Newborn Screening in the United States: A Vision for Sustaining and Advancing Excellence (2025)
Chapter: 5 The Responsible Application of Emerging Technologies in Public Health Newborn Screening
5
The Responsible Application of Emerging Technologies in Public Health Newborn Screening
“What do these new technologies and the data they will produce really mean for families and what families need to deal with?” – Representative from an organization serving families
The prior chapter describes the report’s vision for supporting and sustaining public health newborn screening as it navigates ongoing and nascent challenges. Among these challenges, technologies loom large as tools with the potential to change the way that decision makers, partners in the NBS ecosystem, and the public consider the role of public health newborn screening. One of the technologies garnering the greatest interest, research attention, and momentum is genomic sequencing. This chapter uses genomic sequencing as an illustrative example for considering the novel application of any technology to public health newborn screening, and also discusses the unique technical, operational, and ethical considerations raised by genomic sequencing specifically.
CURRENT LANDSCAPE OF DNA-BASED TESTS IN THE NBS ECOSYSTEM
DNA-based tests encompass a wide range of methodologies and potential screening readouts from those that are highly targeted to those that are more expansive. Different methods have different capabilities regarding the number of genes or genetic variants that can be assessed simultaneously, ranging from a single variant to complete gene
BOX 5-1
Genomic Sequencing Defined
Whole genome sequencing (WGS) is often used to refer to next-generation sequencing (NGS) across the entire genome (Goodwin et al., 2016). This term can be misinterpreted as it suggests that the genome is fully sequenced, analyzed, and reported in its entirety. WGS may generate data across the genome, but not all the sequencing data are typically analyzed and interpreted into reportable results. Throughout this chapter, the term genomic sequencing is used to avoid confusion.
sequencing and deletion/duplication analysis. When necessary, DNA can be amplified by polymerase chain reaction (PCR) followed by targeted gene/genetic variant assessment. Next-generation sequencing (NGS) can be used to generate sequences that range from targeted genetic variants, a limited number of targeted genes, exome sequences of the coding regions of all genes, to a genome sequence that includes coding and non-coding regions of all genes. Critically, all sequencing data produced do not need to be analyzed to become reportable information (see Box 5-1) (Goodwin et al., 2016).
Different sequencing collection and analysis approaches are used in clinical care, including for the diagnosis of symptomatic newborns and children (Kingsmore et al., 2024; Retterer et al., 2016; Willig et al., 2015; Yang et al., 2013). Most of these strategies have not been applied to screening healthy infants at birth outside of research contexts (Figure 5-1) (Furnier et al., 2020; NASEM, 2023). This section describes the current status of molecular analysis using DNA-based tests in public health newborn screening as well as in research initiatives within the United States.
Public Health Newborn Screening
Conditions included in NBS panels are largely genetic disorders. Historically, a reliable biochemical marker for a condition has served as the screening test of choice, but for some disorders, including severe combined immunodeficiency and spinal muscular atrophy, DNA-based testing is the only option (see Box 2-4) (ACHDNC, 2011; Almannai et al., 2016; Kraszewski et al., 2018). Heretofore, sequencing across a single gene has been used in a second-tier or reflex test setting to provide independent molecular genetic analysis after a first-tier biochemical or enzymatic testing result is out of range or as additional information to help clinical decision making and patient communication (e.g., sequencing of CFTR to screen for
NOTE: NBS = newborn screening.
SOURCE: CDC, 2024.
cystic fibrosis) (Furnier et al., 2020). Genomic sequencing that enables more expansive readouts has yet to be applied toward screening for conditions in public health newborn screening (NASEM, 2023).
Research Landscape
Recent advances in sequencing technology, including developments that decrease cost, have attracted large-scale research investment to determine the usefulness and acceptability of genomic sequencing in newborns (Minear et al., 2022). The Newborn Sequencing in Genomic Medicine and Public Health (NSIGHT) program was a research initiative jointly funded by the National Human Genome Research Institute (NHGRI) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) from 2013 to 2019, with an initial funding commitment totaling $25 million (NIH, 2022).1 The consortium was composed of four centers that investigated sequencing in newborns within different contexts, including clinical diagnosis of sick newborns in intensive care
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1 https://grants.nih.gov/grants/guide/rfa-files/RFA-HD-13-010.html (accessed March 24, 2025).
unit settings and screening of healthy newborns at birth. Together, the centers aimed to address three research questions:
- For disorders currently screened in newborns, how can genomic sequencing replicate or augment known NBS results? Can sequencing replace current screening modalities; if so, for which conditions?
