as a criterion to limit recruitment; nevertheless, we do feel that saturation was reached for the themes presented in this study.

| Data analysis
The interviews were recorded and transcribed verbatim. In the primary study, the interviews were conducted by several researchers, producing the report. The first author coded the material in tandem with authors KBF, SHK, and CvdL. The codes were organized under thematic headings. Analysis was seen as a recursive process, and detailed notes were written throughout. Themes were subsequently chosen for their prevalence and/or their apparent importance in relation to the research questions. The themes and the organization of results were discussed by three of the co-authors (KBF, SHK, and CvdL) until a consensus was reached. Themes and data extracts were reviewed by referring to the transcripts and to the research questions, and quotes that were representative of the themes were selected. Illustrative quotes were translated into English, and the participants were given pseudonyms.

| RE SULTS
Three main themes were identified, as follows: 'a life in preparation for disease' (Theme 1), 'factors influencing the test decision' (Theme 2), and 'the test result' (Theme 3). These themes and their corresponding subthemes are presented in Table 3.

| Theme 1: A life in preparation for disease
Regardless of the participants' decision of whether or not to undergo a genetic test to determine their mutation status and regardless of whether they tested positive or negative for the mutation, a substantial number of the participants said that they had lived in an anticipation of having inherited the disease. Being uncertain of whether they had the HD mutation, the participants consistently described their experience of having demanding thoughts, emotions, and perceptions, and they organized their life around the possibility or certainty of living with HD in the future.

| Thoughts, emotions, and perceptions prior to testing
Prior to deciding whether to get tested, several participants mentioned their struggle with negative thoughts arising from the possibility and/or from an anticipation of having inherited the disease.
Many admitted that they constantly think that they might develop the same symptoms as their parent, impacting their thoughts and emotions.

(Trevor, teenager, male, unknown mutation status)
For some participants, anticipating that they have inherited the disease created the feeling of powerlessness. Anxiety, depression, fear, and hopelessness were also apparent in their descriptions of their experience of uncertainty arising from the possibility of living with the disease in the future. The brutality of such thoughts was vividly described by one of the participants, who found a potentially positive test result to be similar to a death sentence.

Mutation-positive (N = 7)
Age-group (Jake, teenager, unknown mutation status) A few participants could not be tested because they were younger than 16 years old. One participant had a strong negative opinion about the age restriction for taking the pre-symptomatic genetic test; according to him, the inability to get tested increased his feelings of powerlessness.
'It's all out of my control. I am not even allowed to get tested'.

(Jake, teenager, unknown mutation status)
While the anticipation of inheriting the disease instigated a negative outlook in the life for many, some participants had chosen to focus on making the most of their lives in the present.
'I guess we just chose to leave it be, and live our lives'.

Main themes Subthemes
A life in preparation of disease

| Theme 2: Factors influencing the test decision
Apart from describing how their lives were influenced and organized in anticipation of having inherited the disease, the participants also talked about how they arrived at a decision whether or not to get tested for the mutation. The decision-making process was often experienced as complex, and it was influenced by several factors.

| Personal and social influences prior to testing
The participants talked about how other people's presumptions and opinions on whether they should get tested had annoyed them, had been difficult to manage, and had influenced their decisions. These people could be their friends, family members, potential romantic partners, and/or healthcare professionals. In some cases, the same questions and opinions come from several people. (…) That conversation was worth a lot to me'.

| Practical influences prior to testing
In addition to norms and opinions conveyed in social interactions, the participants' decision of whether or not to get tested was influenced by practical concerns and arrangements needed to make future plans. Hence, the decision was influenced by one's personal goals or marital goals more than by other people's opinion of the disease. Nevertheless, the decision-making process seemed intertwined with the norms and opinions conveyed by others.

| Theme 3: Test result
The participants who got tested and had received their test results described their experience of going through a range of psychological reactions and outcomes. Most of them talked about how they felt, how they perceived the consequences of the test result, how they will share and whether to share their test results with others, and how the follow-up they had received from healthcare services went.

| Handling the knowledge of disease
Most of the participants who had received a positive result (mutation positive) shared this outcome to be emotionally and psychologically difficult to handle. The test result had affected various aspects of their lives, and for some, learning that they had the mutation for HD led to powerful negative thoughts. One participant shared that her negative emotions were so overwhelming that it led to suicidal ideation.
'I considered suicide several times; I was devastated.
There was so much going on at once'.

(Klara, young adult female, mutation positive)
Another participant expressed that she felt concerned for her children, who were now at risk for HD. She shared feelings of fear and sadness, and admitted that she was even searching for symptoms in her children's behavior. She also expressed a wish for her son to get tested, with a hope for a negative result so that she would not have to worry about him anymore.
'My son keeps saying that he will get tested. Most of the participants who tested positive were pleased with the post-result follow-up consultations conducted by the providers of healthcare and support services.
'I have been very happy with the follow-up. I went to a couple of sessions with a psychologist, and that was beneficial, being able to talk to someone other than those at home'.

