NBS indicates newborn screening.
eTable 1. Reference List of 51 Opinion Pieces Identified in Literature Review
eTable 2. Data Extraction From Included Studies
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Downie L, Halliday J, Lewis S, Amor DJ. Principles of Genomic Newborn Screening Programs: A Systematic Review. JAMA Netw Open. 2021;4(7):e2114336. doi:10.1001/jamanetworkopen.2021.14336
Based on current evidence, how should a genomic newborn screening (gNBS) program be designed and implemented?
This systematic review identified 36 relevant articles to inform important points to consider in the design of a gNBS program. These covered parental interest and uptake of testing; gene selection; clinical validity and utility; and ethical, legal, and social implications.
The findings suggest that gNBS should be introduced with key considerations regarding choice, flexible consent, and transparent gene and disease selection, maximizing validity and utility while minimizing uncertainty and reflecting the ethical values of society.
Genomic newborn screening (gNBS) may optimize the health and well-being of children and families. Screening programs are required to be evidence based, acceptable, and beneficial.
To identify what has been discovered following the reporting of the first gNBS pilot projects and to provide a summary of key points for the design of gNBS.
A systematic literature review was performed on April 14, 2021, identifying 36 articles that addressed the following questions: (1) what is the interest in and what would be the uptake of gNBS? (2) what diseases and genes should be included? (3) what is the validity and utility of gNBS? and (4) what are the ethical, legal, and social implications? Articles were only included if they generated new evidence; all opinion pieces were excluded.
In the 36 articles included, there was high concordance, except for gene disease inclusion, which was highly variable. Key findings were the need for equitable access, appropriate educational materials, and informed and flexible consent. The process for selecting genes for testing should be transparent and reflect that parents value the certainty of prediction over actionability. Data should be analyzed in a way that minimizes uncertainty and incidental findings. The expansion of traditional newborn screening (tNBS) to identify more life-threatening and treatable diseases needs to be balanced against the complexity of consenting parents of newborns for genomic testing as well as the risk that overall uptake of tNBS may decline. The literature reflected that the right of a child to self-determination should be valued more than the possibility of the whole family benefiting from a newborn genomic test.
Conclusions and Relevance
The findings of this systematic review suggest that implementing gNBS will require a nuanced approach. There are gaps in our knowledge, such as the views of diverse populations, the capabilities of health systems, and health economic implications. It will be essential to rigorously evaluate outcomes and ensure programs can evolve to maximize benefit.
Genomics has altered the landscape of human genetics, with relevance to all medical specialties across all life stages. The technology is being used to improve rates of diagnosis, understand disease prognosis, and develop new therapies.1,2 While the concept of precision medicine has evolved to be a realistic goal for individual health care, questions remain about the feasibility and ethics of using genomics for public health benefit.3
Genomics in the newborn period as a screening test for asymptomatic babies has the potential to identify hundreds of diseases which, although individually rare, together have significant health and economic burdens on the population.4 In addition, newborn genomic samples have the potential to be reanalyzed throughout life for ongoing screening or based on clinical need. Traditional newborn screening (tNBS) has been guided by the principles set out by Wilson and Junger5 in the 1960s, when screening programs emerged, targeting severe and treatable pediatric conditions. While the number of conditions screened for has increased, the principles by which conditions are selected has been consistent. Using genomic sequencing for NBS (gNBS) does not necessarily align with these criteria, as it offers the potential to screen for both untreatable and adult-onset diseases.
In response, a reinterpretation of criteria for NBS was published in 2008, taking genetics into account.6 Among these criteria, there is no mention of treatment, but the concepts of informed choice and equity of access are introduced. Later, in 2011, the US Centers for Disease Control and Prevention (CDC) published the ACCE tool, a framework through which to evaluate the use of genetic tests in a healthy population, comprising the 4 key domains of analytical validity; clinical validity; clinical utility; and ethical, legal, and social implications (ELSI).7 In 2018, a systematic review of the NBS literature8 was undertaken to refine the criteria to reflect modern perspectives, but it did not address genomics specifically.
Genomics adds extra complexity and risk to NBS. Most frequently cited are the need for education and consent, risks of loss of autonomy of the child, genetic discrimination, decreased uptake of tNBS programs, the burden of variants of uncertain significance (VUS) and of diseases with decreased penetrance, cost and storage, and privacy of data.9,10 But benefits are also cited, such as the ability to screen for more diseases, provide children access to preventative health care measures, and increase the health of the entire family.11
Recently, evidence has emerged investigating different aspects of gNBS.12,13 Most notably, the first studies offering actual testing of newborns have been completed,14,15 providing insights that complement the larger body of hypothetical and laboratory-based studies. Here we summarize the literature generating new evidence on gNBS and, from this, provide practical considerations for designing a gNBS program, reflecting particularly on the existing NBS and ACCE criteria.
