Addressing underrepresentation in genomics research through community engagement.

The vision of the American Society of Human Genetics (ASHG) is that people everywhere will realize the benefits of human genetics and genomics. Implicit in that vision is the importance of ensuring that the benefits of human genetics and genomics research are realized in ways that minimize harms and maximize benefits, a goal that can only be achieved through focused efforts to address health inequities and increase the representation of underrepresented communities in genetics and genomics research. This guidance is intended to advance community engagement as an approach that can be used across the research lifecycle. Community engagement uniquely offers researchers in human genetics and genomics an opportunity to pursue that vision successfully, including by addressing underrepresentation in genomics research.

Early Intervention services in the era of genomic medicine: setting a research agenda.

Newborn genomic sequencing (NBSeq) has the potential to substantially improve early detection of rare genetic conditions, allowing for pre-symptomatic treatment to optimize outcomes. Expanding conceptions of the clinical utility of NBSeq include earlier access to behavioral early intervention to support the acquisition of core motor, cognitive, communication, and adaptive skills during critical windows in early development. However, important questions remain about equitable access to early intervention programs for the growing number of infants identified with a genetic condition via NBSeq. We review the current NBSeq public health, clinical, and research landscape, and highlight ongoing international research efforts to collect population-level data on the utility of NBSeq for healthy newborns. We then explore the challenges facing a specific Early Intervention (EI) system-the US federally supported "Part C" system-for meeting the developmental needs of young children with genetic diagnoses, including structural limitations related to funding, variable eligibility criteria, and lack of collaboration with newborn screening programs. We conclude with a set of questions to guide future research at the intersection of NBSeq, newborn screening, and EI, which once answered, can steer future policy to ensure that EI service systems can optimally support the developmental needs of infants impacted by broader implementation of NBSeq. IMPACT: Existing literature on the clinical benefits of genome sequencing in newborns tends to focus on earlier provision of medical interventions, with less attention to the ongoing developmental needs of very young children with genetic conditions. This review outlines the developmental needs of a growing number of children diagnosed with genetic conditions in infancy and describes the strengths and limitations of the United States Early Intervention system (IDEA Part C) for meeting those needs.

Scaling genetic resources: New paradigms for diagnosis and treatment of rare genetic disease.

Development of genetic tests for rare genetic diseases has traditionally focused on individual diseases. Similarly, development of new therapies occurred one disease at a time. With >10,000 rare genetic diseases, this approach is not feasible. Diagnosis of genetic disorders has already transcended old paradigms as whole exome and genome sequencing have allowed expedient interrogation of all relevant genes in a single test. The growth of newborn screening has allowed identification of diseases in presymptomatic babies. Similarly, the ability to develop therapies is rapidly expanding due to technologies that leverage platform technology that address multiple diseases. However, movement from the basic science laboratory to clinical trials is still hampered by a regulatory system rooted in traditional trial design, requiring a fresh assessment of safe ways to obtain approval for new drugs. Ultimately, the number of nucleic acid-based therapies will challenge the ability of clinics focused on rare diseases to deliver them safely with appropriate evaluation and long-term follow-up. This manuscript summarizes discussions arising from a recent National Institutes of Health conference on nucleic acid therapy, with a focus on scaling technologies for diagnosis of rare disorders and provision of therapies across the age and disease spectrum.

Gene-targeted therapies: Towards equitable development, diagnosis, and access.

Genomic and gene-targeted therapies hold great promise in addressing the global issue of rare diseases. To achieve this promise, however, it is critical the twin goals of equity in access to testing and diagnosis, and equity in access to therapy be considered early in the life cycle of development and implementation. Rare disease researchers and clinicians must simultaneously recognize the life-altering potential of early diagnosis and administration of gene-targeted therapeutics while acknowledging that not everyone who experiences a rare disease and needs these therapies will be able to afford or access them. Achieving equity in the development of and access to gene-targeted therapies will not only require innovations in research, clinical, regulatory, and reimbursement frameworks, but will also necessitate increased attention to the ethical, legal, and social implications when establishing research paradigms and the translation of research results into novel interventions for rare genetic diseases. This article highlights and discusses the growing importance and recognition of health equity across the spectrum of rare disease research and care delivery.