(Jenny, adult female, mutation positive)
A few participants also said that they coped with the difficult news by hoping for the development of a cure for their disease in the near future.
'When the disease develops, it might take some time before I become really sick, and by that time, there might be, probably, a cure, before I become really sick'.

| Handling the absence of the disease
The participants who received the result that they did not have the mutation also felt that the absence of the disease affected various aspects of their lives. Most of them experienced joy and relief, and they and/or their children felt as though they have been spared.
'I was so incredibly happy that my kids weren't going to experience the same insecurity that I did.

(Julie, adult female, mutation negative)
One participant who had received a follow-up had initiated this process herself; that is, she took the initiative of asking for a follow-up consultation. However, she felt that it was difficult having to be the one asking for support.
'I felt that I had to be the one to reach out to get further follow-up, and then it's just not that easy'.

(Louise, young adult female, mutation negative)
The participants also shared their need for social support after receiving their test result; such a need could not be addressed by the follow-up consultations offered by the providers of healthcare services.
One participant explicitly mentioned that peer support is important given that only a few people without a direct experience with HD could understand the magnitude and complexity of her situation.
'I wanted to talk to someone that was going through the same thing as I was. Someone who is not going to become sick, but who has a mother or father who is, and who has a sibling who might be affected too. I missed that'.

(Olivia, adult female, mutation negative)
Some participants said that they did not want to share their test result since they felt no one would really understand its personal importance and impact.

| D ISCUSS I ON
This qualitative study shows that predictive testing for HD is a highly complex process that may impact the lives of those at risk long before they decide whether or not to get tested. The participants described that they lived as if they were preparing for the onset of the disease, even prior to deciding to take the test. The decision of whether to get tested or not seems to be influenced by social, practical, and personal factors. Regardless of the outcome, test results may impact the lives of people long after results have been received. Dealing with the test result was difficult regardless of the mutation status. The participants who had received a negative mutation status expressed a need for more follow-up than they had received.

| Organizing one's life and preparing for the worst
The participants lived their lives as if they had the mutation before they decided to undergo predictive testing. Preparing for the worst may be a prevention-focused coping mechanism (Hazlett, Molden, & Sackett, 2011;McAllister, 2003), and pessimism has been shown to reduce some people's anxiety levels (Norem & Illingworth, 1993).
Further, people's health expectations and/or how they believe a disease will progress have been found to mediate both the actions taken and the measurable outcomes of health and disease (Williams & Bond, 2002). In our study, the participants consistently reported negative beliefs about the possibility of having inherited HD; they also planned their future taking into consideration the limitations posed by their disease, and they even reported symptoms of HD despite having no idea of their mutation status.
Placebo and nocebo effects may help us understand the possible impact of negative assumptions held by the participants about living with HD in the future. Placebo effect can be defined as the positive effect produced by a substance without inert treatment, and nocebo effect can be defined as the negative effect produced by the negative beliefs and expectations of individuals (Colloca & Miller, 2011;Wolman, 1989). Placebo and nocebo effects are a widely recognized phenomenon in clinical studies, and they have been found to influence cognition in many medical conditions (including motor disorders) and perception of pain (Benedetti, Lanotte, Lopiano, & Colloca, 2007). Expectancies also appear to play a substantial role in the actions taken to ensure health and to address a disease. For instance, positive expectancies have been found to decrease a range of physical symptoms for both chronically ill and healthy individuals (Andersson, 1996;Beckham, Rice, Talton, Helms, & Young, 1994).
However, negative expectancies may have an unfavorable impact on one's health status (Reed, Kemeny, Taylor, & Visscher, 1999). The present study did not investigate the long-term emotional, psychological, or somatic effect of the certainty of having inherited HD.
Nevertheless, the participants shared powerful stories about the choices they had made based on this certainty, which could easily produce detrimental nocebo effects. Their descriptions of the symptoms of HD years before knowing they were found mutation-negative also illustrate the nocebo effect in this population. The present findings therefore illustrate the possible negative psychological impact that the belief of inheriting HD may have on individuals at risk, even in the absence of a confirmed diagnosis. Clinical geneticists and genetic counselors involved in the follow-up of individuals at risk for HD should explore the magnitude of this potential psychological impact and help address its consequences to prevent its possible damaging impact on the individuals at risk.

| Socio-ecological framework
An important finding in this study is that the participants' experiences and decision were influenced by several factors related to their upbringing, including family and social relations, and by their interactions with healthcare professionals. Given the various relationships and situations that influence a participant's cognition of the disease and the testing for HD, a socio-ecological framework (Bronfenbrenner, 1979) is an appropriate tool for the analysis and Individuals affected by HD through their immediate family environment could therefore be predisposed for a greater risk for and sensitivity to stress, which could lead to more adverse reactions to a challenging test process, or instigate the development of depression or anxiety, as a reaction to test results, regardless of mutation status (Heim, Shugart, Craighead, & Nemeroff, 2010;McLaughlin, Conron, Koenen, & Gilman, 2010;Van der Meer et al., 2012). Hence, the participants' experiences while they were growing up in a family affected by HD may significantly influence their decision to undergo genetic testing, as well as their reactions to the test result. Earlier research has shown that it may be important to identify the need for psychological intervention before a pre-symptomatic testing for HD is performed (Tibben et al., 1992).
According to the socio-ecological framework, the decision about whether or not to get tested is closely intertwined with the reactions, opinions, and presumptions of other people, including one's family circle, friends, or remote acquaintances; also, the de-

