Parental Perspectives Regarding the Return of Genomic Research Results in Neurodevelopmental Disorders in South Africa: Anticipated Impact and Preferences

Few policies and little research exist regarding the disclosure of genomic results to research participants in Africa. As understanding participant preferences would be pivotal to the success of the feedback process, this study set out to address this issue by engaging with enrolled participants from an ongoing genomics research project on neurodevelopmental disorders with the aim to assess the anticipated impact of receiving pertinent results and explore the preferences for feedback in a South-African context. Twelve semi-structured interviews were conducted with 17 parents of children participating in the research study. Transcribed interview data and observational notes were analysed using thematic analysis and framework matrices. Participants linked their own meaning to the impact of receiving a pertinent result and perceived the information as useful for reasons other than only clinical utility. These included closure, improved management of their child’s condition and information regarding recurrence risks. In terms of preferences for feedback, an in-person result delivery session, conducted by a member of the study team or medical professional familiar with their child was preferred. In addition, participants felt a sense of ownership over their blood or their contribution to the research study, finding meaning even in non-pertinent (secondary findings) or negative results. These findings provide insight into the type of discussions that may be valuable in enabling the development of best practices and guidelines for the return of individual genetic research results, in a culturally appropriate manner, within South-African communities.


Introduction
One pertinent challenge in genomics research relates to questions about what to do with individual genomic research results that are relevant to the health of the participant.Deciding whether to disclose individual genomic research results, and the researcher's obligations in this regard, has been the topic of much controversy nationally and internationally, particularly where minors are concerned (Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, and Social Sciences and Humanities Research Council of Canada, 2018; Council for International Organizations of Medical Sciences [CIOMS], 2016, Ekstein, Garret and Berkman, 2014, Green et al., 2013, Miller et al., 2023).With the advent of whole-exome and whole-genome sequencing technologies, the identi cation of genetic information that is relevant to the health of the individual is inevitable.Whilst initially the question of what to return at what stage, was hotly debated in the context of genomics research, there now seems to be consensus that ndings that are actionable, unlikely to have been diagnosed without the genetic research and for which there exists su cient evidence of pathogenicity, ought to be fed back, especially if research participants have indicated that they are willing to receive such results (Ekstein et al 2014).This view is also the case in the African genomics research community (Matimba et al., 2022, Wonkam and De Vries 2020; Nabukenya et al., 2023).
In Africa, the Human Heredity and Health in Africa (H3Africa) Consortium developed a set of guiding principles to inform decisions about returning individual genetic results to research participants.These guidelines suggest that there may be strong ethical obligations to return pertinent ndings ( ndings related to the disease or condition being investigated by the study) with important health implications for the participant (and/or family) and which have the potential to be medically actionable (proven therapeutic or preventive intervention) in relation to the population being investigated.Other considerations also include the analytic utility, the personal utility of the nding to the participant, and whether participants have consented for the return of results (Rotimi et al., 2014, Matimba et al., 2022).However, in the case of secondary ndings, due to the consideration that the evidence base to support the feedback of this information for African populations is currently weak (underrepresentation of African ancestry in clinical and research databases and concern for underrepresentation of African speci c disorders within the ACMG actionable genes list), taken together with the socio-economic context of Africa (many areas characterized by relative poverty, under-resourced healthcare systems and over-burdened healthcare work all affecting access to healthcare), the return of these ndings is not considered obligatory, although recommended where feasible (Matimba et al., 2022, Wonkam and de Vries 2020).
With the exception of the H3Africa feedback of individual genetic research ndings guidelines, few other policies and little research exists regarding the disclosure of genetic results to research participants in Africa.As understanding participant preferences is pivotal to the success of the feedback process, this work set out to address the issue by engaging with enrolled participants from a genomics research study conducted through the NeuroDev project, to (1) asses the anticipated impact of receiving pertinent results and (2) explore the preferences for feedback in the South-African context.The NeuroDev study is a large-scale, international collaborative project aimed at mapping genetic variation amongst children with neurodevelopmental disorders (NDD) by performing in-depth phenotyping and exome sequencing on children aged 2-17 years old from populations in South-Africa and Kenya (de Menil et al., 2019, Kipkemoi et al., 2023).NDDs are a group of complex conditions characterised by developmental de cits such as impaired functioning on a social, personal, academic or occupational level.These conditions typically manifest in early development and according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), can include conditions such as autism spectrum disorders (ASD), attention-de cit hyperactivity disorders (ADHD), intellectual disability (ID), global developmental delay (GDD), communication disorders and speci c learning disorders (such as dyslexia) (American Psychiatric Association [APA], 2013).In keeping with the H3Africa guidelines, the NeuroDev study is only returning clinically actionable results associated with the NDD.Variants of uncertain signi cance (VUS), incidental and secondary ndings are not being returned.The feedback process is planned to include several steps, namely: re-contacting the participant's family after identifying a causative genetic variant within the context of the research study, reconsenting, and testing a second sample in a clinical diagnostic laboratory for con rmation, followed by a result-delivery session.This study speci cally set out to investigate preferences for feedback of genomic research results from the South-African parents of an affected child with a NDD enrolled in the NeuroDev study, ahead of the clinical con rmation phase.Therefore, any important ndings or recommendations were intended to further shape the feedback of ndings process.

