Newborn screening for neurodevelopmental diseases: Are we there yet?

In the US, newborn screening (NBS) is a unique health program that supports health equity and screens virtually every baby after birth, and has brought timely treatments to babies since the 1960's. With the decreasing cost of sequencing and the improving methods to interpret genetic data, there is an opportunity to add DNA sequencing as a screening method to facilitate the identification of babies with treatable conditions that cannot be identified in any other scalable way, including highly penetrant genetic neurodevelopmental disorders (NDD). However, the lack of effective dietary or drug-based treatments has made it nearly impossible to consider NDDs in the current NBS framework, yet it is anticipated that any treatment will be maximally effective if started early. Hence there is a critical need for large scale pilot studies to assess if and how NDDs can be effectively screened at birth, if parents desire that information, and what impact early diagnosis may have. Here we attempt to provide an overview of the recent advances in NDD treatments, explore the possible framework of setting up a pilot study to genetically screen for NDDs, highlight key technical, practical, and ethical considerations and challenges, and examine the policy and health system implications.

Ethical and public health implications of genetic testing for suicide risk: family and survivor perspectives.

PURPOSE: Death from suicide has an estimated heritability of ~50%. Research may soon allow calculation of polygenic risk scores (PRS) for suicide death, which could be marketed directly to consumers. This raises ethical concerns. Understanding how consumers will utilize this information is urgent. METHODS: We conducted three focus groups involving suicide attempt survivors ("survivors") and family members of suicide decedents ("family members") to gauge their reactions to this technology. Questions focused on positive and negative implications of PRS results. Qualitative research methods were used to summarize studio results. RESULTS: Eight survivors and 13 family members participated. Both groups postulated benefits of suicide PRS, including prevention and reduced stigma. Their concerns ranged from increased stigma to adverse psychological effects. They suggested that suicide PRS should be accompanied by extensive education and counseling. Participants experienced no adverse effects. CONCLUSION: Many ethical, legal, and social implications of genetic testing for suicide risk are highly salient to community stakeholders. Our participants hoped that suicide PRS could have significant individual and community-level benefits, but had concerns about effects in several domains, including stigma, access to insurance and employment, and increased anxiety and depression.

Cost-Effectiveness of Nusinersen and Universal Newborn Screening for Spinal Muscular Atrophy.

OBJECTIVE: To evaluate the cost-effectiveness of nusinersen with and without universal newborn screening for infantile-onset spinal muscular atrophy (SMA). STUDY DESIGN: A Markov model using data from clinical trials with US epidemiologic and cost data was developed. The primary interventions studied were nusinersen treatment in a screening setting, nusinersen treatment in a nonscreening setting, and standard care. Analysis was conducted from a societal perspective. RESULTS: Compared with no screening and no treatment, the incremental cost-effectiveness ratio (ICER) for nusinersen with screening was $330 558 per event-free life year (LY) saved, whereas the ICER for nusinersen treatment without screening was $508 481 per event-free LY saved. For nusinersen with screening to be cost-effective at a willingness-to-pay (WTP) threshold of $50 000 per event-free LY saved, the price would need to be $23 361 per dose, less than one-fifth its current price of $125 000. Preliminary data from the NURTURE trial indicated an 85.7% improvement in expected LYs saved compared with our base results. In probabilistic sensitivity analysis, nusinersen and screening was a preferred strategy 93% of the time at a $500 000 WTP threshold. CONCLUSION: Universal newborn screening for SMA provides improved economic value for payers and patients when nusinersen is available.

Secondary research uses of residual newborn screening dried bloodspots: a scoping review.

PURPOSE: Residual newborn screening dried bloodspots (DBS) are a valuable resource for research but the extent, type, and nature of uses are unknown. The objective of this research was to systematically review the published literature about secondary research uses of residual DBS using a scoping review protocol. METHODS: A total of 654 publications meeting the inclusion criteria with a 94% interrater reliability were identified. A coding template was created with input from expert advisory board to summarize the data. Electronic literature search of Ovid MEDLINE, Embase (via Embase.com), CINAHL (EBSCO),and Science and Social Sciences Citation Indices (via Web of Science) was conducted. RESULTS: A large proportion of the secondary research with DBS was conducted within the United States (30%). The number of published studies utilizing DBS are increasing each year, primarily with observational or case-control designs. Only a small number of studies reported whether or not consent was obtained and if the DBS were identifiable or not. CONCLUSION: Outcomes of this research indicate that residual DBS are well utilized worldwide for research addressing individual and public health issues. Future analyses will summarize outcomes of disease-specific research and provide evidence of the use of residual DBS in research on health outcomes.

