Young people's understanding, attitudes and involvement in decision-making about genome sequencing for rare diseases: A qualitative study with participants in the UK 100,000 genomes project

29 Genome sequencing (GS) will have a profound impact on the diagnosis of rare and inherited 30 diseases in children and young people. We conducted 27 semi-structured interviews with 31 young people aged 11-19 having GS through the UK 100,000 Genomes Project. Participants 32 demonstrated an understanding of the role and function of genes and DNA, however the 33 terms ‘genome’ and ‘genome sequencing’ were less well understood. Participants were 34 primarily motivated to take part to get a diagnosis or identify the gene causing their 35 condition. The majority of participants understood they might not receive a diagnostic result. 36 Most were unconcerned about data security or access, however anxieties existed around 37 what the results might show and the potential for disappointment if the result was negative. 38 Signing an assent form empowered young people, formalised the process and instilled a 39 sense of responsibility for their choice to participate. Most young people (≥16 years) had 40 consented to receive secondary findings and had come to that decision without parental 41 influence. Our research suggests that at least some young people are capable of making 42 informed decisions about taking part in GS, and that involving them in discussions about 43 testing can empower them to take responsibility over healthcare decisions that affect them. 44 45 46


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Genome sequencing (GS) will have a profound impact on the diagnosis of rare and inherited 30 diseases in children and young people. We conducted 27 semi-structured interviews with 31 young people aged 11-19 having GS through the UK 100,000 Genomes Project. Participants 32 demonstrated an understanding of the role and function of genes and DNA, however the 33 terms 'genome' and 'genome sequencing' were less well understood. Participants were 34 primarily motivated to take part to get a diagnosis or identify the gene causing their 35 condition. The majority of participants understood they might not receive a diagnostic result.

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Most were unconcerned about data security or access, however anxieties existed around 37 what the results might show and the potential for disappointment if the result was negative.

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Signing an assent form empowered young people, formalised the process and instilled a 39 sense of responsibility for their choice to participate. Most young people (≥16 years) had 40 consented to receive secondary findings and had come to that decision without parental 41 influence. Our research suggests that at least some young people are capable of making Introduction 50 51 The majority of rare diseases affect children and in many cases there is an underlying 52 genetic cause for their condition (Wright et al., 2018). Many children with rare diseases, 53 particularly those with developmental disorders, are undiagnosed (Firth and Wright, 2011).

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However, the advent of next generation sequencing technologies has revolutionised the way 55 genetic testing can be conducted, enabling multiple genes or entire exomes or genomes to 56 be sequenced simultaneously (Sun et al., 2015;Wright et al., 2018). Genome sequencing 57 (GS) has been shown to increase diagnostic yield almost twofold compared to conventional 58 panel testing (Lionel et al., 2017) and fourfold compared to chromosome microarray 59 (Stavropoulos et al., 2016). The possible clinical benefits of a genetic diagnosis include 60 ending the 'diagnostic odyssey' (Basel and McCarrier, 2017), access to information on 61 management and therapy, a clearer prognosis, reproductive planning and opportunities to 62 make contact with other families through disorder-specific support groups (Griffin et al., 63 2017;Thevenon et al., 2016). GS is therefore set to have a profound impact on children and 64 young people with rare diseases and its implementation is being evaluated in a number of 65 paediatric settings (Bowdin et al., 2016;Green et al., 2016;Turnbull et al., 2018).

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Although a significant body of work has emerged in recent years exploring adult patients' 68 experiences and attitudes towards GS, (Boeldt et al., 2017;Mackley et al., 2018;Roberts et 69 al., 2018;Sanderson et al., 2015) very little empirical research in this area has included 70 young people (Pervola et al., 2019;Raghuram Pillai et al., 2019) (sometimes referred to as 71 'adolescents' and defined as aged 10-19 years by UNICEF (UNICEF, 2019)). To date, the 72 limited work that has been done has primarily used hypothetical scenarios (Hufnagel et al., 73 2016;McGowan et al., 2018), or assessed adults' perspectives on sequencing in the 74 paediatric setting (Fernandez et al., 2014;Levenseller et al., 2014). Young people with 75 health-related issues are likely to face significantly different physical, psychological and 76 social challenges from those of both young children and adults (Frederick, 2016). They may 77 J o u r n a l P r e -p r o o f have specific information and support needs including peer support, provision of age-78 appropriate information and healthcare providers who proactively raise salient issues 79 (D'Agostino and Edelstein, 2013) Therefore, it is important to give them a voice regarding 80 their understanding of the benefits and potential risks of GS as well as their preferences for 81 involvement in decision-making.

