Trust in prenatal exome sequencing for expectant families facing unexplained fetal anomalies

Abstract

Objective:

Despite exome sequencing (ES) becoming increasingly incorporated into the prenatal setting, few studies have elucidated motivations for and trust in ES and genomic research among a diverse cohort of patients and their partners.

Methods:

This is a qualitative study that involved semi-structured interviews with pregnant or recently pregnant individuals and their partners, interviewed separately, in the setting of ES performed through research for a fetal structural anomaly. All interview transcripts were coded thematically and developed by the multidisciplinary team.

Results:

Thirty-five individuals participated, the majority of whom (66%) self-identified as of a racial or ethnic group underrepresented in genomic research. Many patients and their partners expressed trust in the healthcare system and research process, and appreciated the extensive testing for information and closure. There were nonetheless concerns about data privacy and protection for individuals, including among those underrepresented, who participate in genomic testing and research studies.

Conclusion:

Our findings illustrate important elements of motivation, trust and concern related to prenatal ES performed in the research setting, taking into account the perspectives not only of diverse and underrepresented study participants but also partners of pregnant individuals.

Introduction

Exome sequencing (ES) can identify a breadth of genetic diseases in utero and is increasingly utilized for pregnancies with fetal anomalies [1–4]. Recent largescale analyses of fetal anomalies found that the diagnostic yield of prenatal ES in chromosomally normal fetuses ranged from 8–34%, with variability across fetal phenotypes and number of anomalies [1, 2, 5–7]. Prenatal ES has the potential to establish fetal genetic diseases in utero, as well as to inform decisions around continuation of pregnancy, plans for management and surveillance during pregnancy, and choices around neonatal interventions [3, 4].

Despite these potential benefits, there are challenges to prenatal ES including cost, insurance coverage, availability, and turnaround time [8, 9]. In addition, patient trust in this technology and barriers to the use of prenatal ES are important factors that have not been well studied. Factors such as data storage and sharing, equity in access, and viewpoints of diverse individuals, particularly those underrepresented in genomic research, need further attention [10, 11]. When ES is conducted in the context of a research study, there are additional considerations such as security of the database and further research use of collected data, which expand the scope of considerations beyond ES. As ES continues to be integrated into the prenatal setting, it is imperative that patients’ and their partners’ trust in this technology are evaluated and that diverse and underrepresented perspectives are incorporated.

Existing studies have suggested that patient concerns include data protection, privacy, and lack of definitive clinical answers [12, 13]. Outside of the prenatal setting, it has been shown that parents and children taking part in ES for the 100,000 Genomes Project have positive views on research, data sharing, and the healthcare system [13]. In terms of commercial access to health data, a recent report found that individuals are more trusting if they are given more information on the processes and safeguards in place for data collection and sharing [14]. There is a need for similar qualitative research involving pregnant individuals who are undergoing genetic testing though. Wide disparities also exist in inclusion of underrepresented populations in genomic medicine and research; there is a critical need to incorporate the views of diverse populations to mitigate existing disparities in health and healthcare for pregnant individuals, as well as to avoid exacerbation of these disparities in the advancement of prenatal genomic diagnostics and precision therapeutics [15–22].

This qualitative study aimed to investigate diverse participants’ and their partners’ experiences of, motivations for, and trust in prenatal ES performed in a research setting.

Methods

This is a qualitative study involving semi-structured interviews with pregnant or recently pregnant individuals and their partners, to examine the experiences of, motivations for, and trust in prenatal ES performed for a fetal structural anomaly.

Participants and Exome Sequencing

The University of California, San Francisco (UCSF) is a tertiary referral center for a wide range of fetal anomalies. Expectant parents, henceforth referred to as ‘patients,’ were offered enrollment for prenatal ES if their fetus had one or more structural anomalies and/or fetal effusions on prenatal ultrasonography, and these abnormalities were not explained by chromosomal microarray analysis or other standard testing. All patients meeting these criteria were offered enrollment for ES by a genetic counselor, Maternal-Fetal Medicine specialist, or Geneticist. Results of the original ES studies are reported separately [5, 7].

The UCSF Genomic Medicine Laboratory, a Clinical Laboratory Improvement Amendments certified program, performed ES and results were delivered back to patients. Methods of the ES and variant interpretation have been previously described by our group [5, 7]. In cases of ongoing pregnancies and live births, results of ES were prioritized to inform decision-making and clinical management. In all cases, participants received genetic counseling prior to undergoing ES, as well as after results returned to explain the findings and their implications. The cost of ES was covered through study funds. Race and ethnicity were self-reported by participants.

