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.

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.

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.

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.

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.

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.

Evaluating Harms in the Assessment of Net Benefit: A Framework for Newborn Screening Condition Review.

BACKGROUND: The Department of Health and Human Services (HHS) Advisory Committee on Heritable Disorders in Newborns and Children ("Advisory Committee") makes recommendations to the HHS Secretary regarding addition of new conditions to the national Recommended Uniform Screening Panel for newborns. The Advisory Committee's decision-making process includes assessing the net benefit of screening for nominated conditions, informed by systematic evidence reviews generated by an independent Condition Review Workgroup. The evidence base regarding harms associated with screening for specific conditions is often more limited than that for benefits. PROCEDURES: The process for defining potential harms from newborn screening reviewed the frameworks from other public health evidence-based review processes, adapted to newborn screening by experts in systematic review, newborn screening programs and bioethics, with input from and approval by the Advisory Committee. MAIN FINDINGS: To support the Advisory Committee's review of nominated conditions, the Workgroup has developed a standardized approach to evaluation of harms and relevant gaps in the evidence. Types of harms include the physical burden to infants; psychosocial and logistic burdens to families from screening or diagnostic evaluation; increased risk of medical treatment for infants diagnosed earlier than children with clinical presentation; delayed diagnosis from false negative results; psychosocial harm from false positive results; uncertainty of clinical diagnosis, age of onset or clinical spectrum; and disparities in access to diagnosis or therapy. CONCLUSIONS: Estimating the numbers of children at risk, the magnitude, timing and likelihood of harms will be integrated into Workgroup reports to the Advisory Committee.

Ethical issues with newborn screening in the genomics era.

Continued technological advances have made the prospect of routine whole-genome sequencing (WGS) imminent. To date, much of the discussion about WGS has focused on its application and use in clinical medicine. Relatively little attention has been paid to the potential integration of WGS into newborn screening programs. Given the structure and scope of these programs, it is possible that the early applications of WGS will occur in state-run newborn screening programs. Assessment of the pressing ethical issues currently facing the newborn screening community will provide insight into the challenges that lie ahead in the genomics era.

IRB practices and policies regarding the secondary research use of biospecimens.

BACKGROUND: As sharing and secondary research use of biospecimens increases, IRBs and researchers face the challenge of protecting and respecting donors without comprehensive regulations addressing the human subject protection issues posed by biobanking. Variation in IRB biobanking policies about these issues has not been well documented. METHODS: This paper reports on data from a survey of IRB Administrative Directors from 60 institutions affiliated with the Clinical and Translation Science Awards (CTSAs) about their policies and practices regarding secondary use and sharing of biospecimens. Specifically, IRB ADs were asked about consent for future use of biospecimens, assignment of risk for studies using biobanked specimens, and sharing of biospecimens/data. RESULTS: Our data indicate that IRBs take varying approaches to protocol review, risk assessment, and data sharing, especially when specimens are not anonymized. CONCLUSION: Unclear or divergent policies regarding biospecimen research among IRBs may constitute a barrier to advancing genetic studies and to inter-institutional collaboration, given different institutional requirements for human subjects protections.

Is there a space for place in family history assessment? Underserved community views on the impact of neighborhood factors on health and prevention.

Family health history tools rarely incorporate environmental and neighborhood factors, although the social and physical environments in which people live are recognized as major contributors to chronic diseases. This paper discusses beliefs about neighborhood influences on chronic disease risk among racially and ethnically diverse individuals in low-income communities in Cleveland, Ohio. We report findings from a qualitative study consisting of 121 interviews with White, African American, and Hispanic participants. Results are organized into four major themes: (1) social and economic environment, (2) physical environment, (3) barriers to healthy behaviors, and (4) participants' views on integrating genetic and non-genetic determinants of health to understand and address disease prevention and management. Findings suggest that integrating environmental factors into family health history assessments would better reflect lay perceptions of disease causation. Results have implications for improving patient-clinician communication and the development of strategies to prevent and manage chronic diseases.

Parents' interest in whole-genome sequencing of newborns.

PURPOSE: The aim of this study was to assess parents' interest in whole-genome sequencing for newborns. METHODS: We conducted a survey of a nationally representative sample of 1,539 parents about their interest in whole-genome sequencing of newborns. Participants were randomly presented with one of two scenarios that differed in the venue of testing: one offered whole-genome sequencing through a state newborn screening program, whereas the other offered whole-genome sequencing in a pediatrician's office. RESULTS: Overall interest in having future newborns undergo whole-genome sequencing was generally high among parents. If whole-genome sequencing were offered through a state's newborn-screening program, 74% of parents were either definitely or somewhat interested in utilizing this technology. If offered in a pediatrician's office, 70% of parents were either definitely or somewhat interested. Parents in both groups most frequently identified test accuracy and the ability to prevent a child from developing a disease as "very important" in making a decision to have a newborn's whole genome sequenced. CONCLUSION: These data may help health departments and children's health-care providers anticipate parents' level of interest in genomic screening for newborns. As whole-genome sequencing is integrated into clinical and public health services, these findings may inform the development of educational strategies and outreach messages for parents.

Decision-making process for conditions nominated to the recommended uniform screening panel: statement of the US Department of Health and Human Services Secretary's Advisory Committee on Heritable Disorders in Newborns and Children.

PURPOSE: The US Secretary of Health and Human Services provides guidance to state newborn screening programs about which conditions should be included in screening (i.e., the "Recommended Uniform Screening Panel"). This guidance is informed by evidence-based recommendations from the Secretary's Advisory Committee on Heritable Disorders in Newborns and Children. This report describes the Advisory Committee's revised decision-making process for considering conditions nominated to the panel. METHODS: An expert panel meeting was held in April 2012 to revise the decision matrix, which helps to guide the recommendation process. In January 2013, the Advisory Committee voted to adopt the revised decision matrix. RESULTS: The revised decision matrix clarifies the approach to rating magnitude and certainty of the net benefit of screening to the population of screened newborns for nominated conditions, and now includes the consideration of the capability of state newborn screening programs for population-wide implementation by evaluating the feasibility and readiness of states to adopt screening for nominated conditions. CONCLUSION: The revised decision matrix will bring increased quality, transparency, and consistency to the process of modifying the recommended uniform screening panel and will now allow formal evaluation of the challenges that state newborn screening programs face in adopting screening for new conditions.