- What knowledge could genomic sequencing provide about conditions not currently screened in newborns?
- What additional clinical information could be learned from genomic sequencing relevant to the clinical care of newborns (Berg et al., 2017)?
Each center used different approaches with minimal coordination and had a sequencing project, a clinical project, and an ethics project.
The investment in NSIGHT led to several major findings relevant to considering sequencing as a screening tool for healthy newborns. At the time of study publication in 2020, sequencing alone was insufficiently sensitive or specific to replace traditional screening methods (Adhikari et al., 2020; Roman et al., 2020). However, sequencing demonstrated usefulness as a second-tier test to reduce false-positive results and facilitate informed decisions about the infant’s care, and, in some cases, enabled the identification of infants with nonclassical forms of NBS conditions that were missed with conventional screening (Adhikari et al., 2020; Ceyhan-Birsoy et al., 2019; Woerner et al., 2021). Studies highlighted the breadth of parental and clinical perspectives on sequencing healthy newborns, including interest in the potential of sequencing to uncover actionable health insights and apprehension about receiving ambiguous or uncertain results.
Many parents chose not to participate in these studies, citing concerns about privacy and insurance discrimination (Genetti et al., 2019). Ultimately, members of the NSIGHT Ethics and Policy Advisory Board published a Hasting Centers Report in which they recommended that targeted sequencing may be appropriate “as a primary test to screen for conditions that meet existing NBS criteria, where sequencing is either the more appropriate or only method for screening for that particular condition.” Members of the board recommended strongly against the integration of genomic sequencing to return results that would expand the scope of public health newborn screening beyond conditions that are serious, urgent, and actionable (Johnston et al., 2018, p. S6).2
Since the ending of NSIGHT’s funding, several large-scale research programs have continued to explore how genomic sequencing could be integrated into public health newborn screening and its potential ethical ramifications (see Box 5-2). The International Consortium of Newborn
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2 NSIGHT did not make a position statement on the use of genomic sequencing in public health newborn screening.
BOX 5-2
Ongoing Newborn Sequencing Studies
Researchers around the world are independently studying the usefulness and effectiveness of genome sequencing of healthy newborns. Ongoing studies have varied designs and return different information to newborns and their families. Here is a list of a few such studies conducted in the United States:
BabySeq Project is a randomized controlled trial designed to rigorously assess the medical, social, and psychosocial effects of genome sequencing in healthy newborns (Holm et al., 2018). Families of newborns randomized to the sequencing arm receive information that extends beyond the risk for actionable childhood-onset conditions to include pathogenica and likely pathogenic variants (including carrier status) in more than 4,300 genes associated with childhood-onset and actionable adult-onset conditions (Ceyhan-Birsoy et al., 2019; Smith et al., 2024). Ongoing work aims to characterize the outcomes of genome sequencing in a larger, more representative cohort of infants (Smith et al., 2024).
BeginNGS is an international precompetitive public–private consortium that aims to implement a system for screening newborns for genetic diseases, diagnostic confirmation, implementation of effective treatment, and acceleration of drug development. BeginNGS is recruiting from study sites across the United States and internationally with the goal of more representative inclusion of different ancestries. Results will be reported for approximately 400 early-onset, actionable genetic conditions (Kingsmore, 2022; Rady Children’s Institute for Genomic Medicine, 2025a). Pathogenic and likely pathogenic variants will be reported (Rady Children’s Institute for Genomic Medicine, 2025b). The primary study endpoints are clinical usefulness and cost-effectiveness of BeginNGS versus standard-of-care testing determined at 1 year of age (Kingsmore, 2022).
Early Check is a statewide, consented NBS pilot study conducted in North Carolina that aims to understand the acceptability, feasibility, implementation, and effect of integrating genomic sequencing into public health newborn screening (Bailey et al., 2019). Participants are offered screening for a panel of 178 pediatric-onset, actionable genetic conditions, as well as a second panel of 29 less actionable conditions. Only pathogenic and likely pathogenic variants are reported (Cope et al., 2024). Early Check is assessing the recruitment, education, and consent approaches and evaluating genetic counseling, confirmatory testing, and follow-up protocols across a state with representation from many different ancestral groups (Cope et al., 2023; Kucera et al., 2021; Paquin et al., 2021; Peay et al., 2022).