Qualitative Interviews

As part of the initial consent process, patients and their partners indicated their willingness to participate in subsequent interviews. Participants who agreed to interviews were then contacted by research coordinators, and the research team prioritized those who were considered underrepresented in genomic research. Consenting participants were interviewed prior to receipt of ES results, then again approximately 1 month after receipt of ES results (Figure 1). All participants received a $40 gift card for completion of each interview.

Figure 1.

Study workflow for patients and their partners starting with recruitment and ending with the follow-up interview once exome sequencing results were returned.

Two members of the study team (JB, Anthropologist and Bioethicist; TS, Maternal-Fetal Medicine physician and Clinical Geneticist), conducted interviews via videoconference. While some bias was inevitable due to our qualitative research team being embedded within the original ES studies, the vast majority of interviews were conducted by a non-clinical researcher (JB), who played no role in clinical care or treatment decisions. Patients and their partners were interviewed separately to obtain their individual viewpoints without influence from the other. A semi-structured interview guide was followed to gather participants’ views on reasons for undergoing ES, perceived risks and benefits of ES including ES in a research setting, meaning of ES results and their implications for current and future pregnancies, and additional use of the provided samples for ongoing research. Interviews ranged in length from one to two hours. Consent forms were available in multiple languages, and participants were not turned away due to language. For non-English speaking participants, a professional medical interpreter translated interviews into English in real time, which were then transcribed in English.

Data Analysis

Interviews were recorded and transcribed for analysis. All interview transcripts were coded thematically and developed by the multidisciplinary team, and resultant themes were participant driven. Themes were elucidated through initial readings, codes were iteratively created and revised, and each transcript was coded twice to ensure intercoder reliability [7]. An inductive approach was implemented whereby emerging patterns and themes were determined a posteriori [23, 24]. Multiple themes were identified and summarized to provide an overall picture of participants’ perspectives over time. Participants from self-identified racial/ethnic groups historically underrepresented in genomic research were categorized as such to evaluate social constructs that impact healthcare inequities [15–17].

Results

Thirty-five participants consented to interviews, including 22 patients and 13 partners. A total of 54 interviews were conducted, including 31 interviews before the return of ES results and 23 after return of results. Overall, 59.1% of patients and 76.9% of partners self-identified as a race/ethnicity that is underrepresented in genomic research (UGR) (Table 1). Five participants (three patients and two partners) who participated in initial interviews declined a follow-up interview to discuss ES results, and three participants were unable to be reached for follow-up. Interviews were conducted in English (n=50), Spanish (n=2), and Dari (n=2). Further participant characteristics, ES results, pregnancy outcomes, and interviews completed among patients and partners are outlined in Table 1. The characteristics of patients and partners who participated in the original ES studies but declined all interviews were similar to those who consented to interviews (Supp. Table 1).

Table 1.

Patient and partner characteristics among those who chose to participate in interviews. ART, Assisted Reproductive Technology; ES, exome sequencing; IUI, In Utero Insemination; IVF, In Vitro Fertilization.

Patient and Pregnancy Characteristics	Patient (n = 22)	Partner (n = 13)
Self-identified Race/Ethnicity [n (%)]
Asian	7 (31.8%)	7 (53.8%)
Black/African American	3 (13.6%)	1 (7.7%)
White	9 (40.9%)	3 (23.1%)
Hispanic/Latino(a)	3 (13.6%)	2 (15.4%)
Interview Participation [n (%)]
Before return of results	22 (100%)	9 (69.2%)
Follow-up after return of results	15 (68.2%)	8 (61.5%)
ART Pregnancy [n (%)]
IUI Pregnancy	1 (4.5%)
IVF Pregnancy	3 (13.6%)
Pregnancy without ART	18 (81.8%)
Pregnancy Outcome [n (%)]
Live Birth	6 (27.3%)
Spontaneous pregnancy loss or stillbirth	4 (18.2%)
Termination	12 (54.5%)
ES Result [n (%)]
Definite Positive	3 (13.6%)
Probable Positive	3 (13.6%)
Inconclusive	3 (13.6%)
Negative	13 (59.1%)

We identified trust as a key theme throughout interviews. Participants’ feelings of trust regarding prenatal ES fell into three broad categories: 1) trust in the healthcare system and scientific research, 2) concerns about privacy and sharing of genomic data, and 3) personal utility and benefits to society of genomic data.