Moving away from one disease at a time: Screening, trial design, and regulatory implications of novel platform technologies.

Most rare diseases are caused by single-gene mutations, and as such, lend themselves to a host of new gene-targeted therapies and technologies including antisense oligonucleotides, phosphomorpholinos, small interfering RNAs, and a variety of gene delivery and gene editing systems. Early successes are encouraging, however, given the substantial number of distinct rare diseases, the ability to scale these successes will be unsustainable without new development efficiencies. Herein, we discuss the need for genomic newborn screening to match pace with the growing development of targeted therapeutics and ability to rapidly develop individualized therapies for rare variants. We offer approaches to move beyond conventional "one disease at a time" preclinical and clinical drug development and discuss planned regulatory innovations that are necessary to speed therapy delivery to individuals in need. These proposals leverage the shared properties of platform classes of therapeutics and innovative trial designs including master and platform protocols to better serve patients and accelerate drug development. Ultimately, there are risks to these novel approaches; however, we believe that close partnership and transparency between health authorities, patients, researchers, and drug developers present the path forward to overcome these challenges and deliver on the promise of gene-targeted therapies for rare diseases.

Analogies in Genomics Policymaking: Debates and Drawbacks.

The analogy between genomics and imaging has been an important touchstone in the debate on how secondary findings should be handled in both clinical and research genomics contexts. However, a critical eye is needed to understand whether an analogy like this one provides an adequate basis for policymaking in genomics. Genomics and imaging are undoubtedly similar in certain ways, but whether that similarity is adequate to justify adopting identical policies is a task that requires further analysis. This is highlighted by the fact that secondary findings are produced in other domains of medicine and public health, such as newborn screening programs, routine laboratory panels, and antibiotic sensitivity testing, and that the practices for handling secondary findings in each of these areas are different. These examples demonstrate that medicine has no single comprehensive policy or set of practices for managing secondary findings. Analogies to imaging, newborn screening, routine testing panels, and antibiotic sensitivity testing all lead to different policy options for genomics. In this piece we argue that analogies are a powerful way of driving policy discussions by rendering two different areas of medical practice similar, but an overdependence on a single analogy risks limiting policy discussions in potentially deleterious ways.

Rare Disease, Advocacy and Justice: Intersecting Disparities in Research and Clinical Care.

Rare genetic diseases collectively impact millions of individuals in the United States. These patients and their families share many challenges including delayed diagnosis, lack of knowledgeable providers, and limited economic incentives to develop new therapies for small patient groups. As such, rare disease patients and families often must rely on advocacy, including both self-advocacy to access clinical care and public advocacy to advance research. However, these demands raise serious concerns for equity, as both care and research for a given disease can depend on the education, financial resources, and social capital available to the patients in a given community. In this article, we utilize three case examples to illustrate ethical challenges at the intersection of rare diseases, advocacy and justice, including how reliance on advocacy in rare disease may drive unintended consequences for equity. We conclude with a discussion of opportunities for diverse stakeholders to begin to address these challenges.

North American genetic counselors' approach to collecting and using ancestry in clinical practice.

Current guidelines from the National Society of Genetic Counselors (NSGC) recommend that patients' ancestry be obtained when taking a family history. However, no study has explored how consistently genetic counselors obtain or utilize this information. The goals of this study included assessing how genetic counselors collect their patients' ancestry, what factors influence this decision, and how they view the utility of this information. Genetic counselors working in a direct patient care setting in the US or Canada were recruited to participate in an anonymous survey via an NSGC email blast. Most participants (n = 115) obtain information about their patients' ancestry (96.5%), with the most common methods being directly asking the patient (91%) and utilizing intake forms (43.2%). Of participants who ask about ancestry directly, 50.5% always ask about the presence of Ashkenazi Jewish ancestry and 70.3% always ask about additional ancestries, suggesting that for most genetic counselors' collection of ancestry is standard practice. However, the clinical utility of ancestry information is highly variable, with the impact on genetic testing choice being particularly low. A slight majority of participants support a reevaluation of current ancestry guidelines (51.3%), with many participants suggesting that the varying utility of ancestry in different clinical indications/specialties should be incorporated into guidelines. Despite being standard practice for most genetic counselors, no unified approach or standard for how ancestral information should be used in genetic counseling practice was identified.