Genomic Uniform-screening Against Rare Disease in All Newborns (GUARDIAN) study is a multisite, single-group, prospective, observational investigation assessing the implementation of genomic sequencing to assess the feasibility of population-based screening of newborns for early-onset genetic conditions. Two panels of genetic conditions are assessed: (1) 327 early-onset genetic conditions with interventions that prevent or lessen symptoms, and (2) 142 infant or childhood-onset disorders for which medical treatment of epilepsy is effective but medication only partially treats the condition (GUARDIAN Study, n.d.). Pathogenic
and likely pathogenic variants are reported, with variants of unknown significance only reported if they co-occur with a pathogenic or likely pathogenic variant for recessive conditions. A recent report of interim findings from this study discusses the feasibility of this approach, and the need for more studies to understand its effect on clinical management and health outcomes (Ziegler et al., 2024).
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aA pathogenic variant is a genomic variant that may increase a person’s risk of developing a condition, disorder, or disease (NHGRI, 2025).
Sequencing (ICoNS) was recently established to convene experts in this field and harmonize and aggregate data across newborn sequencing projects. ICoNS aims to offer evidence-based resources to inform clinical and public health research and implementation.3
Public Health Feasibility Studies
In September 2024 a new initiative was announced at the National Institutes of Health (NIH) Council of Councils meeting: the Newborn Screening by Whole-Genome Sequencing (NBSxWGS) Collaboratory. The goal of the initiative is to demonstrate feasibility for public health newborn screening by whole genome sequencing through a collaborative model with public health programs (Sheely, 2024). The initiative is intended to enable the early identification of infants at risk for serious, but treatable, genetic conditions. A transparent informed consent process will be implemented, and public perception of genomic sequencing as part of public health newborn screening will be assessed.4 Many other details of the NBSxWGS Collaboratory have yet to be announced, including how conditions will be selected for inclusion, which conditions will be included, which variants will be reported, and how results will be communicated to families.
CONSIDERATIONS FOR INCORPORATING GENOMIC SEQUENCING INTO PUBLIC HEALTH NEWBORN SCREENING
“We can reuse these core [genomic] technologies for this very, very different application of screening healthy newborns as opposed to testing affected individuals with a high pretest probability of genetic disease. However, there are some substantial differences, which make this a complex problem to solve” – Newborn Sequencing Researcher
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3 See https://www.iconseq.org/the-consortium (accessed March 4, 2025).
4 See https://commonfund.nih.gov/venture/nbsxwgs (accessed December 19, 2024).
Decisions around the inclusion of any given technology—including genomic sequencing—require the same level of scrutiny, analysis, and alignment with vision and ethical principles as other decisions that affect the practice of public health newborn screening. Genomic sequencing opens the possibility and opportunity of screening for all genetic diseases that meet the criteria for inclusion on the NBS panel by using a single platform as an initial step (Berg et al., 2017; Ziegler et al., 2024). Applying this technology could also afford greater flexibility to add new conditions and variants as knowledge and new treatments emerge. However, considering the application of genomic sequencing in public health newborn screening raises specific challenges and considerations. This section discusses these considerations and presents key areas and selected questions that must be addressed if genomic sequencing were ever to be applied to public health newborn screening.
Ethical Considerations
Technological advances will provide increasingly detailed health information that may not be clinically actionable (Jameson and Longo, 2015). Different philosophies conflict on how society should approach the development and adoption of such technologies, particularly in the face of uncertainty and risk. Among these philosophies, the technological imperative reflects the notion that if a technology can be developed, its development and implementation are inevitable and obligatory (Koenig, 1988). In contrast, the precautionary principle argues against implementing a technology until there is a fulsome understanding of its potential risks and impact (COMEST, 2005). The tension between these philosophies arises from their conflicting priorities and assumptions—with the technological imperative prioritizing potential rewards over risks and assuming the inevitability of adoption, and the precautionary principle prioritizing evidence of safety over potential progress.
When applied to public health newborn screening, the technological imperative would favor maximizing the use of available screening technologies and using the technologies’ capabilities to drive decision making (Moyer et al., 2008; Pereira and Clayton, 2018). Alternatively, the precautionary principle would advocate for a more cautious approach, emphasizing the need to fully understand the potential benefits, risks, and ethical implications before widespread implementation. In practice, decision making about new applications of genomic sequencing in public health newborn screening can balance these competing views by doing the following:
- Remain grounded in public health ethical principles and values (see Chapter 3) (APHA, 2019).
