The Parent PrU: A measure to assess personal utility of pediatric genomic results.

PURPOSE: We aimed to adapt and validate an existing patient-reported outcome measure, the personal-utility (PrU) scale, for use in the pediatric genomic context. METHODS: We adapted the adult version of the PrU and obtained feedback from 6 parents whose child had undergone sequencing. The resulting measure, the Parent PrU, was administered to parents of children in 4 pediatric cohorts of the Clinical Sequencing Evidence-Generating Research consortium after they received their children's genomic results. We investigated the measure's structural validity and internal consistency. RESULTS: We conducted a principal-axis factor analysis with oblimin rotation on data from 755 participants to determine structural validity. These analyses yielded a 3-factor solution, accounting for 76% of the variance in the 16 items. We used Cronbach's α to assess the internal consistency of each factor: (1) child benefits (α = .95), (2) affective parent benefits (α = .90), and (3) parent control (α = .94). CONCLUSION: Our evidence suggests that the Parent PrU scale has potential as a measure for assessing parent-reported personal utility of their children's genomic results. Additional research is needed to further validate the Parent PrU scale, including by comparing its findings with utility assessments reported by clinicians and children themselves.

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

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 a multidisciplinary team. RESULTS: Thirty-five individuals participated, the majority of whom (66%) self-identified as 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 those underrepresented, who participated in genomic testing and 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.

Conducting clinical genomics research during the COVID-19 pandemic: Lessons learned from the CSER consortium experience.

Clinical research studies have navigated many changes throughout the COVID-19 pandemic. We sought to describe the pandemic's impact on research operations in the context of a clinical genomics research consortium that aimed to enroll a majority of participants from underrepresented populations. We interviewed (July to November 2020) and surveyed (May to August 2021) representatives of six projects in the Clinical Sequencing Evidence-Generating Research (CSER) consortium, which studies the implementation of genome sequencing in the clinical care of patients from populations that are underrepresented in genomics research or are medically underserved. Questions focused on COVID's impact on participant recruitment, enrollment, and engagement, and the transition to teleresearch. Responses were combined and thematically analyzed. Projects described factors at the project, institutional, and community levels that affected their experiences. Project factors included the project's progress at the pandemic's onset, the urgency of in-person clinical care for the disease being studied, and the degree to which teleresearch procedures were already incorporated. Institutional and community factors included institutional guidance for research and clinical care and the burden of COVID on the local community. Overall, being responsive to community experiences and values was essential to how CSER navigated evolving challenges during the COVID-19 pandemic.

Access to prenatal exome sequencing for fetal malformations: A qualitative landscape analysis in the US.

OBJECTIVE: There is increasing evidence supporting the clinical utility of next generation sequencing for identifying fetal genetic disorders. However, there are limited data on the demand for and accessibility of these tests, as well as payer coverage in the prenatal context. We sought to identify clinician perspectives on the utility of prenatal exome sequencing (ES) and on equitable access to genomic technologies for the care of pregnancies complicated by fetal structural anomalies. METHOD: We conducted two focus group discussions and six interviews with a total of 13 clinicians (11 genetic counselors; 2 Maternal Fetal Medicine/Geneticists) from U.S. academic centers and community clinics. RESULTS: Participants strongly supported ES for prenatal diagnostic testing in pregnancies with fetal structural anomalies. Participants emphasized the value of prenatal ES as an opportunity for a continuum of care before, during, and after a pregnancy, not solely as informing decisions about abortions. Cost and coverage of the test was the main access barrier, and research was the main pathway to access ES in academic centers. CONCLUSION: Further integrating the perspectives of additional key stakeholders are important for understanding clinical utility, developing policies and practices to address access barriers, and assuring equitable provision of prenatal diagnostic testing.

Perspectives and preferences regarding genomic secondary findings in underrepresented prenatal and pediatric populations: A mixed-methods approach.