Lived experiences of individuals with cystic fibrosis on CFTR-modulators.

BACKGROUND: CFTR-modulators are a category of drugs that facilitate trafficking and opening of the abnormal CFTR protein in individuals with cystic fibrosis (CF) who have certain genetic mutations. Clinical trial data show that individuals taking CFTR-modulators have increased or stable lung function (FEV1) as well as reduced frequency of pulmonary exacerbations. There are no data on whether CFTR-modulators influence psychosocial aspects of the lives of individuals with CF. The purpose of this qualitative study was to explore how the introduction of CFTR-modulators has affected individuals' lived experiences outside of clinical health variables; that is, to explore whether there is a relationship between using CFTR-modulator drugs and the psychological and social aspects of the lives of individuals with CF, including: career, relationships, family planning and psychological functioning. METHODS: Eight men and women with CF ages 24-32, with a history of taking any approved CFTR-modulator for at least six months, were recruited from an adult CF center. A semi-structured interview guide was used to interview the participants. The data were coded using a grounded theory approach with an iterative methodology. RESULTS: Four themes emerged from the data: stability, identity, potentiality, and hope. CONCLUSIONS: Although these themes cannot be generalized to all individuals with CF, this study provides preliminary data for how CFTR-modulators may influence an individual with CF's outlook on life and that these individuals are feeling hopeful about the future.

Digital peer-to-peer information seeking and sharing: Opportunities for education and collaboration in newborn screening.

Parents use the internet to connect with their peers and access information about a multitude of health topics, including newborn screening (NBS). As the NBS system evolves, education about NBS must be evaluated and updated to remain accessible and beneficial to parents. In this article, we aim to describe parents' current NBS educational needs and highlight areas to improve newborn screening education by detailing an analysis of NBS posts on an online parenting discussion platform. We analyzed a total of 317 discussion posts on BabyCenter®, finding that parents had questions about and desired support around many aspects of NBS including processes, results, and follow-up. As a result of this analysis, three recommendations to improve NBS education were developed. Through collaboration and by leveraging technology, we can provide parents with accessible, timely, and desired NBS informational and social support.

"It seems like COVID-19 now is the only disease present on Earth": living with a rare or undiagnosed disease during the COVID-19 pandemic.

PURPOSE: Patients with rare and undiagnosed diseases (RUDs) face significant health challenges, which may be exacerbated during the COVID-19 pandemic. The goal of this study was to identify specific impacts of the pandemic on RUD patients, and targets for improving support and health-care access. METHODS: We conducted an online survey of RUD patients and their family members from 21 April to 8 June 2020, recruited from 76 Facebook groups for RUDs. Questions assessed patient characteristics and impacts of the pandemic on RUD diagnosis and management. RESULTS: Respondents (n = 413), including 274 RUD patients and 139 family members, were predominantly female and white, though income varied. Impacts of the pandemic included (1) barriers to accessing essential health care, (2) specific impacts of restrictive COVID-19 visitation policies on ability to advocate in health-care settings, (3) uncertainty and fear regarding COVID-19 risk, (4) exacerbated physical and mental health challenges, (5) magnified impacts of reduced educational and therapeutic services, and (6) unexpected positive changes due to the pandemic. CONCLUSION: There are specific, serious challenges affecting RUD patients and families during the COVID-19 pandemic. There is an urgent need to develop approaches to mitigate these challenges both during and beyond the pandemic.

Prenatal genetic counselors' perceptions of the impact of abortion legislation on counseling and access in the United States.