Method Study design
A qualitative study was conducted using semi-structured interviews with participants enrolled in the NeuroDev study, to investigate the anticipated impact and parental preferences regarding the return of research results.

Recruitment and samples
Purposive sampling was used to recruit parents of children who participated in the NeuroDev study and had consented to receiving pertinent research results.Eligibility criteria for the qualitative study required parents to be: 1) the biological parent or primary caregiver of a participant in the NeuroDev study 2) illustrate cognitive capacity to consent and 3) have consented in the NeuroDev study to be contacted for secondary/any further research.
Participants were contacted telephonically by one of the authors and informed about the aims and objectives of the study.If they were interested in participating, a date and time was set-up for an inperson interview.Twelve semi-structured interviews were conducted with 17 participants in a private room at the Red Cross War Memorial Children's Hospital in Cape Town South-Africa from May to July 2019.Importantly, whilst all participants were parents of children recruited into NeuroDev, no results from the exome sequencing component of the study were yet available and none of the parents had yet received research results.At this stage it was not yet evident which parents would receive individual genetic results directly relevant to the condition of their child.

Procedures
The interview guide was developed based on a review of the literature and examination of any previously developed guides from similar research conducted in other settings.The questions were structured around the following topics: anticipated impact of pertinent genetic research results and preference for the feedback of ndings.Questions were adapted to suit the South-African setting and align them with the study's objectives.Pilot interviews were performed to explore the utility and structure of the interview questions.While South-Africa has eleven o cial languages, those that are dominant in the Western Cape include English, Afrikaans and isiXhosa (Western Cape Language Audit, 2001).Therefore, translation services were offered to all participants however they declined this, and all interviews were subsequently conducted in English by the rst author.Interviews lasted approximately one hour and were audiorecorded.Field notes were written immediately following interviews and captured any elements or observations relevant to the research and data analysis.Transcription was done by a dedicated transcription company and the research team reviewed the transcripts for accuracy.The interview guide appears in S1.

Data analysis
Interview data and observational notes were analysed using thematic analysis and framework matrices.
Themes were extracted from the data following transcription of the initial interviews.Through using framework analysis, robustness and rigour was attained by allowing for clear audit trails of cases (Gale et al., 2013, Hackett & Strickland, 2019).The research team manually analysed the rst three transcripts together, examining the relevance of themes and agreeing on any required re-classi cations or modi cations.The rst author then continued with the coding and discussed any new ndings with the rest of the research team, to enable agreements to be reached to prevent potential bias of a single rater.An open coding strategy, which assigned open codes to relevant or interesting text excerpts, was utilized.Drawing on the list of open codes, a mind map was compiled with preliminary themes, after which both themes and coded text were imported into Excel and further reorganized into subthemes/categories.Transcripts were imported into NVivo 12 to assist with managing and organizing the data for analysis.Emerging insights were recorded in eld notes and were further probed in subsequent interviews.To ensure further credibility, quotations from research participants were incorporated into text excerpts which assisted with providing thick descriptions and context of participant meaning and experiences (Korstjens & Moser, 2018).
Ethical approval for this study was obtained from the University of Cape Town Human Research Ethics Committee (HREC 784/2018).