- Draw on existing frameworks for implementing biomedical technologies (NASEM, 2019).
- Incorporate public engagement to ensure alignment with societal views (APHA, 2019; Mori et al., 2024).
- Reflect a robust review of the evidence and a high standard of evidence (Moyer et al., 2008).
- Incorporate data collected through consented research studies that allow for real-world learning while minimizing risks.
Methodological Considerations
This section briefly describes the opportunities and shortcomings presented by different approaches for genomic sequencing and data analysis. Strategies are considered through the lens of their potential application to public health newborn screening.
Generating exome or genome sequences requires DNA, which can be isolated from newborn dried blood spots (Ziegler et al., 2024). Sequencing methods include short-read sequencing that generates sequence fragments of 150 base pairs or so, and long-read sequencing, which generates sequence lengths of 10,000–100,000 base pairs. Generating long-read sequence data from dried blood spots is currently more difficult and expensive than generating short-read sequence data. Some genomic sequencing methods can also assess methylation-based epigenetic changes (Goodwin et al., 2016). Regardless of what sequence data are generated, analysis can be limited to a prespecified set of genes and/or variants, and analysts can be blinded to data that do not map to the target areas of reporting. This testing strategy of selective analysis is currently employed by many genetic testing laboratories in the context of clinical care with panels of genes in genetic testing (Jezkova et al., 2022).
What to include in the target for sequencing is a balance between the cost of sequencing and data storage and longer-term flexibility to add conditions for analysis without the need to revalidate the test. Test revalidation will become increasingly costly, time-consuming, and complicated with the proposed new Food and Drug Administration (FDA) regulations that reclassify laboratory-derived tests as medical devices/in vitro diagnostic tests and subject them to the entire FDA approval process (Willmarth, 2015).5 Therefore, whole genome sequencing with analysis limited to a prespecified set of genes and/or variants may afford the greatest flexibility to efficiently add variants and/or conditions as knowledge of disease-causing variants and genes evolves and as treatments
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5 https://www.federalregister.gov/documents/2023/10/03/2023-21662/medical-devices-laboratory-developed-tests (accessed March 24, 2025).
become available. However, privacy concerns raised by sequencing may be exacerbated when more sequencing data are collected than are analyzed (Tarini and Goldenberg, 2012).
Sequence data must be aligned to the reference genome, and variants must be called. Variant calling is the process of identifying sequence differences between an individual’s sequence data with respect to a reference genome (Olson et al., 2023). Most single nucleotide variants can be readily called. With short-read data, small insertions and deletions (<10 base pairs) are generally called correctly, large deletions and duplications (3 or more exons and 500,000 base pairs or more) are reliably called, and many triplet repeats can be correctly sized with appropriate algorithms. There are significant limitations to short-read data for deletions, duplications, and insertions between 10 and 500,000 base pairs and for variants in complex repetitive regions of the genome. Long-read data have the advantage of being able to correctly call more complex variant types, methylation status, and phase variants for recessive conditions; however, the cost of generating long-read data is currently significantly higher than that of short-read data (Goodwin et al., 2016; Olson et al., 2023).
Because of the extensive experience validating the presence of genetic variants from next-generation sequencing data, most single nucleotide variants do not require confirmation by another method (Beck et al., 2016). However, copy number variants are not as reliably called and often require orthogonal confirmation by quantitative PCR, digital droplet PCR, or an array-based assay (Rajagopalan et al., 2020; Teo et al., 2012). DNA from dried blood spots may not be sufficient for these assays and may therefore require contacting the family and obtaining an additional sample for variant confirmation.
Condition Considerations
Public health newborn screening must remain focused on conditions that are serious, urgent, and treatable to align with public health ethical principles (Chapter 3). Which conditions to include in public health newborn screening must be guided by these criteria rather than the scope of conditions any given technological tool might enable.
Genomic sequencing generates tremendous amounts of data, and much of that should not be the focus of public health newborn screening. For example, all individuals are carriers for multiple autosomal recessive conditions, and being a carrier has no immediate clinical usefulness for the newborn (Clayton, 2010; Fridman et al., 2021; Gao et al., 2015). This information should not be analyzed or returned as part of the public health NBS program both because it does not align with the goals of the program and because of the enormous infrastructure that would be
required to support returning this information (see Chapter 3 for further discussion). As described in the methodological considerations section, bioinformatics pipelines may be developed to avert findings related to carrier status when screening for a particular condition. Similarly, data that lead to information that is not medically actionable until adulthood should not be analyzed to become reportable information (hereditary cancer risk such as BRCA1/BRCA2 or Huntington disease) as it is beyond the scope of the public health program.