The Use of a Game-Based Decision Aid to Educate Pregnant Women about Prenatal Screening: A Randomized Controlled Study.

PURPOSE: This project developed and evaluated the efficacy of a game decision aid among pregnant women about prenatal screening in a randomized controlled study. STUDY DESIGN: Participants were recruited from an obstetric clinic of an academic urban medical center and randomized (n = 73) to one of two study groups: the control group (n = 39) that used a brochure or the intervention group (n = 34) that also used a game decision aid. RESULT: Participants who played the game had higher knowledge scores (m = 21.41, standard deviation [SD] = 1.74) than participants in the control group (m = 19.59; SD = 3.31), p = 0.004. The median time of game playing was 6:43 minutes (range: 2:17-16:44). The groups were similar in frequency of completing screening after the study, control = 6 (15%) versus intervention = 11 (32%), p = 0.087. However, the more interaction with the game resulted in more positive attitudes toward screening. CONCLUSION: The addition of a game decision aid was effective in educating pregnant women about prenatal screening. As other genetic testing decisions continue to increase within clinical care, game-based decision tools may be a constructive method of informed decision-making.

Points to Consider: Ethical, Legal, and Psychosocial Implications of Genetic Testing in Children and Adolescents.

In 1995, the American Society of Human Genetics (ASHG) and American College of Medical Genetics and Genomics (ACMG) jointly published a statement on genetic testing in children and adolescents. In the past 20 years, much has changed in the field of genetics, including the development of powerful new technologies, new data from genetic research on children and adolescents, and substantial clinical experience. This statement represents current opinion by the ASHG on the ethical, legal, and social issues concerning genetic testing in children. These recommendations are relevant to families, clinicians, and investigators. After a brief review of the 1995 statement and major changes in genetic technologies in recent years, this statement offers points to consider on a broad range of test technologies and their applications in clinical medicine and research. Recommendations are also made for record and communication issues in this domain and for professional education.

Experiences among Women with Positive Prenatal Expanded Carrier Screening Results.

The offering and acceptance of expanded carrier screening is increasing among pregnant women including women without an increased risk based on race, ethnicity or family history. The chances of a positive screening test have been reported to be as high as 24 % when multiple conditions are screened. Yet, little is known about the way these tests are offered and how patients are affected by a positive test result. To explore this area of genetic testing, interviews (n = 17) were conducted among women who received positive expanded carrier results in the context of obstetric care. A content analysis was conducted on the transcript data from the interviews. Outcomes of this research suggest that educational interventions are needed to improve maternal understanding of positive carrier screening results. Most of the participants in this study confused the results with other prenatal screening test options. In addition, the way the results were discussed varied greatly, and influenced participants' thoughts about reproductive decisions that led to a range of emotional uncertainty. Our data suggests that genetic counseling improved participants' understanding of positive results. More research is needed to further understand if our results are consistent within a larger, more diverse sample, and to explore how to best provide education about expanded carrier screening.

Ethical issues in pediatric genetic testing and screening.

PURPOSE OF REVIEW: Developments in genetic test technologies enable a detailed analysis of the genomes of individuals across the range of human development from embryos to adults with increased precision and lower cost. These powerful technologies raise a number of ethical issues in pediatrics, primarily because of the frequent lack of clinical utility of genetic information, the generation of secondary results and questions over the proper scope of parental authority for testing. RECENT FINDINGS: Several professional organizations in the fields of genetics and pediatrics have published new guidance on the ethical, legal, and policy issues relevant to genetic testing in children. The roles of predictive testing for adult-onset conditions, the management of secondary findings and the role of informed consent for newborn screening remain controversial. However, research and experience are not demonstrating serious adverse psychosocial impacts from genetic testing and screening in children. The use of these technologies is expanding with the notion that the personal utility of test results, rather than clinical utility, may be sufficient to justify testing. SUMMARY: The use of microarray and genome sequencing technologies is expanding in the care of children. More deference to parental decision-making is evolving in contexts wherein information and counseling can be made readily available.