PURPOSE: Patients undergoing clinical exome sequencing (ES) are routinely offered the option to receive secondary findings (SF). However, little is known about the views of individuals from underrepresented minority pediatric or prenatal populations regarding SF. METHODS: We explored the preferences for receiving hypothetical categories of SF (H-SF) and reasons for accepting or declining actual SF through surveying (n = 149) and/or interviewing (n = 47) 190 families undergoing pediatric or prenatal ES. RESULTS: Underrepresented minorities made up 75% of the probands. In total, 150 families (79%) accepted SF as part of their child/fetus's ES. Most families (63%) wanted all categories of H-SF. Those who declined SF as part of ES were less likely to want H-SF across all categories. Interview findings indicate that some families did not recall their SF decision. Preparing for the future was a major motivator for accepting SF, and concerns about privacy, discrimination, and psychological effect drove decliners. CONCLUSION: A notable subset of families (37%) did not want at least 1 category of H-SF, suggesting more hesitancy about receiving all available results than previously reported. The lack of recollection of SF decisions suggests a need for alternative communication approaches. Results highlight the importance of the inclusion of diverse populations in genomic research.

Making Abortion Safer in Rwanda: Operationalization of the Penal Code of 2012 to Expand Legal Exemptions and Challenges.

Penal code was revised in Rwanda in 2012 allowing legal termination of pregnancy resulting from rape, incest, forced marriage, or on medical grounds. An evaluation was conducted to assess women's access to abortion services as part of an ongoing program to operationalize the new exemptions for legal abortion. Data was collected from eight district hospitals; seven gender-based violence (GBV) centers and six intermediate courts. Three focus group discussions and 22 in-depth interviews were conducted with key informants. At hospitals, of the 2,644 uterine evacuation records (July 2012-June 2014), and 312 monitoring cases (August-December 2014), majority of all uterine evacuations (97% and 85% respectively, for the two periods) were for obstetric conditions, and induced abortion on medical grounds accounted for 2% vs. 15% respectively. Medical abortion was the prominent method of uterine evacuation. At the GBV centers, 3,763 records were identified retrospectively; 273 women were pregnant. Since the legal reform there was only one abortion for a pregnancy resulting from rape. Abortion stigma and court order requirement are major barriers to access services. The operationalization program has made significant contributions to make abortion safer in Rwanda but this evaluation demonstrates that further work is required to reach the goal of providing safe abortion services to all eligible women. Addressing abortion stigma at the community, organizational and structural levels; further strengthening of service provision; and streamlining legal requirements to protect particularly young women from sexual violence and making abortion a realistic option for GBV victims are some of the important next steps.

Genetic ancestry and diagnostic yield of exome sequencing in a diverse population.

It has been suggested that diagnostic yield (DY) from Exome Sequencing (ES) may be lower among patients with non-European ancestries than those with European ancestry. We examined the association of DY with estimated continental/subcontinental genetic ancestry in a racially/ethnically diverse pediatric and prenatal clinical cohort. Cases (N = 845) with suspected genetic disorders underwent ES for diagnosis. Continental/subcontinental genetic ancestry proportions were estimated from the ES data. We compared the distribution of genetic ancestries in positive, negative, and inconclusive cases by Kolmogorov-Smirnov tests and linear associations of ancestry with DY by Cochran-Armitage trend tests. We observed no reduction in overall DY associated with any genetic ancestry (African, Native American, East Asian, European, Middle Eastern, South Asian). However, we observed a relative increase in proportion of autosomal recessive homozygous inheritance versus other inheritance patterns associated with Middle Eastern and South Asian ancestry, due to consanguinity. In this empirical study of ES for undiagnosed pediatric and prenatal genetic conditions, genetic ancestry was not associated with the likelihood of a positive diagnosis, supporting the equitable use of ES in diagnosis of previously undiagnosed but potentially Mendelian disorders across all ancestral populations.

Lessons learned while starting multi-institutional genetics research in diverse populations: A report from the Clinical Sequencing Evidence-Generating Research (CSER) consortium.

