ScreenPlus: A comprehensive, multi-disorder newborn screening program.

The increasing availability of novel therapies highlights the importance of screening newborns for rare genetic disorders so that they may benefit from early therapy, when it is most likely to be effective. Pilot newborn screening (NBS) studies are a way to gather objective evidence about the feasibility and utility of screening, the accuracy of screening assays, and the incidence of disease. They are also an optimal way to evaluate the complex ethical, legal and social implications (ELSI) that accompany NBS expansion for disorders. ScreenPlus is a consented pilot NBS program that aims to enroll over 100,000 infants across New York City. The initial ScreenPlus panel includes 14 disorders and uses an analyte-based, multi-tiered screening platform in an effort to enhance screening accuracy. Infants who receive an abnormal result are referred to a ScreenPlus provider for confirmatory testing, management, and therapy as needed, along with longitudinal capture of outcome data. Participation in ScreenPlus requires parental consent, which is obtained in active and passive manners. Patient-facing documents are translated into the ten most common languages spoken at our nine pilot hospitals, all of which serve diverse communities. At the time of consent, parents are invited to receive a series of online surveys to capture their opinions about specific ELSI-related topics, such as NBS policy, residual dried blood spot retention, and the types of disorders that should be on NBS panels. ScreenPlus has developed a stakeholder-based, collective funding model that includes federal support in addition to funding from 14 advocacy and industry sponsors, all of which have a particular interest in NBS for at least one of the ScreenPlus disorders. Taken together, ScreenPlus is a model, multi-sponsored pilot NBS program that will provide critical data about NBS for a broad panel of disorders, while gathering key stakeholder opinions to help guide ethically sensitive decision-making about NBS expansion.

Moving to the Middle Ground: Redefining Genomic Utility to Expand Understanding of Familial Benefit.

Translational research has tended to ignore the question of whether receiving a genomic diagnosis provides utility in community care contexts outside of doctors' offices and hospitals. However, empirical research with parents has highlighted numerous ways that a genomic diagnosis might be of practical value in the care provided by teachers, physical or occupational therapists, speech-language pathologists, behavior analysts, and nonphysician mental health providers. In this essay, we propose a new conceptual model of genomic utility that offers the opportunity to better capture a broad range of potential implications of genomic technologies for families in various social and organizational systems. We explore crucial research directions to better understand how redefined utility might affect families and nonphysician professionals.

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.

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.

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.

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.

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.

Parental Depression and Anxiety Associated with Newborn Bloodspot Screening for Rare and Variable-Onset Disorders.

The ability to screen newborns for a larger number of disorders, including many with variable phenotypes, is prompting debate regarding the psychosocial impact of expanded newborn bloodspot screening (NBS) on parents. This study compares psychological outcomes of parents of children with a range of NBS/diagnostic experiences, with a particular focus on lysosomal storage disorders (LSDs) and X-linked adrenoleukodystrophy (X-ALD) as representative disorders with complex presentations. An online cross-sectional survey with six domains was completed in 2019 by a volunteer sample of parents with at least one child born between 2013 and 2018. Parents were classified in the analysis stage into four groups based on their child's rare disorder and means of diagnosis. Stress and depression were estimated using dichotomous measures of the depression subscale of the Hospital Anxiety and Depression Scale and the Parental Stress Scale. Logistic regression models were estimated for the relationship between the parent group and stress/depression, controlling for demographic variables (region of the US, income, education, major life events, relationship to the child, number of children, parent age, and race/ethnicity). One hundred seventy-four parents were included in this analysis. Parents of children with an LSD or X-ALD diagnosis clinically may have higher odds of depression (OR: 6.06, 95% CI: 1.64-24.96) compared to parents of children with the same disorders identified through NBS, controlling for covariates. Although a similar pattern was observed for parental stress (OR: 2.85, 95% CI: 0.82-10.37), this did not reach statistical significance. Ethically expanding NBS and genome sequencing require an understanding of the impacts of early detection for complex disorders on families. These initial findings are reassuring, and may have implications as NBS expands. Given our small sample size, it is difficult to generalize these findings to all families. These preliminary trends warrant further investigation in larger and more diverse populations.

