This work highlights important tensions that our participants held about potential trade-offs between cost and which conditions to offer as part of a gNBS program. A strength of our approach was that we did not limit discussions by proposing specific ways to decide which conditions should be screened or how to fund gNBS programs. This enabled participants to propose their own suggestions and revealed some of their underlying assumptions about the necessity to limit the number of conditions to be screened.
Could parents be allowed to choose which conditions to include in gNBS?
For the participants in our study, decisions about which conditions to include in a gNBS program rested on whether parents are permitted flexibility within the program. Regarding parental choice about conditions included in the gNBS program, participants identified two potential models: 1) the program screens for a set list of conditions (i.e., no parental choice); and 2) the program allows some flexibility for individual parents/families to decide which conditions are screened. In the former option, participants assumed that some external expert(s) would decide, whereas in the latter, it is unclear whether participants appreciated that although each parent or family would be allowed choice, this would still be from a set, albeit longer (and with less stringent criteria) list of expert-approved conditions.
Allowing parents to choose which conditions they want to screen their infant for would impact service delivery in several ways. Allowing such individualisation of screening panels will require greater education of parents and greater support for their decision making. It would impact the level of informed consent required for gNBS, potentially requiring a more detailed consent process the more conditions are offered, affecting scalability and creating complexity in testing processes. Our participants suggested ‘grouping’ conditions to allow such decisions to be made more easily by parents. This aligns with the proposals of others of a tiered approach to informed consent for genomic sequencing, whereby individuals can opt to receive results from some tiers (or groups of conditions) and not others.(12)
If the set list of conditions is limited, which ones should be included?
If instead screening is limited to a set list of conditions, which parents could either choose to opt-in or opt-out of as a whole, the decision about which conditions should be screened is perhaps even more critical. In our study, participants saw benefits in screening for all types of conditions, including those which were untreatable, mild, variable, and had onset in adulthood. However, if asked to prioritise, participants recognised that treatable, severe, early-onset, and highly penetrant conditions should be included over others.
In deciding which conditions to include in this type of list, lessons can be learned from other population-wide genomic sequencing programs such as reproductive carrier screening(13) and other gNBS projects.(14–18) Gene list development for such other programs has involved consultation with a variety of stakeholders, including clinical geneticists, genetic counsellors, laboratory geneticists, and other specialists.(13–18) Some have engaged ethicists and parents(13) as well as the public(14) in the decision-making process, although patient support organisations should also be included in these discussions.
Existing gene lists proposed for gNBS programs are highly variable, but tend to be based on similar criteria of test validity, treatability, and age of onset of disease.(15–18) These programs have generally chosen to include only conditions which are severe (having a significant risk for morbidity or mortality(15, 18)), have onset in early childhood(15–18), and for which an effective treatment or intervention is available.(15–18) Recommendations from bodies such as the Global Alliance for Genomics and Health also suggest that gNBS should be limited to conditions with early onset and that would benefit from early intervention.(19)
Other gNBS programs have also recognised the importance of having accurate testing for all conditions or variants screened, with strong supporting evidence for genotype-phenotype correlation.(15, 16, 18) Our focus group participants were cognisant of the potential increased anxiety that receiving an uncertain or inaccurate result could cause new parents, and wanted reliable results for conditions if they were to be included. Finally, frequency of a condition was not a strong deciding factor for participants as to whether it should be included in gNBS panels; this is reflected in other gNBS programs, whereby conditions are not prioritised based on how common or rare they are.(15–18)
Including untreatable conditions
Interestingly, participants’ desire to include both treatable and untreatable conditions in a gNBS panel does not align with current recommendations, nor most existing gNBS programs (with the BabySeq Project in the US an outlier(16)). The question of whether to include untreatable conditions in such programs is contentious as guidelines state that the primary purpose of NBS should be early intervention (and even prevention) for conditions with treatability as a key criteria.(19) Yet results previously published from this study show that participants recognise that knowing about conditions for which no treatment is available also has benefits, such as: the avoidance of a lengthy diagnostic odyssey and unnecessary testing and investigations; allowing time for parents to adjust to the diagnosis and make changes to their lifestyle accordingly; and providing information which may be used for reproductive planning(9). This raises questions about whether it is justifiable not to offer to screen for untreatable conditions when some parents would find it valuable and it is possible to do so.
