Page 87 - Read Online

Magnifico et al. Rare Dis Orphan Drugs J 2023;2:16 https://dx.doi.org/10.20517/rdodj.2023.17 Page 3 of 15

(3) Safety with a focus on incidental findings, false negatives, and false positives;

(4) Clinical Effectiveness trying to answer the question: What is the number of newborns per year we could
expect to identify as positive?

(5) Costs and economic evaluation to investigate which methods and models were used to estimate the costs
of GS-based NBS by ongoing initiatives;

(6) Ethical analysis considering in particular that in the case of NBS the patient cannot make any decision
by himself/herself, as all decisions are taken by the parents;

(7) Organizational aspects - again looking at recent pilots, trying to identify the major obstacle(s) to the full
deployment as part of the standard of care of a GS-NBS program;

(8) Patients and Social aspects with a focus on the acceptability of GS-based screening programs by citizens
and the methodology adopted by other pilot programs to consult and engage citizens;

(9) Legal aspects to first answer the question of whether a genomic screening program could be made
mandatory (as it is now for the traditional Italian NBS program) or should be voluntary.

Trying to cover all the above-mentioned issues, we selected a wide search algorithm without limiting our
review to a specific domain but limiting it to newborn/neonatal screening AND WGS (that includes, as a
MeSH term, WES). For results and conclusions, we grouped the above-listed domains into three main areas:
Clinical (covering issues 1 to 4), Societal (covering issues 7 and 8), and Governance (covering issues 5, 6,
and 8).

METHODS
Search strategy
Three different sources were identified for the selection of the papers in order to obtain a various and
unbiased set of articles. The sources included (1) the PubMed online database via a query performed on
September 28th, 2022; (2) the Mendeley library shared within the clinicians working group; and (3) the final
selection of articles that were selected for Downie et al.’s 2021 systematic review “Principles of Genomic
[21]
Newborn Screening Programs: a systematic review ”.

The search algorithm used in PubMed was defined according to the objective of the review, i.e., to provide
the practical and theoretical background for the application of WGS or WES techniques to population-wide
NBS programs. The search was performed for all study types published in English, with the full texts
available using MeSH terms (whole-genome sequencing) AND (neonatal screening). These MeSH terms
were selected because they include all the possible synonyms, and in the case of WGS, it includes WES as
well. The query on the PubMed online database with that algorithm gave 147 articles as a result.

The Mendeley Library has been populated by the multidisciplinary team working on the feasibility study
mentioned in the introduction. 79 articles were identified and used to guide the conception, design, and
start-up phases of the study.