Genetic counselors have an important role in offering and appropriate coordinating abortion services for patients identified with a fetal abnormality. Few studies have been conducted to determine the effects of legislation on genetic counselors and patients. This study aimed to further our understanding of genetic counselors' perception of the impact of abortion regulations on their practice, the perceived financial and emotional impact on their patients and their ability to access abortion. A 22-question survey was developed based on themes identified by a qualitative study (Koenig et al., 2019, Journal of Genetic Counseling, 28, 790-801), and distributed to members of the National Society of Genetic Counselors; data from 113 respondents are analyzed. For analysis, participants were categorized into three groups based on the restrictiveness of their state's abortion legislation (supportive, middle ground, hostile) using the Guttmacher Institute's designation based on the amount of restrictive abortion legislation in their state. Participants reported that legislative gestational age restrictions significantly impact their counseling and coordinating of abortion services. Participants reported emotional and financial burdens that impact their patients seeking abortion; however, those in hostile states were significantly more likely to report a perceived financial or emotional impact on their patients. Participants in hostile states were more likely than those in supportive states to report that many of the addressed legislative and institutional regulations impact patients' ability to access abortion. Abortion regulations limiting the decision-making time frame for patients with a fetal abnormality have a significant impact on the practice of prenatal genetic counseling. Further restrictions may change how genetic counselors choose to counsel their patients about the option of abortion, but also may limit the availability of choices particularly for patients in rural areas, in hostile states, and those without the financial resources to travel or pursue termination at later gestational ages.

The limited use of US residual newborn screening dried bloodspots for health disparity research.

PURPOSE: State-run newborn screening programs screen nearly all babies born in the United States at the time of delivery. After newborn screening has been completed, some states store the residual dried bloodspots. It is unknown how they have been used to address health disparities-related research. METHODS: In 2017-2018, a scoping review was conducted to evaluate the extent, type, and nature of how residual dried bloodspots. The review included 654 eligible publications, worldwide, published before May 2017. A post hoc analysis of the US-based studies using residual dried bloodspots (n = 192) were analyzed. RESULTS: There were 32 (16.7%) articles identified that studied a condition of a known health disparity or focused on a key population: 25 studies assessed a disease or condition, 6 expressly enrolled a key population, and 1 study included both (i.e., heart disease and African American/Black). CONCLUSION: Excluding 12 studies that researched leukemia or a brain tumor, only 20 studies addressed a known health disparity, with 6 stating a specific aim to address a health disparity. This resource could be used to gain further knowledge about health disparities, but is currently underutilized.

Public involvement in the governance of population-level biomedical research: unresolved questions and future directions.

Population-level biomedical research offers new opportunities to improve population health, but also raises new challenges to traditional systems of research governance and ethical oversight. Partly in response to these challenges, various models of public involvement in research are being introduced. Yet, the ways in which public involvement should meet governance challenges are not well understood. We conducted a qualitative study with 36 experts and stakeholders using the World Café method to identify key governance challenges and explore how public involvement can meet these challenges. This brief report discusses four cross-cutting themes from the study: the need to move beyond individual consent; issues in benefit and data sharing; the challenge of delineating and understanding publics; and the goal of clarifying justifications for public involvement. The report aims to provide a starting point for making sense of the relationship between public involvement and the governance of population-level biomedical research, showing connections, potential solutions and issues arising at their intersection. We suggest that, in population-level biomedical research, there is a pressing need for a shift away from conventional governance frameworks focused on the individual and towards a focus on collectives, as well as to foreground ethical issues around social justice and develop ways to address cultural diversity, value pluralism and competing stakeholder interests. There are many unresolved questions around how this shift could be realised, but these unresolved questions should form the basis for developing justificatory accounts and frameworks for suitable collective models of public involvement in population-level biomedical research governance.

Correction: Experiences and perspectives on the return of secondary findings among genetic epidemiologists.

In the original published version of Table 2 the number of respondents who said "No" to the question "Does your consent form distinguish between targeted and incidental findings?" was indicated as "4." It should have read "44." This has now been corrected in both the PDF and HTML versions of the Article.