Theme #1: Trust in the healthcare system and scientific research

Patients who felt well cared for by the healthcare system demonstrated a high level of trust. One patient stated: “We trust you guys. We trust UCSF… because you guys did such a thorough job from start to finish with the fetal treatment and everything” [ID 434 Patient]. Another patient expressed more general trust in the technology offered: “I trust the science is going to help me or find out what’s going on” [ID 444 Patient, UGR].

In addition to general trust in the healthcare system, some participants found comfort in being in a research study involving genetic information because they had received clear communication. A partner expressed that he “got a lot of input on what was going to be done, why it was being done, and got clear specification on what they will do with that data” [ID 462 Partner, UGR]. This partner felt confident that their data would be used, distributed, and stored in the ways described by the study team.

For other participants, trust in the healthcare system and genomic research stemmed from a general feeling of benevolence and belief in data security. In response to interview questions about genomic data protections and future sample use, one patient said she “think[s] the research is for good … I also believe there’s always a protection for the information” [ID 444 Patient, UGR]. In another instance, a partner explained in an initial interview that he is “not that kind of person who has really strong opinions on the privacy or on the genetic privacy or genetic information … As long as it is good intention, for the good purpose, it can be used for any other research as well, as long as it can benefit science and advance” [ID 472 Partner, UGR].

Historical context, including unethical treatment of people of color in research, left some participants weary about the healthcare system and ongoing studies today. A partner mentioned that he is “very familiar with the history, at least of Hopkins, Baltimore, Henrietta Lacks, and other, I’ll call it mixed history of the medical community” [ID 522 Partner, UGR]. This partner also expressed feeling profiled by providers during his life based on his “personal background” and “educational bias” [ID 522, UGR]. He felt that his trust in a healthcare setting comes from “the nature of the first … few minutes of interaction with the physician.” In the end, he stated that “there’s a complicated messaging challenge in this type of testing. I think [information] … needs to be communicated in that kind of a clear, concise way to build trust” [ID 522 Partner, UGR].

Other patients felt that participating in genomic and other research as an underrepresented minority was an important contribution to science. For example, one patient expressed that minority patients are often “experiencing stuff that’s kept a lot of people away from healthcare” [ID 418 Patient, UGR]. She elaborated:

“[Medical researchers] are going to find a lot of resistance in the African American community to participate in these things, to answer questions and stuff like that. As much as we try to reassure them that this is not the Tuskegee experiment all over again, it’s just that trust is gone. It’s a relationship that’s hard to get it back and you have to prove to my community that you’re actually here to help.” [ID 418 Patient, UGR].

Her conviction comes from her “passions … to break those [healthcare] disparities to make it an even playing field for all” [ID 418 Patient, UGR]. She explained her goals regarding advocacy in her community:

“It’s going to take a continuous stream of people like me in my community, who are advocating and teaching our loved ones how to advocate or advocating on their behalf, before you get to a point where you’ll have more representation in things like this” [ID 418 Patient, UGR].

Theme #2: Concerns about privacy and sharing of genomic data

We found that the main sources of ambivalence or concern came from participant’s views around potential commercial benefit and the relative novelty of broad genomic sequencing. Multiple participants expressed worry about improper use of the data by third parties or unsecure data storage. For example, one partner was concerned about data being shared with insurance companies. In his initial interview, he stated:

“I really am trying to give UCSF and the research team the benefit of the doubt to really better the lives of other people to help the medical field. But when it’s tied to some of these newer practice with this huge emerging field of genetic testing … This is tied to insurance and … it’s hard for me to fully trust and believe the true intentions of the people that are funding and supporting. I don’t question anything that you all, the two of you [interviewers], are doing. I know your intentions are really pure and mean well, but it’s the people that are overseeing it” [ID 383 Partner, UGR].

Another partner described the push-pull decision the couple had to make in balancing their concerns with data privacy and the potential benefits of ES. He stated:

“Data privacy, obviously, is something that we were a little bit concerned [about] … because there is always a risk that it can be used for whatever nefarious purposes … But at least in my mind, the benefits for us and for others would outweigh this. So we were okay with that. And also, I mean, we trust UCSF will take care of stuff.” [ID 415 Partner, UGR]

The relative novelty of genomic sequencing made some patients nervous about privacy protections and sharing of genomic data. One patient in her initial interview already “gave [her] data to 23andMe … so a corporation already has it. A university having it is not that concerning for me. But again, it’s how it will be repurposed” [ID 462 Patient, UGR]. This patient was worried about the blurred lines between science and industry. One solution she recommended was for patients to “re-consent … every year, every five years, because people can change their minds based on what’s going on” [ID 462 Patient, UGR].

