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Bros-Facer et al. Rare Dis Orphan Drugs J 2023;2:21 https://dx.doi.org/10.20517/rdodj.2023.26 Page 11 of 14

Figure 5. Outcome metrics that will be assessed during the follow-up.

identifying and interpreting pathogenic variants [27,31,32] , and reduced sequencing costs [33,34] , mean that the next
few years will be pivotal in the transformation of NBS as we know it today.

The survey results indicate that most studies are in the planning stage. Although there is heterogeneity in
study design across the initiatives surveyed, there is broad agreement that in the upcoming years, NGS-
based approaches to NBS will be implemented in parallel with current screening programs. Most envision
that NGS will supplement rather than replace current NBS. These initiatives are not only essential to
evaluate the utility, feasibility, and acceptability of NGS-based screening in countries with different
healthcare systems, processes, and cultures, but they also help to improve our collective understanding of
rare diseases by enabling future research and drug development.

Diversity in the choice of and access to secondary and tertiary analytical software is represented within the
surveyed initiatives. Not all secondary and tertiary pipelines are able to identify all types of variants.
Consequently, there might be limitations in the detection of specific variants depending on the capabilities
of the selected analytical software.

The heterogeneity in the design of initiatives extends to decisions about how many and what conditions
might be included in an expanded NBS program. In general, there was consensus in using a modified
Wilson and Jungner framework, which included concepts such as treatability and actionability. As would be
expected, how these concepts were operationalized was dependent on the context of the different national
policies and healthcare systems. There are also inherent difficulties in defining what would constitute proof
that early intervention leads to improved outcomes. The reality of implementation in a real-world setting is
complex, and each individual project will contribute helpful information for setting up such programs
relevant to the setting in which they occur.

Current newborn screening programs tend to vary globally both in the number of conditions included on
the screen and screening practice in general. In Europe, for example, ~ 85%-100% of the 4.2 million babies
born each year receive some form of screening with a range of 2-40 or more disorders on the screen. In the
US, nearly 100% of the estimated 3.7 million babies born each year receive NBS, which includes 35 core
conditions and 26 secondary conditions.

The clinical utility of NGS-based testing in neonates with indications of genetic disease is well established.
Clinical studies such as NSIGHT1 and Project Baby Bear have demonstrated that when used as a first-line
test, GS reduces healthcare expenditures by $6,000 to 15,000 per child and between $1 M to $3 M per health