Serious conditions that are genetic and amenable to detection by genomic sequencing methods, for which there is an available, effective intervention with proven benefit, and for which individuals are routinely symptomatic at a young age, should all be routinely considered for public health newborn screening even if the condition is rare. Birth prevalence is not a critical factor since the marginal cost of adding a condition once the platform is in use would be minimal. There is a need for ongoing research outside of public health feasibility studies that generates scientific and programmatic evidence to inform decisions about whether to include additional conditions for which treatment is available but not completely effective, for lethal/severe conditions with open clinical trials, and for conditions with gene variants that may or may not result in diseases.
Some conditions require early recognition and treatment and have a readily detectable biomarker with well-established reference ranges (e.g., maple syrup urine disease and galactosemia) (Ding and Han, 2022). It is likely that metabolites and enzyme activities will continue to be the first-tier test and will not be soon supplanted by genomic sequencing unless and until the turnaround time and predictive value of sequencing matches that of metabolite and enzyme activities screening (Bick et al., 2022; Friedman et al., 2017; Tarini and Goldenberg, 2012). Further, some conditions do not have a known genetic cause of all cases and therefore biochemical screening is appropriate (e.g., congenital hypothyroidism) (Persani et al., 2018). On the other hand, given the evolving gene-editing methods that require precise information about the DNA variants causing disease, molecular confirmation of the condition could act as an orthogonal confirmation and determine eligibility for gene therapy (Henderson et al., 2024).
Variant Interpretation and Inclusion Considerations
Currently, NBS tests are designed to identify nearly all affected infants (high sensitivity) but may have a high rate of false positives (lower specificity). For biochemical tests, this paradigm determines how cutoff values are set for biochemical markers (Moyer et al., 2008). For DNA-based screens, which variants to include is also determined based on a balance of
sensitivity and specificity. Variants are interpreted and categorized as either pathogenic, likely pathogenic, uncertain significance, likely benign, and benign based on the American College of Medical Genetics and Genomics (ACMG) guidelines (Richards et al., 2015).6 Variants of uncertain significance (VUS) are challenging when considering what to report as part of public health newborn screening as they could potentially be biologically deleterious (Burke et al., 2022). However, with thousands of VUS, extending the current paradigm of high sensitivity, lower specificity to genome-based screens could risk overwhelming public health programs, clinical care, and families with too many false positives and too much ambiguity (Woerner et al., 2021).
Variant interpretation is not currently accurate across all populations based on the representation of different genetic ancestries in genomic and clinical databases (Gudmundsson et al., 2021; Manrai et al., 2016; Petrovski and Goldstein, 2016). For instance, there is a significant bias toward individuals of European ancestry in ClinVar7 (Naslavsky et al., 2021). Therefore, variant interpretation pipelines that filter in only pathogenic and likely pathogenic variants may lead to underreporting of disease-causing variants for individuals who are not of European ancestry (Mori et al., 2024). Conversely, if all rare variants were filtered in for manual review, many variants that are rare or absent in the Genome Aggregation Database (gnomAD)8 (Figure 5-2) yet common in some part of the world would be at greater risk for misclassification (Shah et al., 2018), potentially leading to prognostic odysseys and taxing both public health and clinical care systems (Friedman et al., 2017).
Challenges posed by variant interpretation replicate other challenges that arise in public health newborn screening based off limited knowledge. Sequencing across a population invariably reveals new information beyond what has been learned through clinical populations. Such information could change the interpretation of a particular variant or the understanding of that variant’s phenotypic penetrance, among other factors. Therefore, continued research with nonclinical populations and across different ancestral groups is critical to improve variant interpretation.
Given the many genetic ancestries of people born in the United States (Bryc et al., 2015), a more comprehensive understanding of variants and
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6 Updated standards for sequence variant classification will be released by ACMG in the spring of 2025.
7 ClinVar is a public archive of human genetic variants and their relationships to disease and drug responses maintained by the NIH. See https://www.ncbi.nlm.nih.gov/clinvar/ (accessed March 6, 2025).
8 gnomAD is a publicly available collection of human genetic data developed by an international coalition of investigators with the goal of aggregating and harmonizing both exome and genome sequencing data from across the world. See https://gnomad.broadinstitute.org/ (accessed March 6, 2025).