BACKGROUND: Increasing diversity in clinical trial participation is necessary to improve health outcomes and requires addressing existing social, structural, and geographic barriers. The Clinical Sequencing Evidence-Generating Research Consortium (CSER) included six research projects to enroll historically underrepresented/underserved (UR/US) populations in clinical genomics research. Delays and project re-designs emerged shortly after work began. Understanding common experiences of these projects may inform future trial implementation. METHODS: Semi-structured interviews with six CSER principal investigators and seven project managers were performed. An interview guide included questions of research/clinical infrastructure, logistics across sites, language, communication, and allocation of grant-related resources. Interviews were recorded, transcribed verbatim; transcripts were analyzed using inductive coding, thematic analysis and consensus building. RESULTS: All projects collaborating with new clinical sub-sites to recruit UR/US populations. Refining trial logistics continued long after enrollment for all projects. Themes of challenges included: sub-site customization for workflow and genetics support, conflicting input from participant advisory groups and approval bodies, developing research personnel, complex data management structures, and external changes (e.g. subcontractors ending contracts) that required redesign. Themes of beneficial lessons included: domains with prior experience were easier, develop project champions at each sub-site, structure communication within the research team, and simplify research design when possible. CONCLUSIONS: The operational aspects of expanding clinical research into novel sub-sites are significant and require investment of time and resources. The themes arising from these interviews suggest priority areas for more quantitative analyses in the future including multi-institutional approval policies and processes, data management structures, and incremental research complexity.

Parent-Reported Clinical Utility of Pediatric Genomic Sequencing.

BACKGROUND AND OBJECTIVES: Genomic sequencing (GS) is increasingly used for diagnostic evaluation, yet follow-up care is not well understood. We assessed clinicians' recommendations after GS, parent-reported follow-up, and actions parents initiated in response to learning their child's GS results. METHODS: We surveyed parents of children who received GS through the Clinical Sequencing Evidence Generating Research consortium ∼5 to 7 months after return of results. We compared the proportion of parents who reported discussing their child's result with a clinician, clinicians' recommendations, and parents' follow-up actions by GS result type using χ2 tests. RESULTS: A total of 1188 respondents completed survey measures on recommended medical actions (n = 1187) and/or parent-initiated actions (n = 913). Most parents who completed recommended medical actions questions (n = 833, 70.3%) reported having discussed their child's GS results with clinicians. Clinicians made recommendations to change current care for patients with positive GS results (n = 79, 39.1%) more frequently than for those with inconclusive (n = 31, 12.4%) or negative results (n = 44, 11.9%; P < .001). Many parents discussed (n = 152 completed, n = 135 planned) implications of GS results for future pregnancies with a clinician. Aside from clinical recommendations, 13.0% (n = 119) of parents initiated changes to their child's health or lifestyle. CONCLUSIONS: In diverse pediatric clinical contexts, GS results can lead to recommendations for follow-up care, but they likely do not prompt large increases in the quantity of care received.

Diagnostic Yield of Exome Sequencing in a Diverse Pediatric and Prenatal Population is not Associated with Genetic Ancestry.

Purpose: It has been hypothesized that diagnostic yield (DY) from Exome Sequencing (ES) may be lower among patients with non-European ancestries than those with European ancestry. We examined the association of DY with estimated continental genetic ancestry in a racially/ethnically diverse pediatric and prenatal clinical cohort. Methods: Cases (N=845) with suspected genetic disorders underwent ES for diagnosis. Continental genetic ancestry proportions were estimated from the ES data. We compared the distribution of genetic ancestries in positive, negative, and inconclusive cases by Kolmogorov Smirnov tests and linear associations of ancestry with DY by Cochran-Armitage trend tests. Results: We observed no reduction in overall DY associated with any continental genetic ancestry (Africa, America, East Asia, Europe, Middle East, South Asia). However, we observed a relative increase in proportion of autosomal recessive homozygous inheritance versus other inheritance patterns associated with Middle Eastern and South Asian ancestry, due to consanguinity. Conclusions: In this empirical study of ES for undiagnosed pediatric and prenatal genetic conditions, genetic ancestry was not associated with the likelihood of a positive diagnosis, supporting the ethical and equitable use of ES in diagnosis of previously undiagnosed but potentially Mendelian disorders across all ancestral populations.

Diagnostic yield of pediatric and prenatal exome sequencing in a diverse population.

