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Page 4 of 6 Tsipouras et al. Rare Dis Orphan Drugs J 2023;2:17 https://dx.doi.org/10.20517/rdodj.2023.15

Sharing pathogenic variants: Defining the frequency and prevalence of a pathogenic variant in diverse
populations is essential. Access to the pathogenic variant libraries of the various initiatives will impact the
predictive value of a screen positive, and it might help in the reclassification of Variants of Uncertain
Significance (VUS).

Sharing care paths: Newborn genome screening is a risk stratification test that places a person in a high- or
low-risk group for a particular genetic disease. The accuracy and validity of establishing the presence of
disease have an enormous impact on the well-being of the person and the family, the timing of therapeutic
intervention, possibly the modality of intervention, and ultimately healthcare cost.

Sharing clinical outcomes: Managing individuals with latent or early-stage disease can potentially increase
the burden on health care providers and the health care system. Therapeutic interventions, to the extent
possible, will need to be evidence-based. Individual genetic illnesses are often uncommon, and randomized
clinical studies are difficult to conduct. Sharing clinical outcomes, on the other hand, may provide an
incentive for synthetic clinical studies.

Sharing the analytic modality used to generate a variant: The validity of a variant is frequently linked to the
analytical platform used to generate the information, i.e., panel, short-read NGS, and long-read NGS.
Providing a barcode record could be helpful in assessing a variant and its possible value as a biomarker.

Recently, a pioneering example of a multi-party federation between Genomics England and Cambridge
Biomedical Research Centre (BRC) was demonstrated. This allowed secure data analysis across TREs in the
UK’s first known demonstration of genomic data federation. This highlights that the technology now
facilitates secure data access via federation for authorized researchers to perform joint secure data analysis
on global cohorts. Data sharing via federated databases also decreases the danger of unauthorized access and
[17]
encourages the adoption of advanced privacy-preserving encryption methods when analyzing data . It is
conceivable to imagine that this technology could be used in an undiagnosed disease program targeting
newborns to help the integration of clinical, genomic, therapeutic, and outcome inputs residing in different
datasets. A summary of how this could work is provided in Figure 1.

The Federated European Genome-Phenome Archive (EGA) is another program that uses federation to
provide global discovery and access to human data for research while still adhering to jurisdictional data
protection rules. The Federated EGA promotes data reuse, facilitates reproducibility, and accelerates
biomedical research by providing a solution to increasing issues in the safe and efficient handling of human
omics and related data .
[18]

While there are significant advantages to moving towards a genomic approach to newborn screening, these
programs also have challenges. These include considerations of the ethical, legal, and social implications
(ELSI) of newborn genomic screening - these can include concerns surrounding sensitive data sharing,
patient autonomy, and consent. A detailed discussion of these issues is out of the scope of this piece, but we
refer the reader to other references that have discussed these issues more completely [19,20] .

As federation is an emerging technology, careful consideration must be given to scaling up federation across
different TREs, particularly surrounding governance and assurances in particular across different
jurisdictions. Additionally, genomic data federation could potentially have risks, which may include
improper use of data, hacking, and identification of incidental findings such as detection of variants
associated with pathologies not immediately treatable or relevant to the newborn . It is important that
[21]