SOURCE: Genome Aggregation Database (gnomAD); https://gnomad.broadinstitute.org/stats#diversity (accessed March 11, 2025).
their pathogenicity across ancestral groups is essential. Current challenges to this goal include inadequate representation of genetic ancestries in genomic databases (Corpas et al., 2025), lack of standardized data formats across global large-scale sequencing studies (Abdelhalim et al., 2022), and insufficient information about the pathogenicity of VUS (Burke et al., 2022). Continued actions are needed to address these issues with the goal of improving variant interpretation across all populations. Large-scale sequencing research studies (e.g., All of Us,9 H3Africa,10 GenomeAsia 100K11) can continue expanding representation of ancestral groups from across the globe through thoughtful community engagement, among other approaches (Lemke et al., 2022, NASEM, 2018, 2024). These studies can also collaborate on standardizing data formats to enable data integration across studies. Data can be shared with a central resource, such as gnomAD, which is currently the largest and most widely used publicly available collection of population variation from harmonized sequencing data (Gudmundsson et al., 2021). Functional studies in animal models can also begin to unravel the pathogenicity of VUS (Yamamoto et al., 2024). Continued research in these areas is crucial for high-quality variant interpretation across the population of the United States.
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9 See https://allofus.nih.gov/ (accessed February 13, 2025).
10 See https://h3africa.org/ (accessed February 13, 2025).
11 See https://www.genomeasia100k.org/ (accessed February 13, 2025).
If genomic sequencing were incorporated into public health newborn screening, strategies would be needed for interpreting and reporting variants that consider the limitations described above. A balance could be struck by returning only a subset of VUS based on the probability that the variant is truly deleterious determined by a predefined threshold of computational predictions along with availability of inexpensive orthogonal confirmatory assays and an effective treatment, as well as the severity of the clinical consequences of missing a treatment window. Employing confirmatory assays, for example biochemical assays that confirm reduced levels of a certain metabolite, would be essential for restricting reporting to relevant variants. With time, the sensitivity of screening for a condition using sequencing could increase as variant interpretation for the causative gene improves. However, incorporating genomics into public health newborn screening may necessitate a shift toward accepting more false negatives in favor of fewer false positives initially to avoid reporting unclear and unactionable information to parents (Gelb, 2024). This initial practice would be improved over time with knowledge growth about variants across ancestral groups (as indicated in Figure 5-2) and can be mitigated by including only a subset of VUS that can be orthogonally confirmed as pathogenic. Further research is needed to address variant interpretation accuracy across all ancestral populations and how to navigate this issue in a transparent and trustworthy manner.
Data Considerations
“Blood spots contain genetic material that is intensely personal.” – Parent
Ensuring data privacy and security would be a challenge to implementing genomic sequencing in public health newborn screening. Ethicists, data privacy advocates, and others have raised concerns about the loss of genetic privacy that could be furthered by sequencing healthy newborns (NASEM, 2023). Unethical uses of genetic information would also be possible in the absence of appropriate regulations. For example, law enforcement could misuse genetic data, mirroring prior seizures of newborn dried blood spots as part of a criminal investigation, if protections are not put in place (Grant, 2022, 2023; Ram, 2022). Parents have expressed concerns about genetic information leading to insurance or employment discrimination (Genetti et al., 2019). Although the Genetic Information Nondiscrimination Act provides protections against health insurance and employment discrimination,12 it does not provide federal protections against genetic discrimination by life, long-term care, or
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12 The Genetic Information Nondiscrimination Act of 2008, P.L. 110-233, 122 Stat. 881.
disability insurers nor does it apply to private companies with fewer than 15 employees, the U.S. military health system, the Indian Health Service, and others (Laboratory, 2023). Beyond these factors, sequencing generates tremendous amounts of data that could challenge public health storage capacities if raw sequence data were stored.
If genomic sequencing were applied to public health newborn screening, privacy concerns must be addressed at several stages including methodological design, storage, governance, and disposition. Methodological design would need to be responsive to concerns about data privacy and only analyze, report, and potentially store sequences relevant to the conditions screened (Tarini and Goldenberg, 2012). Strict governance about who can access the data and under what circumstances would need to be established to ensure trustworthiness. For example, law enforcement would need to be barred from access to NBS samples or the associated data at least for the purposes of prosecution (Grant, 2022, 2023; Ram, 2022; Suter, 2022).13 Robust encryption and security protocols would be needed, and capacity to store such data would need to be built.