A literature search of online databases, including PubMed, OVID MEDLINE, OVID Embase, and ProQuest, was performed on April 14, 2021. Searches were performed for all study types published in the English language using MeSH headings and key words: (Neonatal Screening) AND (Genome, Human/ genome/ or exome/) OR (sequence analysis, dna/ or dna mutational analysis/) OR (genomics/or human genome project/) OR (sequence analysis/ or high-throughput nucleotide sequencing/ or molecular sequence annotation/). Articles were screened by title and abstract for relevance. Full text articles were then assessed for eligibility. Reference lists of all included articles that met criteria were reviewed to identify additional papers for inclusion.
Inclusion criteria were established, which included original studies that addressed 4 key areas of investigation: (1) parental interest and uptake, (2) disease and gene selection, (3) validity and utility, and (4) ELSI. We excluded conference abstracts. Opinion pieces were also excluded on the basis that they did not provide new evidence. A list of identified articles is provided in eTable 1 in the Supplement. Furthermore, articles investigating genomic sequencing as a second-tier test to follow up existing NBS results were excluded on the basis that these represent genomics for a diagnostic purpose.10 This incorporated literature regarding NBS for cystic fibrosis. Articles on alternative genetic technology, such as targeted microarray, T-cell receptor excision circles (TREC), and genomewide association studies (GWAS) were also excluded. These technologies are either applied to specific disease groups (eg, TREC for immunodeficiencies) or provide screening regarding a susceptibility (eg, GWAS for likelihood of developing type 1 diabetes). These analyses raise different issues to those encountered when considering genomic sequencing for monogenic disease. Finally, we excluded articles assessing the feasibility of using stored dried blood spot samples for DNA extraction, as we determined that the ability to perform sequencing on DNA extracted from small amounts of blood or saliva has superseded the relevance of this as a method.
Data were extracted by standard form from all studies according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.16 Recorded information included first author, year of publication, location, study design, sample size, study population, scope and method of testing, outcome measures, key results, and strengths and limitations of the study (eTable 2 in the Supplement).
A flow diagram outlining the literature review process is presented in Figure 1. The search strategy yielded 650 articles. After records were screened for relevance and duplicates removed, 143 remained for assessment. Overall, 107 records were excluded, leaving 36 studies. These were collated into 4 categories, as detailed in the Table and summarized in what follows.14,15,17-33,35-51
Fourteen articles15,17-30 addressed parental and population interest in gNBS. Twelve studies17-24,26-29 used a hypothetical offer of gNBS, of which 9 studies17-19,23,24,26-29 used a survey or questionnaire methodology and 3 studies20-22 used interviews. Two studies15,30 offered genomic sequencing for newborns and addressed parental uptake and motivations for accepting or declining testing. The populations sampled included parents generally, parents of newborns, pregnant couples, the general adult population, and health professionals. In every study, most respondents were White women.
Three studies31-33 addressed detailed processes for selecting genes and/or conditions to be tested in gNBS. These articles came from 2 US studies; NC NEXUS and Babyseq. They took different approaches to curating genes and arrived at different lists for gNBS: BabySeq with 954 genes compared with 292 genes for NC NEXUS, not all of which were assessed by the BabySeq group and vice versa. A single study35 assessed direct-to-consumer gNBS gene lists.
Ten studies14,36-44 addressed the validity and utility of using genomic sequencing to complement or replace tNBS. Four studies36,37,43,44 investigated the use of genomic testing with targeted analysis to complement tNBS. Only 3 studies14,41,44 tested a cohort of well infants, while the remainder selected cohorts with findings on tNBS. Two studies39,41 used first-pass automation to identify pathogenic and likely pathogenic variants. One study43 was a simulated model of gNBS for cancer predisposition syndromes.
Seven articles45-51 were identified that evaluated the ELSI. Two studies45,52 provided expert recommendations, guidelines, and considerations on the ethical aspects of gNBS broadly, generated by consensus from groups of individuals with expertise in the relevant fields of genomics and ethics. One article46 reviewed the literature to determine how to assess the psychosocial outcomes of their study in gNBS (BabySeq). Three articles48,51,53 used case studies to highlight and identify important ethical considerations, particularly around the scope of results returned. Two of these51,53 were about the same case from the Babyseq study and present different arguments around the ethical approach to gNBS. A single study49 examined the US legal framework, regulations, and constitutional underpinnings of existing NBS programs and how gNBS might fit within or challenge these.
Based on the 4 identified areas, we developed a summary of the considerations for a gNBS program. These are illustrated in Figure 2.