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.

Deliberative Discussion Focus Groups.

This article discusses a new approach for the conduct of focus groups in health research. Identifying ways to educate and inform participants about the topic of interest prior to the focus group discussion can promote more quality data from informed opinions. Data on this deliberative discussion approach are provided from research within three federally funded studies. As healthcare continues to improve from scientific and technological advancements, educating the research participants prior to data collection about these complexities is essential to gather quality data.

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.

Proposed regulations for research with biospecimens: responses from stakeholders at CTSA consortium institutions.

Secondary research with biospecimens acquired through clinical care and through research is often conducted without the informed consent of individuals from whom the specimens were acquired. While such uses are consistent with the current federal regulations, surveys of the general public suggest that many individuals would prefer more information and choice regarding research use of biospecimens. The federal government issued an Advance Notice of Proposed Rulemaking (ANPRM) in 2011 that proposed a number of potential changes in the regulations governing human subjects. These proposed regulations are particularly pertinent to institutions committed to research involving human subjects-including institutions in the NIH-funded Clinical and Translational Science Awards (CTSA) consortium. In this study, we reviewed public responses by CTSA-funded institutions and CTSA-affiliated organizations and groups regarding the proposed changes in the ANPRM with respect to research with biospecimens. Our results indicate that the majority of responses to the ANPRM from CTSA institutions were not supportive of the proposed changes. While many responses acknowledge a need to change current research practices regarding biospecimens, the proposed changes in the ANPRM received only limited support from this subgroup of academic research institutions.

What parents want to know about the storage and use of residual newborn bloodspots.

Many state newborn screening programs retain residual newborn screening bloodspots for a variety of purposes including quality assurance, biomedical research, and forensic applications. This project was designed to determine the information that prospective parents want to know about this practice. Eleven focus groups were conducted in four states. Pregnant women and their partners and parents of young children (N = 128) were recruited from the general public. Focus group participants viewed two educational movies on newborn screening and DBS retention and use. Transcripts were analyzed with qualitative methods and the results were synthesized to identify key information items. We identified 14 categories of information from the focus groups that were synthesized into seven items prospective parents want to know about residual DBS. The items included details about storage, potential uses, risks and burdens, safeguards, anonymity, return of results, and parental choice. For those state programs that retain residual dried bloodspots, inclusion of the seven things parents want to know about residual dried bloodspots in educational materials may improve parental understanding, trust, and acceptance of the retention and use of stored bloodspots.

Public attitudes regarding a pilot study of newborn screening for spinal muscular atrophy.

A population-based pilot study of newborns screening for a rare genetic condition, spinal muscular atrophy (SMA), is being conducted with funding from the National Institutes of Health. The first component of the study is to assess the ethical, legal, and social implications of population-based pilot studies with a focus on public engagement and parental decision-making for the proposed opt-out approach in this research. We conducted focus groups with members of the general public to ascertain attitudes about the pilot study and acceptability of an opt-out approach in two states, Colorado and Utah, where the pilot screening is being proposed (N = 70). We developed an informational video for the project and showed it to the groups prior to the discussion in order to inform participants about population-based research, newborn screening (NBS), permission/consent models, and SMA. Results indicated support for the conduct of pilot studies that is consistent with the current standard of practice for similar population-based programs. There was support for an opt-out approach for parental decision-making; however there was limited parental knowledge about population-based research, NBS and SMA. In general, our participants considered this pilot study to be low risk and of potential benefit to infants and families. The majority of participants were supportive of an opt-out approach with information delivered through various avenues

A framework for key considerations regarding point-of-care screening of newborns.

Newborn screening is performed under public health authority, with analysis carried out primarily by public health laboratories or other centralized laboratories. Increasingly, opportunities to improve infant health will arise from including screening tests that are completed at the birth centers instead of in centralized laboratories, constituting a significant shift for newborn screening. This report summarizes a framework developed by the US Secretary of Health and Human Services Advisory Committee on Heritable Disorders in Newborns and Children based on a series of meetings held during 2011 and 2012. These meetings were for the purpose of evaluating whether conditions identifiable through point-of-care screening should be added to the recommended universal screening panel, and to identify key considerations for birth hospitals, public health agencies, and clinicians when point-of-care newborn screening is implemented.