Options for data destruction after a period of time (e.g., after diagnosis or a set number of years), at the request of the individual or their parents, or with sensitivity to local, community, and cultural contexts would need to be considered (Fleskes et al., 2022; Lewis, 2019; NASEM, 2023). Existing frameworks can guide the ethical stewardship of samples or data generated through public health newborn screening at each of these steps (see Box 5-3) (NASEM, 2023; WHO, 2024). See Chapter 4 for an exploration of the complicated landscape of policies and ligation concerning residual dried blood spots and data derived from public health newborn screening, including areas of consideration for genomic data.
Implementation and Scaling Considerations
If genomic sequencing were to be implemented at scale, sufficient and sustainable funding would be necessary to meet the technical and workforce needs and to avert straining a resource-constrained environment (Andrews et al., 2022; Currier, 2022; NASEM, 2023). The cost of the sequence data generation and interpretation depends on the scale since there is an economy
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13 A thornier issue is whether exceptions could be made for using a dried blood spot to identify a missing or deceased child. See https://www.babysfirsttest.org/newborn-screening/what-happens-to-the-blood-sample#:~:text=The%20dried%20blood%20spots%20can,child%20at%20the%20parent’s%20request (accessed January 16, 2025).
BOX 5-3
Frameworks for Ethical Genomics Data Use and Sharing
Ethical stewardship of samples and data generated through newborn screening, both in research and public health contexts, is vital. Extensive work has been conducted to build frameworks that enhance ethical genomics data use and sharing, particularly for research (Atutornu et al., 2022; Claw et al., 2018; WHO, 2024). These frameworks can be drawn on when considering governance for genomics data generated through newborn sequencing research and if genomic sequencing were ever applied to public health newborn screening. Many of these frameworks concern principles for ethical engagement with groups, including Indigenous communities, who are underrepresented in genomic databases, and thus, are less likely to benefit from genomics and precision medicine (Claw et al., 2018).
The World Health Organization (WHO) recently released guidance for human genome data collection, access, use, and sharing to inform policy makers, researchers, clinicians, and others on handling human genome data in a manner that “advances genomics for individual and population health, protects individual and collective rights and interests, and fosters public trust” (WHO, 2024, p. iv) The guidance aims to (1) promote social and cultural inclusiveness, equity, and justice; (2) promote trustworthiness within the data life cycle; (3) foster integrity and good stewardship; (4) promote communal and personal benefits; and (5) promote the use of common principles in laws, policies, frameworks, and guidelines, within and across countries and contexts. Refer to the WHO guidance for additional details (WHO, 2024).
of scale. Costs include (1) DNA extraction; (2) sequence generation; (3) computational costs for sequence alignment as well as variant filtering and interpretation, data storage, and confirmatory testing; and (4) capital costs for equipment, reagents, and personnel. Sequencing costs have fallen below $1000 per genome (NHGRI, 2023), with variation depending on the test run and the scale at which the tests are performed. These costs are comparatively higher than current fees associated with public health newborn screening, which range from $30 dollars to $258 per test.14 Over time, costs associated with genomic sequencing could decrease as improvements in efficiency and automation of data generation and variant interpretation occur. In addition to sequencing-related costs, investing in the development of the public health workforce would be needed to ensure the appropriate expertise and skills to support sequencing, variant interpretation, and following up on those results (NASEM, 2023).
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14 See https://www.newsteps.org/data-resources/reports/nbs-fees-report (accessed February 11, 2025) for up-to-date information on each state and territorial NBS program’s associated fees. Five programs do not charge a fee.
It would likely be unnecessary for all programs to perform their own sequencing and interpretation. Instead, scaling could be achieved in part by the regionalization of sequencing and/or interpretation either initially or long term as state-run programs consider their approach (Andrews et al., 2022). Efforts would be needed to ensure that the application of sequencing does not drive further geographic disparities between the services provided by different state-run programs. Such strategies could include establishing technical support centers, providing additional funding, and developing distributed systems of clinical expertise (see Chapter 4). With appropriate supports, implementation of genomic sequencing could reduce variations in conditions screened across NBS programs by increasing the efficiency of adding new conditions.
Extensive infrastructure would be required for genomic sequencing to be a first-tier test for public health newborn screening. A harmonized infrastructure within public health or referral/regional laboratories would be necessary for DNA extraction, sequence data generation, and variant interpretation. Variant interpretation would need to be rapid, automated, scalable, accurate, and equitable—with flexibility for manual curation as needed; this could be done in part with artificial intelligence, and would improve with more data and experience. Laboratory information management systems would need to be modernized to accommodate sequence interpretation and reporting with the appropriate security features. Data retention and use policy must be developed, and data storage capacity and security must be sufficient.