There was a high level of interest (>60%) in response to both hypothetical and actual offers of gNBS; however, there was considerable variation in the desired scope of results to be returned. While parental support for expanding NBS to look at untreatable disorders was found,18,24 there was less support for identifying genetic risk factors for disease.54 Consistently, the highest importance was placed on whether the test is accurate at predicting disease.54,55 In addition, while parents overwhelmingly wanted active participation in consent,28,29 there was evidence that the introduction of gNBS and the need for more detailed consent would decrease participation in tNBS.17,20,21 This argues against the integration of genomic testing into existing NBS programs because it may cause harm through lower uptake, leading to missed diagnoses of treatable conditions. Furthermore, in support of separating gNBS from tNBS, 1 study15 found that real-time uptake of additional genomic information was lowest in parents with infants younger than 3 months. However, it is notable that in the study that offered gNBS within 48 hours of birth, no parent declined tNBS, indicating that concerns about gNBS affecting the uptake of tNBS programs may be unfounded.26 In another cohort, followed up over a 2-year period, the level of interest in gNBS remained high, with interest increasing over time among parents who had health concerns for their child.26,27
In support of offering gNBS separate from tNBS is the recognized need for education and informed consent, a point raised in multiple qualitative studies.20 Despite education provisions, parents may not fully grasp the possibility of uncertainty that can be raised by genomic testing. Several studies have identified the importance of using decision aids to increase education and understanding of genomic testing.23,55 Educational resources should ideally be interactive and adaptable to allow for flexible consent. Historically, face-to-face genetic counselling would have been considered the optimum approach; however, with the increasing use of information technology it is more likely that these resources will become the frontline of information provision in population-based screening programs.
A single study25 investigated the opinions of health care professionals working in the field. It found that health care professionals largely agreed with the views of parents, ie, that informed consent is necessary and that gNBS should not be compulsory or opt out as tNBS is in many countries.
Actual uptake was similar between the 2 studies that offered gNBS to parents, ie, 67% (268 of 402)30 and 68% (72 of 106),15 despite these being different cohorts, with 1 comprising a combination of well babies and very unwell babies admitted to neonatal intensive care unit30 and the other comprising systemically well children with congenital deafness.15 A similarity between these studies is that both had already consented participants to research, and therefore, these results may not be generalizable.
In summary, public views about gNBS mostly support its introduction and the premise of expanding what is looked for in tNBS. The collated data suggest a move away from the requirement that a treatment be available for all conditions. There is also a recognition of the importance of personal utility to families and individuals, which is increasingly factored into health care decisions and does not always align with clinical utility.34,56
The scope of gNBS is an important consideration in its evaluation. There is no consensus in the literature about which diseases and genes should be included. Evidence suggests that parents value test accuracy and knowledge about the condition,54,55 indicating that disease association and penetrance could be considered a priority above actionability. Increasingly, open-source shared platforms may be used to provide consistency as to gene list analysis.57
The NC NEXUS group31,33 used a metric that generated a score for each gene-disease pair, representing medical actionability. They combined this score with the age of onset of that condition to bin gene-disease pairs. The first bin included conditions that have childhood onset and are medically actionable and were therefore deemed appropriate for gNBS. They then used this metric to assess the suitability of direct-to-consumer gNBS.35 In contrast, the BabySeq group32 started by scoring evidence around gene-disease association and then assessed genes by age of onset and available penetrance data. This resulted in 3 categories for analysis: “Category A: genes included in the Newborn Genomic Sequencing Report (NGSR) with definitive or strong evidence to cause a highly penetrant childhood-onset disorder. Category B: genes included in the NGSR based on actionability during childhood. Category C: genes that did not meet criteria to be returned in the NGSR.”32 Both groups agreed that a transparent process for selecting and reporting genes was essential.
Many of the other studies15,39-41 included details on how they created gene lists for analysis in the methods. These were highly variable according to the criteria selected by the research group.
Seven studies addressed clinical validity of gNBS vs tNBS by investigating cohorts that had findings on tNBS. These found that the addition of gNBS led to an earlier and faster diagnosis but that it was not superior in terms of sensitivity and specificity. gNBS has been shown to be particularly useful in unwell newborns, whereas tNBS results can be difficult to interpret.36,37 Only 3 studies14,41,44 tested cohorts of well infants and again supported the idea that tNBS and gNBS are complementary, with overlapping sensitivity and specificity. Other studies38,42 addressed whether gNBS could replace tNBS and concluded that the burden of VUS results as well as the difficulty in interpreting them without biochemical data make replacement unfeasible. Proposals to address this included increased integration between clinician and laboratory to make variant interpretation more accurate and therefore lead to fewer VUS results38 or pathogenic variant detection only,42 which also improves analytical validity.