The diagnostic yield of exome sequencing (ES) has primarily been evaluated in individuals of European ancestry, with less focus on underrepresented minority (URM) and underserved (US) patients. We evaluated the diagnostic yield of ES in a cohort of predominantly US and URM pediatric and prenatal patients suspected to have a genetic disorder. Eligible pediatric patients had multiple congenital anomalies and/or neurocognitive disabilities and prenatal patients had one or more structural anomalies, disorders of fetal growth, or fetal effusions. URM and US patients were prioritized for enrollment and underwent ES at a single academic center. We identified definitive positive or probable positive results in 201/845 (23.8%) patients, with a significantly higher diagnostic rate in pediatric (26.7%) compared to prenatal patients (19.0%) (P = 0.01). For both pediatric and prenatal patients, the diagnostic yield and frequency of inconclusive findings did not differ significantly between URM and non-URM patients or between patients with US status and those without US status. Our results demonstrate a similar diagnostic yield of ES between prenatal and pediatric URM/US patients and non-URM/US patients for positive and inconclusive results. These data support the use of ES to identify clinically relevant variants in patients from diverse populations.

Parental Hopes and Understandings of the Value of Prenatal Diagnostic Genomic Sequencing: A Qualitative Analysis.

Objective: To provide qualitative empirical data on parental expectations of diagnostic prenatal genomic sequencing and the value of the results to families. Methods: We interviewed 15 families-mothers and/or fathers-who had had prenatal genomic sequencing about their expectations and their respective evaluations of the benefits of genomic sequencing. Results: Families' hopes for genetic sequencing clustered around three themes: hoping to identify the cause of the fetal anomaly in a terminated pregnancy; hopes for guidance as to the likely outcome of current pregnancy; and hopes for information to support future family planning. In addition, hopes were discussed in terms of the potential for results to be beneficial in acquiring greater knowledge, while at the same time recognizing that new knowledge may raise more questions. Assessment of the value of sequencing largely mirrored these expectations when positive results seen. Negative results can also be seen as valuable in ruling out a genetic cause and in providing certainty that families had done everything that they could to know about the cause of fetal demise. Conclusion: It would appear that with guidance from genetic counsellors, families were largely able to navigate the many uncertainties of prenatal genomic sequencing and thus see themselves as benefitting from sequencing. However, support structures are essential to guide them through their expectations and interpretations of results to minimize possible harms. Engaging in the process of genomic sequencing was seen as beneficial in of itself to families who would otherwise be left without any options to seek diagnostic answers.

"Let's Just Wait Until She's Born": Temporal Factors That Shape Decision-Making for Prenatal Genomic Sequencing Amongst Families Underrepresented in Genomic Research.

Genomic sequencing has been increasingly utilized for prenatal diagnosis in recent years and this trend is likely to continue. However, decision-making for parents in the prenatal period is particularly fraught, and prenatal sequencing would significantly expand the complexity of managing health risk information, reproductive options, and healthcare access. This qualitative study investigates decision-making processes amongst parents who enrolled or declined to enroll in the prenatal arm of the California-based Program in Prenatal and Pediatric Genome Sequencing (P3EGS), a study in the Clinical Sequencing Evidence-Generating Research (CSER) consortium that offered whole exome sequencing for fetal anomalies with a focus on underrepresented groups in genomic research. Drawing on the views of 18 prenatal families who agreed to be interviewed after enrolling (n = 15) or declining to enroll (n = 3) in P3EGS, we observed that the timing of sequencing, coupled with unique considerations around experiences of time during pregnancy and prenatal testing, intersect with structural supports beyond the clinic to produce preferences for and against prenatal sequencing and to contain the threat of unwelcome, uncertain knowledge. Particularly for those without structural supports, finding out consequential information may be more palatable after the birth, when the first stage of the uncertain future has been revealed. Future research should examine the role of temporality in decision-making around prenatal genomic sequencing across diverse population cohorts, in order to observe more precisely the role that structural barriers play in patient preferences.

User experiences and acceptability attributes of the diaphragm and lubricant gel in an HIV prevention trial in southern Africa.