Even if there is agreement that treatability is a critical criterion, determining what this means is not straightforward. Others have examined the concept of treatability (or actionability) in the context of genomic secondary findings.(20) Richer and colleagues suggest that the definition of actionability in childhood should be based on the proportion of cases that present in childhood, as well as the quality of the evidence supporting any available treatments or intervention.(20) Interestingly, our participants saw that treatability could mean anything from a medication available to an early intervention measure (such as additional education support). These various concepts of treatability or actionability further complicate decisions about criteria for deciding which conditions to include in gNBS. This was indeed the most common reason for discrepancies between existing gNBS panels in a recent comparison,(15) and therefore a factor that will need to be considered carefully based on both current research and local context.
Assessing severity
While our participants saw benefits in screening for less severe conditions, most gNBS programs prioritise severe conditions over their mild counterparts.(14, 15, 18, 19) However, some authors have raised concerns over the very concept of severity, noting that a clear definition is lacking.(21) Newson and Dive suggest that using a concept such as severity (or seriousness) of a condition requires deep ethical and conceptual analysis and should take into account the views of health professionals and those living with the condition.(21) Importantly, they highlight that conditions should not be categorised into universally-applicable ‘buckets’ based on severity, but that descriptions of severity instead need to incorporate complex social, cultural and environmental factors unique to each context and potentially each individual impacted.
These varying perceptions of severity may be reflected in our data, where participants had diverse views about whether severity should be used as a factor in deciding whether to include a condition in a gNBS panel. Furthermore, participants’ perceptions of severe appeared to include concepts ranging from ‘debilitating’, ‘affecting mortality’, or ‘affecting a child’s ability to have a normal life’ [FG5 P6], to simply ‘needing support’ [FG12 P5].
Cost and funding
Ultimately, decisions about which conditions to include in gNBS panels – and how much flexibility to allow individual families to pick and choose the results they want to receive – may come down to funding. Traditionally, in public health programs, funding is limited and prioritisation of what is offered is required.(19) Programs with greater in-built individualisation are likely to require greater resources to implement and deliver both the service and its downstream consequences. A trade-off may therefore be required between tailorability and population-wide benefit.
In Australia, standard newborn screening (stdNBS) is funded for all infants.(22) However, its costs are low, at less than $5 per infant, including downstream costs.(23) gNBS is likely to be at least 50 times more expensive.(5) Despite knowing this, in focus groups, participants demonstrated strong preferences for gNBS to be publicly funded (as is currently the case for stdNBS in Australia) to mitigate potential inequities and to benefit the taxpayer overall by saving healthcare costs in the long term. They also wanted additional public funding to be allocated for support services for those who receive a diagnosis of a genetic condition through gNBS. Other guiding bodies have highlighted justice and equity of access as a key consideration in the development of gNBS programs, reflecting that the success of such programs is predicated on their availability to all.(19) Similarly, Genomics England identified equity of access to treatment as a key principle guiding decisions about which conditions to include in their gNBS panel; that is, they concluded that conditions screened for should only include those for which the interventions are equitably accessible for all.(14)
Some parallels may be drawn here between gNBS and the introduction of other new genomic technologies, such as prenatal cell-free DNA (cfDNA) screening and reproductive genetic carrier screening. In Australia, screening for chromosomal conditions during pregnancy is subsidised by the government for all pregnant people in the form of first-trimester combined screening.(24) Prenatal cfDNA screening – a more accurate screening test available slightly earlier in pregnancy – is available at a cost to families, with no government subsidisation currently available.(24) Similarly, various forms of reproductive genetic carrier screening – from only a few to hundreds or thousands of conditions – is available at a cost to prospective parents in Australia, while screening for the three commonest conditions (cystic fibrosis, spinal muscular atrophy and Fragile X syndrome), is publicly funded.(25)
Despite their strong desire for public funding, participants recognised that partial government subsidisation or private payment may be required as an interim measure. Other gNBS programs have approached this issue by using gNBS as an adjunct to stdNBS, rather than a replacement, as supported by global recommendations.(19) While most stdNBS programs screen for less than 50 conditions, genomic sequencing technologies allow the inclusion of hundreds, if not thousands, of additional conditions, at potentially very little incremental cost. Deciding which – and how many more – conditions to offer for screening presents a fine balance between cost, ethics, and practical limitations of testing. We may consider that, at least at the outset, gNBS could follow a similar implementation trajectory to other new genomic technologies – such as prenatal cfDNA screening and reproductive carrier screening – whereby stdNBS is still funded for all infants, and gNBS is offered as an additional option to those willing to pay. However, this is likely not ethically appropriate in the long-term; should gNBS be shown to improve health outcomes, all babies should have access to this technology.