Theme #3: Personal utility and benefits to society of genomic data

Participant desire for information from ES and trust in the technology was often the motivation for participating in the study, such as to inform ongoing pregnancies or expectations for after birth. In an initial interview, one patient stated, “I want to have as much information as I can, not only for myself but also I’m trying to help him or her grow up healthy, to rule out all the possibilities that might happen to him or her” [ID 444 Patient, UGR]. Other participants trusted that the results of ES could be useful for future reproductive decision-making, such as planning future pregnancies. As one patient put it, she wanted “to know for our future and for our family planning” [ID 443 Patient, UGR]. Another patient mentioned that the data may be useful “in the future, if we or the baby had some kind of sickness” [ID 471 Patient, UGR].

Many participants also trusted that their genomic data would help others by advancing science. For example, one patient “wanted to participate in this to be able to help find a solution for fetal hydrops and other similar scenarios for other babies in the future so that we can help” [ID 443 Patient, UGR]. This sentiment of altruism was common in the study cohort. A partner in a follow-up interview hoped “that this kind of data could actually help others to avoid this problem or to make this cure to be possible in the future” [ID 471 Partner, UGR]. Another partner said that by doing “exome sequencing, we can contribute … data points that can help research to develop. Maybe some in the future can have early prevention or there may be [resultant] treatment that could be helpful” [ID 472 Partner, UGR].

Some participants found meaning and consolation in sharing their experience to benefit others. This element of trust is unique to the research setting, as patients undergoing prenatal ES in a commercial setting would not be interviewed in addition to the ES. A patient in her initial interview stated, “that the baby is helpful to research, I will think that’s the best case for the baby. Even though he’s gone, at least he provides some value” [ID 472 Patient, UGR]. Another patient commented,

“I like being asked questions that aren’t just yes or no because when I start to explain myself, I can create my own thought process … That actually makes me realize what I’m really feeling, which is nice … These interviews are good. I think these are really helpful for people to go through it all” [ID 447 Patient].

It is important to acknowledge, however, that not every participant may have benefited in such ways from participating in the study, as five participants declined follow-up interviews for reasons that were not specified.

Discussion

In our diverse cohort of patients and their partners who participated in semi-structured interviews during the process of prenatal ES for fetal anomalies, we identified several important themes related to trust. We found that many participants expressed trust in the healthcare system and research process and appreciated the option of extensive testing for the purposes of information and closure. However, important concerns that arose were data privacy as well as protection for individuals of underrepresented races and ethnicities who consider genomic testing and participation in research studies.

Considering our findings about trust related to the healthcare system and research process, reasons for these feelings often stemmed from clear communication and delineation of expectations. The concept of ES, its potential findings, and decision points such as whether to receive secondary findings, are complex, and layered on top of the already complicated fetal anomalies. As such, it is not unexpected that participants would have a greater degree of trust when they feel they understand the situation and have confidence in their providers and healthcare system. Several participants also expressed that while they had trust in the study team and institution, they still feared the potential for third parties obtaining access to their genomic data. Our findings reiterate the importance of clear communication and building trust not only in healthcare delivered, but also in data security and medical research, given the rapidly expanding field of prenatal diagnosis that is dependent on ongoing studies to guide clinical care.

The majority of participants in our study self-identified as of racial or ethnic categories historically underrepresented in genomic research. An important theme related to trust for underrepresented individuals was protection for those who consider genomic testing and participation in research studies. While some underrepresented participants expressed full trust in the ES and research, others felt hesitancy or concern due to the history of research exploitation involving minority populations [25, 26]. Improving representation in genomic research cannot correct the mistreatment experienced by minority research participants in the past, but it can make the future of genomic medicine more equitable. For example, understanding disease-causing genetic variants among diverse populations will improve the accuracy of diagnoses made in the future for all populations with genomic sequencing [18, 27, 28]. Programs like the Clinical Sequencing Evidence-Generating Research consortium, which is measuring the effectiveness of integrating genomic sequencing into clinical care for diverse and medically underserved individuals, are critical for addressing inequities in healthcare and research related to genetics and genomic testing [7, 29, 30].