Methods for Improving Reproductive Health in Africa (MIRA), a phase III HIV prevention trial, was conducted among 5039 Zimbabwean and South African women to test the Ortho All-Flex diaphragm and Replens(®) lubricant gel. Among the 2418 intervention group participants, 105 women who had completed the trial and 41 male partners participated in focus group discussions and in-depth interviews about the acceptability of the diaphragm and gel and their experiences using the study products. Women who participated in the qualitative study had exited the trial in the prior nine months, were HIV negative, and used the diaphragm and gel for 12-24 months. The comprehensive and flexible conceptual framework was applied to investigate the salient attributes for acceptability of the products as potential HIV prevention methods, and emerging themes for acceptability were framed within three categories of attributes (product, relationship, and sexual intercourse attributes). Both diaphragm and gel were found to be highly acceptable in the study group, and the gel was popular due to its effect of enhancing sexual pleasure. Some of the important product attributes influencing acceptability as reported by users were convenience, ease of use, dual use potential for contraception and disease prevention, and being female-initiated. It was also noted that some elements (such as sexual pleasure, couple communication, and the necessity of diaphragm negotiation) could be more important than others in terms of influencing product acceptability and use. Acceptability attributes reflective of the broader contextual environment (beliefs generated in the trial community suggesting preventive efficacy - preventive method optimism - and gendered norms favoring male superiority in sexual decision making) also emerged as important themes. The high level of acceptability of the diaphragm and gel among MIRA trial participants and their male partners is an indicator of the continued need for an effective female-initiated product.

Feasibility and potential acceptability of three cervical barriers among vulnerable young women in Zimbabwe.

BACKGROUND: We explored the potential acceptability of three cervical barriers (CB) (Ortho All-Flex diaphragm, SILCS diaphragm, FemCap cervical cap) among sexually experienced Zimbabwean young women. METHODS: Forty-five young women (aged 16-21 years) received an individual CB educational session. Participants were then randomly assigned to one of the three CBs in a 1:1:1 ratio, and practised insertion and removal of their device at the clinic. Next, participants were interviewed on their practice experiences, and their post-practice attitudes towards CB. RESULTS: All 45 young women were willing and able to insert their assigned device. The majority reported "easy" insertion and removal and 93% "liked" the device they tried. All showed interest in participating in future CB studies: when asked which device they would like to try in the future, over half (58%) chose SILCS, regardless of the device they had tried. The majority felt comfortable touching their genitals to insert/remove the CB and most participants favoured methods' attributes associated with female-control and non-interference with sex. Over half the participants said they would prefer to use a CB continuously compared to episodic use. Two-thirds of them expressed interest in CB for dual protection. CONCLUSION: The concept of CB, and initial insertion experience, were well accepted in this selected, small group of Zimbabwean young women. Evaluating CB in larger studies seems feasible in this population.

A qualitative study of obstacles to diaphragm and condom use in an HIV prevention trial in sub-Saharan Africa.

Consistent condom use and the substitution of condoms with potential HIV prevention methods of lower or unknown effectiveness are important concerns in the development of new prevention technologies. This qualitative study explored obstacles to consistent condom use with the diaphragm in MIRA, an HIV prevention trial in South Africa and Zimbabwe. We conducted 26 focus group discussions (FGDs) with 206 women and 7 FGDs and 10 in-depth interviews with 41 male partners of intervention-arm women. The belief that the diaphragm/gel prevented HIV, women's difficulties negotiating condom use, and men's unawareness that using the products together was recommended were obstacles to consistent condom use with the diaphragm/gel. Concerns about protection from HIV and pregnancy, recognition that the diaphragm was not yet proven to prevent HIV or sexually transmitted infections, and the trial context were facilitators. Understanding selective study product use in HIV prevention trials may inform improved adherence counseling and male involvement strategies.

Duet for menstrual protection: a feasibility study in Zimbabwe.

BACKGROUND: Managing menses is a challenge for women in developing countries. Duet is a cervical barrier being developed for contraception and STI prevention. We explored the hypothetical acceptability of using Duet as a menstrual cup, among Zimbabwean women. STUDY DESIGN: A survey and focus group discussions (FGD) were conducted with 43 women aged 18-45 years to gain information about their menstrual practices and attitudes regarding the use of Duet for menstrual protection. RESULTS: All 43 women reported that if Duet were available, they would "definitely" try it, and that it was "very important" that Duet is low cost and easy to clean; 86% reported that using it would make a difference in their lives. FGD findings highlighted unhygienic practices due to the lack of affordable options for menstrual management and a genuine interest in Duet, including its potential use for multiple purposes (contraception, disease prevention and menstrual protection). CONCLUSIONS: Accessing affordable and hygienic menstrual protection was a problem for these Zimbabwean women. Duet appeared acceptable and it would be feasible to conduct a user-acceptability study of Duet as a menstrual cup in Zimbabwe.