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The current legal position in the UK is that children under 16 years cannot make decisions 84 about their healthcare without parental consent, unless they prove to have sufficient maturity 85 and intellectual capacity (referred to as "Gillick competence") (Griffith, 2016 (Kuther and Posada, 2004) The American College of 94 Medical Genetics and Genomics recently issued a statement in which they highlighted the 95 importance of engaging young people in meaningful conversations about the goals and 96 implications of genomic testing and potential findings, and consideration of its personal 97 benefits and limitations (Bush et al., 2018). Engaging young people in medical decision-98 making has also been shown to be associated with lower decisional conflict (David et al., 99 2018 (Genomics England, 2015). Of the rare 106 disease proband participants in the 100 000 Genomes Project, around a quarter of them 107 were 15 years of age or under at the time of taking part (data accessed from the Genomics 108 England Research Environment, 11th November, 2018). In that project, consent to take part 109 included consenting to receive a clinical diagnosis where one is found, and allowing de-110 identified, individual clinical and genomic data to be used for research purposes (Turnbull et 111 al., 2018). In addition, participants aged ≥16 years were able to opt in to receive clinically 112 actionable 'secondary findings' such as hereditary breast and ovarian cancer (BRCA1/2) and 113 hereditary colorectal cancer (Lynch syndrome) (Genomics England, 2015). Parents of 114 children < 16 years could also consent to receive secondary findings, which have symptoms 115 which onset in childhood, to be looked-for in their child. These conditions include 116 retinoblastoma, Von Hippel-Lindau syndrome, child onset multiple endocrine neoplasia types 117 1 and 2, and childhood onset familial hypercholesterolaemia (Genomics England, 2015  An abductive approach for coding and analysis was employed starting with codes derived 174 from the topic guide and allowing new codes to emerge from the data (Robert et al., 2015).

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Data analysis was conducted following the principles of thematic analysis (Braun and Clarke, 176 2006). A draft codebook was devised by CL informed from the topic guide. Three transcripts 177 were then independently read and coded by CL and SS and additional codes added. Coding 178 was compared and a second codebook devised. Remaining transcripts were then coded by 179 CL using this second codebook with a subset coded by SS to ensure inter-rater agreement.

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Once all transcripts had been coded, CL and JH reviewed and refined the themes and sub-181 themes (constant comparison). A Framework matrix was also created as a way of ordering 182 the data to facilitate recognition of patterns such as contradictory findings (Gale et al., 2013).

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In particular, we were interested to see how frequently codes concerning participants' 184 motivations and concerns occurred and explore whether they were influenced by factors 185 such as age, gender or whether they had a 'working diagnosis'. were probands and two were unaffected siblings. Participants ages ranged from 11-18 years 193 (mean = 14 years). The most common condition types for affected probands were skeletal 194 (including osteogenesis imperfecta) (n=8) followed by renal (n=4) and dermatological (n=3).

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Fourteen probands had no diagnosis, 11 had a working diagnosis (e.g. epilepsy) but no 196 known genetic aetiology (Table 1) Only a quarter correctly referred to the term 'genome' as being "all the genes" (Kathryn 16 230 years) or "all the DNA letters" (James, 18 years), and these participants were generally older 231 (15-18 years). Regarding the term "genome sequencing", half spoke of looking at the "order" 232 (Ash, 14 years) or "pattern" (Craig, 16 years) of the genes, ten participants explicitly stated 233 they did not know what the term genome sequencing meant (median age 13.5 years), and 234 five did not remember hearing the term during the consent appointment.

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When asked why their parents were also asked to provide their DNA for the study, four 237 participants (13-16 years) understood that it was for comparative purposes. One participant, 238 aged 13 years, articulated how her unique DNA sequence would be compared to her 239 parents' DNA and also potentially other people's with the same condition; When exploring the importance of a diagnosis, some spoke of wanting to know if they had 258 inherited the condition, or whether they might pass the condition on to their own children, a 259 concern notably raised by some of the younger participants in the study: 260 261 "Also, if I ever have children when I'm older, will they get it and will the doctors be 262 able to help them?" (Rowena, 13 years). When comparing the motivations for taking part in the 100,000 Genomes Project, age 298 appeared to be an important factor. Younger participants (11 to 13 years) cited nearly twice 299 as many benefits directly related to them compared to benefits to others. Older participants 300 (14 to 18 years) also cited more benefits to themselves compared to others, but the 301 difference was less pronounced than that apparent among younger participants. No 302 differences were observed when comparing across whether participants had a 'working 303 diagnosis' or no diagnosis.