Numerous additional barriers to research participation may impact trust, such as health literacy, access to care, and preferred language. While our cohort had varying levels of health literacy, all had access to prenatal care by virtue of being seen at UCSF. Interpreters were used for a small number of participants who were non-English speakers, but the cohort consisted primarily of participants who likely felt readily able to communicate with the research team in a shared language, perhaps contributing to a level of pre-existing trust. Additional research is needed to investigate the more precise impact of these factors specifically on trust and participation in prenatal genomic research.

An additional theme we identified was trust in the personal utility of information to be gained from ES, with participants hoping to gain direct information about why the fetal anomaly might have occurred and whether this might affect future pregnancies. There was also recognition from participants that the process of obtaining further genomic testing and engaging in the study not only provided information, but also closure and healing in some cases. Further, many participants cited altruistic reasons for participating in the ES and research, such as hoping to improve care for the future or contribute to knowledge that might lead to novel fetal treatments. Indeed, previous research indicates that both healthy individuals and those with a genetic disease have reported participating in genetic studies to help find a genetic explanation for disease, aid in finding a cure, and raise awareness [31, 32].

Our study has several strengths. Semi-structured interviews allowed participants to voice a range of opinions and concerns both before and after ES results were returned. Sixty-six percent of our cohort self-identified as an underrepresented race or ethnicity, which is crucial to represent a diversity of opinions about genomic testing and research. Additionally, our study included the partners of pregnant individuals, who have less commonly been invited to participate in qualitative research on prenatal diagnosis. Understanding of complex topics such as trust in genomic testing is improved by soliciting in-depth views of not only patients, but also their families. The current study focused on trust, yet many other themes were identified through interviews and future manuscripts will illuminate other important aspects of the patient and partner experiences.

There are, however, important limitations to acknowledge. By virtue of pursuing ES through research, our participants may represent a self-selected group with a greater degree of trust in healthcare and research. There may have been individuals who did not consent to interview participation due to a lack of trust, and these voices were then not captured. Four interviews were conducted in other languages than English, and subsequent transcription of these interviews into English could have resulted in incorrect reinterpretations of the data. Our research team was female and multiple members are White-identifying, which may have influenced our trustworthiness for some participants. While we conducted a large number of interviews, there may be elements of trust that were not elucidated through the participants we interviewed or through the coding process. Due to our sample size, we categorized underrepresented racial and ethnic groups into one underrepresented in genomic research category, to avoid generalizing the perspectives of an individual or small groups of individuals to larger populations. It is important to mention that the perspectives of patients underrepresented in genomic research should be delineated further, in order to understand viewpoints and concerns that may be more relevant to certain racial or ethnic subgroups.

Gaps remain as we work to better understand how to improve research participation and prenatal genomic testing. Future studies should focus on the implementation of known strategies for increasing participation, such as clinical trial transparency and direct engagement [33]. Further, inclusion of diverse populations in prenatal genomic research is an essential step to improve the accuracy of fetal genomic testing, increase the generalizability and impact of results, and represent true breadth in underlying views on trust and other critical factors.

Conclusions

Exome sequencing is a powerful tool in prenatal diagnosis, and ongoing research in prenatal genomics will be essential to improve our understanding of fetal disease. Our study highlights several areas where participants demonstrate the role of trust in healthcare and research. Many patients and their partners expressed trust in the healthcare system and research process, and appreciated the option of extensive testing for information and closure. However, some participants described lack of trustworthiness around data privacy as well as in protection for individuals of underrepresented races and ethnicities. Ongoing research should focus on engaging diverse participants and establishing trust so that a breadth of perspectives are incorporated in the research that we conduct and the healthcare we deliver.

What’s already known about this topic?

• Prenatal exome sequencing is increasingly utilized, yet little is known about motivations for and trust in this testing, particularly from patients underrepresented in genomic research.

What does this study add?

• This study adds perspectives from diverse patients and partners regarding trust in prenatal exome sequencing.

• Participants expressed trust in healthcare and research, and recognized the utility of testing for information and closure. However, concerns were raised about data privacy and protection for individuals of underrepresented races and ethnicities.

Data Availability Statement:

Data that support the findings of this study are available from the corresponding author upon reasonable request and review of regulations based on signed consent forms.