Results
A total of 17 participants were recruited, of whom 12 were female and ve males.Both individual and couple interviews were conducted with the parents of children enrolled in the NeuroDev study.All participants identi ed themselves as either belonging to Mixed Ancestry or African Ancestry groups (Table I).

EXPECTATIONS OF THE IMPACT OF PERTINENT STUDY RESULTS
Broadly speaking, participants recalled consenting to receiving individual genetic research results for their children.The expectation from these results were that they could possibly bring diagnostic closure, help in the management of their child's condition, or help inform reproductive decisions by clarifying the risk of recurrence in other children.

Diagnostic closure
Diagnostic closure encompassed acceptance of their child/situation, addressing guilt and blame and self-empowerment in the form of having a name for their child's condition.

Guilt and self-blame
Most participants felt that results would resolve feelings of guilt and self-blame by offering an understanding of why it happened and where it came from.One mother was searching for con rmation that she was not to blame.She felt that she had done everything right during the pregnancy -in fact more so than in a previous pregnancy which resulted in an unaffected child: "It's just a need to know.Because when I, like in the beginning when we found out … the rst thing we did we stopped smoking.That's the rst thing we did.So, we did everything right.We didn't do unnecessary going out.We just took it easy.In fact, I was more healthy with her to what I was with him [sibling] in my pregnancy.So I would like to know how and why." (Participant 15) A few participants expressed concern that internal guilt could be exacerbated if the condition was found to be inherited: "… But if it's going to come like something that he get from me I'm going to feel guilty on the other side, because even when I look at him suffering or it's di cult to do something I'm going to be like … you are like this because of me" (Participant 7)

Self-empowerment
Participants hoped that results from genomic testing would provide them with a name for their child's condition, thereby providing means for de ned management and treatment.The participant below noted the bene ts of having a name for their child's condition in terms of allowing them to conduct their own research and foster self-empowerment.
"… it will also make things easier for research, for me.When I … like when we discovered when she was born this was wrong … it's easy to Google once you have a name to something.

Recurrence risks
Receiving pertinent results could inform participants of their personal reproductive potential: "I remember like the main reason why we did it, was so that we could nd out if we could have more children without the child having some type of neurological issue" (Participant 1) Or that of their children: "So I said I understand.I don't mind no matter it's not going to help me now, maybe it's going to help my grandchild in the future."(Participant 7)

PREFERENCES REGARDING THE FEEDBACK PROCESS Information related to feedback of preliminary results
The participant's need for information varied.Almost half preferred to only be told of the result after clinical con rmation.The most prominent reasons for waiting for the nal result included avoiding unnecessary stress and worry over an inconclusive result, the need for certainty and to maintain peace of mind.
"Because I want like solid evidence that this is what they've found.I don't like this could be and that could be and then take the second sample and then it's like a totally different ballgame and that's why I'd prefer end results and in fact we're willing to wait longer for that."(Participant 1) A few expressed their desire for receiving preliminary research results, indicating a need for study involvement and to be prepared for the possible outcome.
"I would like to know that yes.Like what is it and why?What did you pick up that you just want to verify.Yes, I know maybe it's not it, but just so I know exactly where they are heading."(Participant 15) reasons included wanting to know if they needed to be concerned, the desire to assist in the research being conducted but expecting researcher transparency throughout, the right to know and be informed.
It's also the need to understand how they got to the point.So yes, they found something they're not sure and they need to double check it.But it would be nice to know that you guys actually … there's some type of progress.Because it's going somewhere and not just, we're back here again.