Experiences and perspectives on the return of secondary findings among genetic epidemiologists.

PURPOSE: While there has been a recent increase in scholarship around developing policies for the return of results from genetic sequencing, it is not clear whether these approaches are appropriate for genetic epidemiology studies. Because genetic epidemiological research increasingly utilizes genome sequencing methods, particularly in large data sets where researchers did not directly ascertain the subjects, it is important to understand researchers' perspectives on the return of results. METHODS: We conducted an online survey of members of the International Genetic Epidemiology Society to document the diversity of experiences and impressions regarding return of results. The survey contained both closed and open-ended questions. RESULTS: Among our respondents who enroll their own research participants, only 21% return secondary findings. Most respondents do not search their sequence data for clinically actionable findings not associated with their disease of interest. Many feel that genetic epidemiologists have a unique perspective on the return of results and that research studies should not follow the same procedures as clinical sequencing studies. CONCLUSION: Precision medicine initiatives that rely on both clinical and "big data" genomic research should account for variation in researcher perspectives and study design limitations when developing policies and standard practices regarding the return of results.

Including ELSI research questions in newborn screening pilot studies.

BACKGROUND: The evidence review processes for adding new conditions to state newborn screening (NBS) panels rely on data from pilot studies aimed at assessing the potential benefits and harms of screening. However, the consideration of ethical, legal, and social implications (ELSI) of screening within this research has been limited. This paper outlines important ELSI issues related to newborn screening policy and practices as a resource to help researchers integrate ELSI into NBS pilot studies. APPROACH: Members of the Bioethics and Legal Workgroup for the Newborn Screening Translational Research Network facilitated a series of professional and public discussions aimed at engaging NBS stakeholders to identify important existing and emerging ELSI challenges accompanying NBS. RESULTS: Through these engagement activities, we identified a set of key ELSI questions related to (1) the types of results parents may receive through newborn screening and (2) the initiation and implementation of NBS for a condition within the NBS system. CONCLUSION: Integrating ELSI questions into pilot studies will help NBS programs to better understand the potential impact of screening for a new condition on newborns and families, and make crucial policy decisions aimed at maximized benefits and mitigating the potential negative medical or social implications of screening.

Genomic Contextualism: Shifting the Rhetoric of Genetic Exceptionalism.

As genomic science has evolved, so have policy and practice debates about how to describe and evaluate the ways in which genomic information is treated for individuals, institutions, and society. The term genetic exceptionalism, describing the concept that genetic information is special or unique, and specifically different from other kinds of medical information, has been utilized widely, but often counterproductively in these debates. We offer genomic contextualism as a new term to frame the characteristics of genomic science in the debates. Using stasis theory to draw out the important connection between definitional issues and resulting policies, we argue that the framework of genomic contextualism is better suited to evaluating genomics and its policy-relevant features to arrive at more productive discussion and resolve policy debates.

Exploring prenatal genetic counselors' perceptions of abortion laws in restrictive states.

In many states, abortion laws are becoming increasingly restrictive. Prenatal genetic counselors often see patients after the diagnosis of a fetal abnormality or genetic disorder and discuss the option of termination of pregnancy. The purpose of this study was to understand prenatal genetic counselors' perspectives on how state abortion laws impact their practice. Qualitative semi-structured interviews were conducted with 16 prenatal genetic counselors in states with restrictive abortion laws who were recruited from the National Society of Genetic Counselors' online directory. Verbatim transcripts were analyzed thematically, yielding five themes: genetic counselors in this study described (a) how state laws restrict access to abortion; (b) how they navigate state laws and institutional policies regarding abortion; (c) how they tailor their professional practice in the context of state abortion laws; (d) how abortion laws burden patients; and (e) how they engage in forms of advocacy. Participants described the financial and emotional burden placed on their patients by state abortion laws and how the laws influence their patient interactions. As access to abortion becomes more restricted, it is important to be aware of how this will impact genetic counselors and their patients.