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Page 4 of 15 Magnifico et al. Rare Dis Orphan Drugs J 2023;2:16 https://dx.doi.org/10.20517/rdodj.2023.17

Downie et al.’s systematic review “Principles of Genomic Newborn Screening Programs: a systematic
review” published in 2021 was considered the benchmark and the 36 final articles were included in our
[21]
initial database .

The three sources all together yielded 262 articles, some of which were duplicated in two or all the sources,
as shown in Figure 1. The final articles to be screened were 219.

Documents selection
The selection of articles to be included in the review followed two steps, both of which were performed
independently by two people:

(1) Titles screening

The first screening was made considering the title of the articles. Articles focusing on one disease only,
carrier screening, case reports, protocols only, and infective outbreaks in the Neonatal Intensive Care Unit
(NICU) were excluded. After this first step, 151 articles were excluded for relevance reasons.

(2) Abstracts screening

The second step consisted of reading the abstracts and assigning each article to one of 14 pre-identified
categories grouped in three areas: clinical, social, and governance [see Figure 2]. Reading the abstracts
allowed a stricter selection of articles with a clear focus on the application of Genome Sequencing (GS) to
population-wide NBS, while excluding the publications that used GS as a diagnostic tool. Finally, we
reduced the redundancy based on the article’s topic and publication date (e.g., for articles on the same topic,
the most recent was preferred). After this step, 36 articles were excluded.

The final number of articles retained for the review was 33.

A flowchart of the selection of the articles can be found in Figure 3.

RESULTS
The mixed methods search brought to the identification of 33 articles distributed as in Figure 4.

For the Clinical subject, 14 publications were identified. Five papers were focused on wide GS discussion in
the last 15 years [22-24,7] Methods to manage the genomic data produced in the GS analysis and a definition of
the clinical actionable conditions have been explored in three publications [2,6,5] . Results and/or discussions
about the impact, feasibility, benefits, and costs of the GS in the clinical care of newborns have been
reported in five publications [14,26-29] .

For the Social subject, 12 publications were identified. Three records dealt with the BabySeq Project,
surveying parents and clinicians involved in the trial, parents who denied participation, and a third one
analyzing the changed protocol and the concept of family benefit [8,12,30] . The study NC-NEXUS was also
taken into consideration, with a publication regarding a Decision Aid tool to support parents in the
decision-making process. If GS is to be implemented in NBS, communication and education are key
[31]
elements that must be considered and promoted . Opinions from genetics professionals were also
considered through a paper that presented a survey to the American College of Medical Genetics and