" (Participant 15)
There was a perceived potential for preliminary research results to cure or treat their child, possibly referring to the timeous receipt of results and early intervention.
"In case there's something maybe we can x." (Participant 14) Most participants would automatically assume that a causative variant was found if they were contacted about the collection of a second sample: "Obviously I would know then that it's got something to do with our genetics.So I'd probably wouldn't want to know because then I'm going to mull over it for the next couple of months while they do the second sample.So I would just assume that something is up with one of us and that they will have to verify it.So I'd prefer to get like actual information rather than this could be and that could be and we're still busy with that."(Participant 1) Who, where and how results should be explained While few participants felt that they had no preference concerning the person who returned their results, the majority preferred the news to come from the original study researchers or doctors managing/treating their child: "Yes.Or even the doctor because this child is going to Dr [name].Even the doctor explain us it will be ne.I would be happy with that.Because the doctor knows everything of the child."(Participant 13) When participants were asked where they would like to receive feedback regarding their results, consensus was that they wanted to be told at the hospital where their child was attending and during an in-person session.For some, a negative result could be communicated telephonically but it was expressed that a face-to-face encounter, even with negative results, would alleviate anxiety and worry.A few participants additionally stated a distrust of technology and fear of breach of security if telephonic delivery was undertaken: "The lines are never secured.You can't say something is secured because even computers, cyber security, that's big." (Participant 10) The value of a negative result The majority of participants wanted to be contacted with a negative result for various reasons, including getting closure, for peace of mind, keeping calm, and to stay informed of research progress.
"Yes.I think that is as important.I think it's more for peace of mind and also to … it's just about us being included.Keep updated.A negative is still a result."(Participant 12) For some individuals, receiving a negative result would bring reassurance that they and the researchers did the best they could, despite a lack of answers over what the meaning of the result may be or the lack of clinical utility.
"Just to let this whole thing come to fruition, I mean like, just have it being done and we … not that I would feel like this has all been for nothing.I mean, I've been educated about some subjects with regards to this, and I know what you do.And, ja I just think that I would be okay with even if they didn't know anything, then at least I know that it's over and that they've done all they could and that it's still a mystery."(Participant 1) A sense of entitlement over their blood and thus their results was also apparent: "I prefer they must call me to tell me that.Because I'm going to sit like now, that year in Red Cross they take my blood and they say I didn't know what they're checking, I didn't know if there's anything that they found in my blood, but that is quiet.Nothing happen after that.I would like to … because it's my blood, I would like to contact me and tell me even if they didn't nd anything."(Participant 7) Whilst many understood that researcher constraints, such as budget restrictions and the large number of participants enrolled in the study, may not allow for the feedback of negative results, they expressed their appreciation for such feedback.
"Yes, I would appreciate that.I do know however that there is a budget for all of this and that, I mean, there's probably hundreds if not thousands of people enrolled in this thing, so it's not imperative that they have to call if they don't nd a result.But if they are able to do so then, yes, I would appreciate getting a phone call."(Participant 16) Need for additional information from the result Whilst participants reiterated that they aware that only pertinent results would be returned, they continued to discuss the likely implications of non-causative or uncertain results.Many participants expressed their wish to receive all types of results, good or bad, including individual results that would be of signi cance to the health of their child (secondary ndings): "If it's something that can affect him, then yes, we would want to know about it…And they pick up something else that's not related, yes." (Participant 5) A few parents believed results would be indicative of their own personal health, also referring to secondary ndings: "Any.I can't say I'm hoping for this, but any result that comes.Anything that they can nd maybe some sicknesses in me or something maybe can … so that they can prevent it to other people…But if they can say the result is coming like this, this is something we found that may cause your child to be like this, then I will accept it.The moment that they come with the result that says this is a condition we found but it's not what caused this on your child.That will be ne too.And then I'm going to look forward to see how they're going to maybe help it or treat it…Everything they nd.Everything." (Participant 7) Others felt it would enable them to provide a better quality of life by being prepared and planning for their family's future.The latter was also described by a participant in terms of his own health, possibly driven by personal fears of having passed the condition on to his child or related to the value of future planning (as a result of the knowledge gained from a secondary nding): "Look, I mean if there is a result there's a result.Obviously we have to know that.I've got dependents, ve of them you know, so I would want to ... if I'm going to die tomorrow or in a few years' time I would like to have that quality of life.I don't just want to leave them behind or whatever" (Participant 17) Some participants seemed to prefer to receive information about all kind of results, including ones that did not have clinically actionable signi cance (such as VUS).They expressed the hope that those results could lead to further research that they could participate in.
"Maybe then someone else would come and try to take that further and then we can be involved in that study."(Participant 1) On the contrary, some were unsure about the usefulness of VUS information and expressed concern over the possibility of discovering new/other information, indicating a preference not to know about VUS results.
"I don't know if I would want to know that part, because now you're going to be sitting with this information and you're thinking what could this be."(Participant 16)