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Only one person raised concerns about health insurance companies accessing his genomic 336 data. In this case, the participants had been reassured by his father who had "assured him 337 that for now, at least until 2019 I think they said health insurance companies wouldn't be 338 able to access any of that information" (James, 18 years).

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One participant linked her motivation to being part of the 'information age'; ""the age in which 405 I live, everybody wants to know as much as they can about themselves" (Claire, 17 years).

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Of the eleven participants eligible to consent to adult onset secondary findings, only one 408 participant declined to receive these. His decision was in part related to the advice he had 409 been given by the health professional consenting him into the 100,000 Genomes Project, 410 that he would be "too young to do anything about it", and that he could receive secondary 411 findings results at a later date. 412 413 414 When participants were questioned as to how they might feel if they were to find out they 415 were at increased risk for certain conditions, six participants reflected that they would find 416 the information "worrying", with Kathryn (16 years) raising concerns that "it would be another 417 thing wrong" that she would have to deal with alongside her current genetic condition.

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Nevertheless, all six who did articulate concerns, commented that they still wanted to know. Most participants who had consented to receive adult-onset secondary findings described 423 making decisions without parental influence, and justified this approach with comments in 424 which they were keen to exert their autonomy around decisions related to their health e.g. "I 425 feel like I was responsible enough to make that decision myself" (Amy, 16 years) and "in the 426 end it's about my body" (Seeta, 17 years). Two participants had, however, included their 427 parents in the decision-making process. In one instance, there were divergent views 428 amongst family members, with a father raising concerns "that if something comes up and it's 429 really bad" he didn't want his daughter to " have to deal with it yet." (Claire, 17 years).

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These findings echo those from our quantitative survey study examining knowledge of 459 genetics and genomics amongst 554 school pupils (Lewis et al., 2020). This finding is likely 460 to reflect the National Curriculum in England where concepts such as genetics and DNA are 461 J o u r n a l P r e -p r o o f introduced from age 11 and the concept of genomics from around age 15 (Department for 462 Education, 2015). The majority of participants in the present study understood that a 463 limitation of GS is that they might not receive a diagnostic result. This is important given that 464 currently around only 40% of paediatric patients get a result from GS (Lionel et al., 2017). did not know how their data could be used against them. This is perhaps not surprising given 488 most young people in this age group have not yet had to think about insurance, but may also 489 J o u r n a l P r e -p r o o f reflect a lack of awareness regarding the potential for genomic data to be used to 490 discriminate against them in the future (e.g. employment). In other contexts, research has 491 also shown that in the context of online personal information, young people feel they have 492 "nothing to hide" and therefore do not consider privacy relevant for them (Adorjan and (Grootens-Wiegers et al., 2017). In this study we found that participants understood that 513 participating was voluntary and were communicative and expressed a choice (capacity 1); 514 they understood why they were undergoing GS (capacity 2); they were able to apply logical 515 reasoning and weigh up the potential benefits and risks of taking part e.g. getting a 516 diagnosis vs. not getting a diagnosis (capacity 3); and they were able to appreciate the 517 J o u r n a l P r e -p r o o f relevance of taking part for them as well as others (capacity 4). Thus, our findings suggest 518 that many of the participants in our study are likely to have had the capacity to make an 519 informed decision and felt empowered by being actively included in the decision-making and 520 assent processes. This is an important finding as it has implications for clinical practice in 521 that it underscores the importance of health professionals actively involving young people in 522 the discussion and decision-making around GS. The finding that young people valued the 523 opportunity to be involved in the decision-making process and in particular provide written 524 assent is also notable and we recommend that this practice should continue.

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Strengths and limitations 527 This study adds much-needed empirical data on a topic that has received relatively little 528 attention to-date, namely the views and experiences of young people having GS. A strength 529 of this study is the diverse range of condition-types that affected participants in the sample.

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As with all qualitative studies, participants were self-selecting; participants with negative 531 experiences may have been less willing to take part. In addition, this study did not include 532 participants with intellectual disability which makes up a sizable number of children who 533 might be offered GS (Wright et al., 2015). Finally, no demographic data on the parents 534 (socioeconomic background or education level) were collected and thus we are unable to 535 comment on the background of the participants. Participants' background may have had an 536 impact on their level of understanding and/or attitudes towards genome sequencing. 537 538 Conclusion 539 Young people understood the potential benefits of GS for both themselves and others, as 540 well as the limitations of the technology. Our research provides evidence to show that there 541 will be some young people with rare diseases that 1. are capable of making informed-542 decisions to take part in testing, and 2. that involving them in testing decisions empowers 543 them to take responsibility over healthcare decisions that affect them.