| Biographical disruption
Individuals who receive the news of being mutation-negative or mutation-positive may experience a biographical disruption (Bury, 1982). In our study, most of the participants had prepared themselves to know that they have inherited the mutation and thus they had created an identity as being mutation-positive. Many participants had constantly searched for symptoms and had even experienced symptoms of HD, some in young age, regardless of whether a future test will reveal a positive or a negative result. With this belief, they organized their lives accordingly, decided to make the most out of their lives as early as possible, or restricted their life choices.
Hence, news of being mutation-negative compels these individuals to change their core identity (as mutation-positive initially) and redefine themselves (Duncan et al., 2007;Williams, Schutte, Evers, & Holkup, 2000). This group will also have to cope with the conscious or unconscious choices they have made prior to receiving the test results. Also, the quality of their relationships may change or may be challenged by the test results. For instance, individuals who do not have the mutation may experience survivor's guilt (Tibben et al., 1992) or feel less connected to family members who do have the mutation (Duncan et al., 2008;Williams et al., 2000).
Understandably, test results could trigger powerful emotions, such as fear, anxiety, anger, or depression, regardless of whether the results were positive or negative. Having chosen not to pursue higher education or not to have children based on the assumption of having inherited the disease is expected to trigger challenging psychological reactions, such as loss and grief in sharp contrast to the more recognized and accepted feelings of happiness and relief. Unfortunately, suicide ideation and suicide rates are higher in HD population than in the general population (Robins et al., 2000;Solberg, Filkuková, Frich, & Feragen, 2018), and these issues must be addressed in the follow-up consultations with the individuals who were found positive and negative for the HD mutation.
Clinical experience and research have proven the occurrence of delayed grief reaction (Sobel & Cowan, 2003) (Gargiulo et al., 2017). Hence, a post-test follow-up should take time into account and if possible be tailored to individual needs.
The progressive nature of HD, for those receiving the news of being mutation-positive, must also be taken into account, wherein the need for follow-up may change over time for both the affected individual and his or her closest relatives, such as a life partner.

| Study limitations and strengths
The strengths and limitations of this study must be considered Unfortunately, given that the interview guide was not developed to systematically explore genetic testing, the participants were not asked about how long before they decided to undergo or not to undergo genetic testing. Nevertheless, we believe that this study sheds light on several important aspects of genetic testing for individuals at risk for HD which are described and discussed in the present study.

| Clinical implications
Clinical experience and research, as well as the present findings, suggest that healthcare professionals should be aware of the need for support and should provide the same to help all individuals at risk of HD throughout the period of decision making. Our findings emphasize the importance of exploring factors that influence individuals' socio-ecological framework in pre-test counseling. Individuals who are found to not have the mutation for HD should be scheduled for a follow-up consultation with a genetic counselor or a healthcare provider with an expertise in psychology; note that such consultations are usually only set for individuals who are found mutation-positive for HD.
Our results highlight the complex and often challenging emotions that the participants experienced prior to the test and after receiving the test result, regardless of the outcome. Their reactions after receiving the result often persist, as well as change, over an extended period of time; thus, the changing needs of the tested individuals should be incorporated in follow-up routines. We therefore suggest that follow-up consultations should be conducted on a regular basis among those who underwent testing, regardless of the test results; moreover, when possible, the individual's closest relatives, such as his or her life partner, should also be offered follow-up consultations.

| Research recommendations
Despite the growing attention given to the possible risks posed on individuals at risk of HD, more knowledge is still needed. Future research should further explore the experiences of those at risk while they were growing up in a family with a parent with HD; moreover, future research should contribute novel insights into issues associated with being at risk, into the choices available in predictive testing, and into the reactions toward and the consequences of the test results.

| CON CLUS ION
Genetic

ACK N OWLED G M ENTS
We thank Counselor G. Ruud and the National Association for Huntington's Disease in Norway for their help in recruiting participants of this study. We also thank the participants for sharing their experiences and insights.

Conflict of interest
Kristine Hansen Tillerås, Siri Hagen Kjoelaas, Elisabeth Dramstad, Kristin B. Feragen, and Charlotte von der Lippe declare that they have no conflict of interest.

Human studies & informed consent
All procedures were performed in accordance with the ethical standards of the concerned committees on human experimentation (institutional and national) and with the Helsinki Declaration of 1975 as revised in 2000. Informed consent was obtained from all participants.

Animal studies
No non-human animal studies were carried out by the authors for this article.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data are not publicly available due to Oslo University Hospital's privacy restrictions, since data contain information that could compromise the privacy of research participants.