Discussion
In this study, participants described the expectation that pertinent results had the potential to have a positive impact by bringing acceptance of their child's condition, dissipate feelings of (self-)blame or guilt and offer a means of self-empowerment.In addition, participants expected individual results to potentially inform on management and recurrence risks.Determining if the condition was inherited or de novo was also found to be associated with participants wanting to resolve feelings of self-blame.
Although participants identi ed that an inherited cause could lead to anxiety as they might feel personally responsible for their child's condition, potentially exacerbating feelings of being at fault, it was also noted to have the potential to reduce (self-)blame by allowing the individual to feel less responsible for the condition given that it was not under their control.According to Faure et al., 2019, genetic information can reduce blame but increase the sense of loss of control and feelings of hopelessness, leading to internalized stigma.Other studies on ASD have highlighted that parents often internalize these feelings, blaming themselves for their child's condition or feel responsible (Broady, Stoyles & Morse, 2017, Oti-Boadi, Dankyi & Kwakye-Nuako, 2020).From our study, there was some expectation that the return of results would impact on resolving feelings of guilt and perhaps some (self-)blame as many participants alluded to seeking con rmation or validation that they were not responsible.Being aware of the impact of receiving results on these feelings (both positive and negative associated outcomes) would be valuable when conducting sessions centred around the feedback of ndings.
Participants gave diverse preferences concerning the return of results process; however, overall perspectives were the desire for certainty over the cause and therefore willingness to wait for clinical con rmation.As research results cannot be fed back to participants unless it has been veri ed in a certi ed diagnostic laboratory, an additional sample would need to be taken for clinical con rmatory testing.Participants in our study described that they would automatically assume a disease-causing variant had been found at the time of contact for a second sample.Whilst some welcomed the opportunity to prepare for the possibility of a positive result and perceived a potential for preliminary results to offer a chance for early intervention, others preferred to receive no explanation; fearing the potential to create anxiety.Although the latter was only identi ed in the minority of our families, it was acknowledged that individuals involved in the feedback process might face the challenge of dealing with managing participant anxieties during this preliminary feedback process.
The timing and amount of information conveyed during the process may have a degree of psychosocial impact for some as well as ensuring researcher transparency, ultimately in uencing participant trust in researchers or the research enterprise.Our ndings further suggest that familiarity with the person delivering the result as well as with a preference for the familiar clinic is important for participants when considering who should communicate results, where it should be done, and who should be involved in the process.An in-person result delivery session, conducted by a member of the NeuroDev team or medical professional familiar with their child was preferred and thought to be able to reduce pre-existing anxiety and alleviate concerns for con dentiality.This nding aligns with the H3Africa recommendations, advising that the result delivery session should be undertaken by the clinician or quali ed health professionals involved in the genomic research project until other staff are su ciently trained to take over this task (Matimba et al., 2022).
Participants felt a sense of ownership over their blood or their contribution to the research study, nding meaning even in non-pertinent (secondary, incidental or VUS) or negative results.Although all participants were aware that only pertinent results would be returned, they mentioned the value that they still placed on the non-pertinent ndings and negative results as they perceived it as a result which could provide answers to issues relating to future health, for themselves or their child, or offer a chance to be involved in forthcoming research studies.and Miller, et al., 2008).It may be important to consider the anticipated value and meaning participants attribute to results in addition to assessments of clinical utility or medical actionability, as participants may classify these concepts differently to researchers (Holm et al., 2015).Participants in our study clearly described that negative results would also be a valuable return for their participation in the NeuroDev study, albeit the lack of an answer as to the cause of their child's condition.They viewed such a result as an answer, with the potential to bring closure, peace and acceptance, perhaps through the knowledge of having done all they could.Reasons for wanting all generated results stemmed from a need to plan for the future, to provide quality of life, to inform personal health risks and to promote future research and information discovery.