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.

Population-Based Screening of Newborns: Findings From the NBS Expansion Study (Part One).

Each year, through population-based newborn screening (NBS), 1 in 294 newborns is identified with a condition leading to early treatment and, in some cases, life-saving interventions. Rapid advancements in genomic technologies to screen, diagnose, and treat newborns promise to significantly expand the number of diseases and individuals impacted by NBS. However, expansion of NBS occurs slowly in the United States (US) and almost always occurs condition by condition and state by state with the goal of screening for all conditions on a federally recommended uniform panel. The Newborn Screening Translational Research Network (NBSTRN) conducted the NBS Expansion Study to describe current practices, identify expansion challenges, outline areas for improvement in NBS, and suggest how models could be used to evaluate changes and improvements. The NBS Expansion Study included a workshop of experts, a survey of clinicians, an analysis of data from online repositories of state NBS programs, reports and publications of completed pilots, federal committee reports, and proceedings, and the development of models to address the study findings. This manuscript (Part One) reports on the design, execution, and results of the NBS Expansion Study. The Study found that the capacity to expand NBS is variable across the US and that nationwide adoption of a new condition averages 9.5 years. Four factors that delay and/or complicate NBS expansion were identified. A companion paper (Part Two) presents a use case for each of the four factors and highlights how modeling could address these challenges to NBS expansion.

Genomics and Newborn Screening: Perspectives of Public Health Programs.

This study assesses the benefits and challenges of using genomics in Newborn Screening Programs (NBS) from the perspectives of State program officials. This project aims to help programs develop policies that will aid in the integration of genomic technology. Discussion groups were conducted with the NBS Program and Laboratory Directors in the seven HRSA Regional Genomics Collaboratives (August 2014-March 2016). The discussion groups addressed expected uses of genomics, potential benefits, and challenges of integrating genomic technology, and educational needs for parents and other NBS stakeholders: Twelve focus groups were conducted, which included participants from over 40 state programs. Benefits of incorporating genomics included improving screening modalities, supporting diagnostic procedures, and screening for a wider spectrum of disorders. Challenges included the costs of genomics, the ability to educate parents and health care providers about results, and the potential negative psychosocial impact of genomic information. Attempts to address the challenges of integrating genomics must focus on preserving the child welfare goals of NBS programs. Health departments will need to explore how genomics could be used to enhance programs while maintaining universal access to screening.

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.

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 future of newborn screening for lysosomal disorders.

The goal of newborn screening is to enhance the outcome of individuals with serious, treatable disorders through early, pre-symptomatic detection. The lysosomal storage disorders (LSDs) comprise a group of more than 50 diseases with a combined frequency of approximately 1:7000. With the availability of existing and new enzyme replacement therapies, small molecule treatments and gene therapies, there is increasing interest in screening newborns for LSDs with the goal of reducing disease-related morbidity and mortality through early detection. Novel screening methods are being developed, including efforts to enhance accuracy of screening using an array of multi-tiered, genomic, statistical, and bioinformatic approaches. While NBS data for Gaucher disease, Fabry disease, Krabbe disease, MPS I, and Pompe disease has demonstrated the feasibility of widespread screening, it has also highlighted some of the complexities of screening for LSDs. These include the identification of infants with later-onset, untreatable, and uncertain phenotypes, raising interesting ethical concerns that should be addressed as part of the NBS implementation process. Taken together, these efforts will provide critical, detailed data to help guide objective, ethically sensitive decision-making about NBS for LSDs.

Ethical Challenges for Pediatric Biobanks.

Biobank participation of children is an ethically complicated process as the vulnerability of this population is a concern throughout the entire process of biobanking. Some ethical issues are more prominent in pediatric biobanking and may not need to be considered in biobanking of adult specimens and data. These include assent, reconsent at the age of majority, capacity to consent, and consequences of genetic results on the child and family members. This article describes current processes and best practices described in the literature as well as our experience at the BC Children's Hospital BioBank, a pediatric institutional biobank in Vancouver, Canada. The focus is on processes more specific to pediatric biobanking, such as assent, as well as topics that affect the pediatric population differently compared to adult biobanking.