Clear and effective communication would be needed to inform, educate, and empower the public, parents, and care providers (APHA, 2019; Johnston et al., 2018; WHO, 2024). A workforce of clinicians would be needed to discuss results with families, confirm the diagnoses, and initiate appropriate care and surveillance (Friedman et al., 2017; NASEM, 2023). A data track in ClinVar would be necessary to share variant interpretations and tag the source as that of newborn screening. Ideally, a federated national infrastructure would be needed to track the clinical outcomes of the newborns identified through sequencing-based public health newborn screening to iteratively improve the process including accurate interpretation of variants, disease penetrance, and effectiveness and timing of treatment (see Chapter 6 for information about long-term follow-up).
At this stage, genomic sequencing is not yet ready for implementation at scale in public health programs outside of a consented research study context. More research is needed to address the scientific, technical, ethical, and practical challenges before genomic sequencing could be considered for implementation in the United States. Box 5-4 presents key areas and selected questions that need to be addressed.
BOX 5-4
Selected Questions to Address Before Considering Applying Genomic Sequencing to Public Health Newborn Screening
Findings from ongoing newborn sequencing studies indicate the potential usefulness of genomic sequencing in public health newborn screening. However, many questions remain about how it could be implemented responsibly, whether it is acceptable to the public, what protections might be needed, how to ensure access and accurate interpretation across all populations, whether it is economically and practically feasible, and more. In addition to scientific and technical research, social and behavioral science research will be needed to address these questions. Although not an exhaustive list, here are key areas and selected questions that must be addressed when considering the potential application of genomic sequencing to public health newborn screening.
Scientific and Technical Questions
- What sequence should be generated, what sequence/variants should be analyzed, and what results should be returned?
- What method is most appropriate to generate the target sequence?
- How should the inclusion of conditions be handled when performing population-wide screening may reveal more nuanced symptomatology than initially understood?
- How should variants to report be chosen when population-wide screening may reveal variable penetrance or different symptomatology?
- What strategies are necessary to address accurate variant interpretation across all ancestral populations?
- Will the turnaround time be sufficiently fast while maintaining accuracy to meet timeliness standards?
Ethical, Legal, and Social Issues (ELSI) Questions
- What are public attitudes concerning the application of genomic sequencing into public health newborn screening as a first-tier screening tool?
- What are public attitudes about the role of consent in newborn screening, and how does changing the consent model affect who receives screening?
- What data should be stored after screening, if any, and how will the privacy of genetic data be protected?
- Should stored genomic data be allowed to be used clinically beyond the initial NBS result, if a child becomes symptomatic and could use the data to diagnose a genetic condition not included in newborn screening?
- What considerations should guide any nonclinical secondary uses of stored genomic data, including in research?
Feasibility Questions
- Is genomic sequencing as a first-tier screening methodology cost-effective?
- If public health newborn screening moved toward a consent model, how would informed consent be obtained from parents? Is collection of informed consent feasible?
- What funding, resource sharing, and/or distributed system of clinical expertise would be necessary and effective to support capacity across NBS programs to employ genomic sequencing as a first-tier tool in a high-quality manner across all populations?
- How would genomic sequencing be integrated with current screening tools?
- What training is needed for health care providers to interpret DNA-based NBS results and provide guidance to families?
CONCLUSIONS
Conclusion 5-1: Decisions on the inclusion of emerging technologies need to be guided by what is the most suitable tool available to screen for conditions that meet inclusion criteria for public health newborn screening, and such decisions need to be consistent with the core principles of these programs.
Conclusion 5-2: Genomic sequencing that collects and returns results beyond the scope of conditions that are serious, urgent, and treatable is not consistent with the public health focus of newborn screening. Consented research and clinical care can be appropriate venues to attain such information.
Conclusion 5-3: Although genomic sequencing for a targeted panel of genes has the potential to be useful, important technical, ethical, psychosocial, and implementation questions need to be addressed to fully understand the anticipated and unanticipated consequences before its application can be considered for public health newborn screening.
Conclusion 5-4: A more comprehensive understanding of genetic variants and their relationship to disease for many ancestral groups is essential to ensure accurate variant interpretation across the population of infants born in the United States.
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