Conclusion
There is limited literature that documents the views of African families with regards to the expectations for the return of individual genetic ndings in genomics research.Our study provides evidence on the views of South-African participants with regards to expectations and preference for return of results.It will be important to consider these ndings in the feedback process, as well as the importance that these ndings may have with regards to discussions around the development of best practices for African-speci c guidelines which are contextually relevant.These may include feeding back negative results as well as consideration of a tiered-consent model to enable feedback of secondary ndings for participants who would like to receive these.

Limitations
Whilst our study has shed some insight into what NeuroDev participants would like to know, the sample was small and narrowly tied for a particular set of conditions.Data may additionally be skewed by the fact that purposive sampling was used whereby the views of those who could not be reached or who declined were not represented.As a result, our ndings may not be generalizable to other communities or regions within South-African or countries across the African continent.Sociodemographic data, beyond gender and ethnic background, was also not obtained.Although these could have had important in uences on participant's coping mechanisms, the data was not considered essential to the study (the sample was too small to make breakdown by this data meaningful) and was therefore omitted from a perspective of "data minimization".
Number of parents with a child with NDD including ASD 15 Number of parents with a child with NDD 2 NDD -Neurodevelopmental disorder ASD -Autism spectrum disorder The thematic domains that were identi ed from the analysis of the interviews are summarised in Figure I.

DeclarationsFunding:
This study is supported by the IFGENERA H3Africa ELSI Collaborative Centre grant, awarded by the National Human Genome Research Institute of the National Institutes of Health under Award Number U54HG009790.IFGENERA supported JDV as well as some of the research costs in this protocol.The study was also supported by Stanley Centre for Psychiatric Research at the Broad Institute and the National Institute of Mental Health (599648) and the National Institute of Mental Health of the National Institute of Health (5U01MH119689-05) which supported KD, EE and some of the research costs in this study.

Figures Figure 1
Figures that whilst the unknown brought fear, results could bring awareness and acceptance.Other participants reported that a genetic answer would bring relief regardless of the meaning of the result or the cause of their child's condition."Awarenessandbeing able to accept whatever it is and ..., it just makes you feel more at peace about whatever, you know, whatever the result is.But not knowing is scary.You don't know how to deal with things and, I mean, we used to think that [child's name] is just being naughty, you know, and sometimes you feel bad because we used to scold him and give him a spanking whatever, and in the meanwhile he had this problem.So ja, I'd rather be aware and know, and then know how to treat it."(Participant16) "It would be a relief.Because now we're just saying, okay, maybe ja, it's the vaccine.But maybe it's not.Maybe there's something wrong with me and [husband's name]…So you know, if they come and say we found something on [name of child], yo, it will be … it doesn't matter if it's bad or wrong but it will be a relief."(Participant11) These three sub-themes are elaborated on below: Acceptance Many participants expressed But before they could tell me what was wrong with her eyes I was laying in the bed after giving birth and was trying to Google, born without a right eye, what does it mean.And ten thousand stuff came up and I'm like, now which one of these does she have.So, it would be nice to know." (Participant 15)Improving management of child's condition For many, becoming as educated as possible about their child's condition meant that they would have a greater understanding and ability to manage their child: "I mean, I just want to be like as educated as I can on the subject.Because I mean, it's part of my life now."(Participant 1) "I think it's going to me something also so that I can know how to handle him, all that.Because if you know what is wrong with this person then you know what to do when you are around this person."(Participant7)Participants further pointed out that having results could make things easier, raise hopes for treatment or medicines and an improved life for their child.One parent expressed that: "Like maybe what medication he can use, or something.I've seen a video of a … I think the girl is 24 and she's got autism, can speak and everything.She's got her own school for autistic children that actually helps them, but it's not here.It's overseas.Basically just to help him to improve his life."(Participant 6) (Halverson, Clift & McCormick 2016 et al., 2021, Ralefala et al. 2022 studies considering the parental preferences and expectations of feedback of ndings from genomic research studies(Matshabane et al., 2020, Ralefala et al., 2021, Ralefala et al. 2022).The authors identi ed that participants expressed a strong interest in receiving secondary results as they were viewed as valuable because they could empower or emancipate individuals or motivate healthier lifestyle choices.While other international studies identi ed that participants found meaning in results of uncertainty and believed that knowledge about such results and analysis would grow, yielding answers in the future outcomes(Halverson, Clift & McCormick 2016