Regarding clinical utility, there is some consensus that analysis of a targeted gene panel is preferable to broad genomic sequencing, reducing the potential harms from detection of VUS and incidental findings.39,40 Two studies39,41 used first-pass automation to identify pathogenic and likely pathogenic variants and concluded that this improved efficacy and cost-effectiveness.
Several articles39,40,42,43 found that gNBS would significantly increase the number of babies diagnosed due to the ability to detect disorders without a biochemical test, with delayed onset or mild phenotype that are likely to be missed with current screening. For diseases such as immunodeficiencies and cancer predisposition syndromes, there was a postulated cost saving to the health care system in the long term.
Utility—clinical or personal—can be difficult to measure, particularly at a single time, as demonstrated in 1 study14 in which several infants were identified as having a pathogenic or likely pathogenic variant in a cardiomyopathy gene with reduced penetrance. Without long-term follow up of large cohorts, it is difficult to predict the positive and negative impacts of this type of result on individuals, families, and the medical system.
Conclusions drawn from the literature are that genomic testing does not currently surpass tNBS in terms of sensitivity, specificity, or cost-effectiveness and, therefore, should not be considered as a replacement. Rather it should be considered complementary or as an independent mode of accessing precision health care for individuals. An important consideration is separating the offers of gNBS and tNBS to avoid jeopardizing the success and efficacy of tNBS. This must be weighed against the benefit of increasing the range of conditions that can be detected in the newborn period, including those that fulfill traditional criteria of being treatable early in life, such as immunodeficiencies. The provision of adequate information and resources for parents to opt in if they deem it beneficial for their own circumstances and beliefs will be an important component of any program.
There is consensus in the literature regarding certain ELSI. One is the importance of minimizing psychological harm and stress to parents. A potential approach is to use targeted analysis,45,46,52 thereby reducing VUS results and the identification of variants in genes with reduced penetrance. Another is to incorporate detailed informed consent so that parents can understand potential risks and only consent if the positives outweigh the potential harms for them.45,47,48 However, it has also been highlighted that more choice is not necessarily better and that more complex choices can undermine comprehension, thereby compromising informed decision making.45
A single article49 assessed the current US legal framework under which tNBS operates and applied it to gNBS. It concluded that genomic testing should only be used to confirm tNBS results in a targeted way and that further disclosure of genomic newborn data to parents would require specific consent procedures and/or legal refinements.
Three studies48,50,51 used individual cases to highlight the ethical and moral issues raised by gNBS, helping to contextualize the considerations. One contentious issue is shifting the goals of NBS from being solely about the child to benefit for the whole family. This has been addressed widely, with most stakeholders placing highest value on the ethical principal of the right of self-determination of the child above the considerations of the family.45,47,51 A major issue is the absence of empirical evidence regarding harm or benefit,46 with most ELSI literature being based on expert opinion. This is a key area of evaluation for the implementation of gNBS.
Limitations of these findings are that the literature reflects a White, female, and higher socioeconomic status view and that more diversity is required in the data. Furthermore, health care systems across the world have different NBS capabilities,58 decreasing the generalizability of these results. In addition, research looking at the burden on the workforce, health economics, and data storage is lacking. The conclusions drawn from this review are subject to evolving research, which is active in this area.
The literature provided insights into the considerations and design of a gNBS program, highlighting that a nuanced approach is required. With advancements in technology and flexibility in the approach, a gNBS program is achievable and potentially of considerable benefit to the population. This review provided evidence and a practical summary on which to base program design. Regardless of how a gNBS program is offered, it will be essential to rigorously evaluate the outcomes and processes and ensure it is able to evolve to meet the needs of the population it serves.59
Accepted for Publication: April 21, 2021.
Published: July 20, 2021. doi:10.1001/jamanetworkopen.2021.14336
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Downie L et al. JAMA Network Open.
Corresponding Author: David J. Amor, PhD, Murdoch Children’s Research Institute, MCRI, Flemington Rd, Parkville, Victoria, Australia 3052 (firstname.lastname@example.org).
Author Contributions: Dr Downie had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: All authors.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Downie, Halliday.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Downie.
Obtained funding: Amor.
Administrative, technical, or material support: Amor.
Supervision: Halliday, Lewis, Amor.
Conflict of Interest Disclosures: Dr Amor reported receiving grants from Melbourne Genomics Health Alliance during the conduct of the study as well as from the National Health and Medical Research Council Australia, the Foundation for Prader-Willi Research, the Prader-Willi Research Foundation Australia, the Financial Markets Foundation for Children, and the National Institutes of Health outside the submitted work. No other disclosures were reported.
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