Genetic newborn screening and digital technologies: A project protocol based on a dual approach to shorten the rare diseases diagnostic path in Europe

Abstract

Since 72% of rare diseases are genetic in origin and mostly paediatrics, genetic newborn screening represents a diagnostic "window of opportunity". Therefore, many gNBS initiatives started in different European countries. Screen4Care is a research project, which resulted of a joint effort between the European Union Commission and the European Federation of Pharmaceutical Industries and Associations. It focuses on genetic newborn screening and artificial intelligence-based tools which will be applied to a large European population of about 25.000 infants. The neonatal screening strategy will be based on targeted sequencing, while whole genome sequencing will be offered to all enrolled infants who may show early symptoms but have resulted negative at the targeted sequencing-based newborn screening. We will leverage artificial intelligence-based algorithms to identify patients using Electronic Health Records (EHR) and to build a repository "symptom checkers" for patients and healthcare providers. S4C will design an equitable, ethical, and sustainable framework for genetic newborn screening and new digital tools, corroborated by a large workout where legal, ethical, and social complexities will be addressed with the intent of making the framework highly and flexibly translatable into the diverse European health systems.

Fig 1. Representation of main factors contributing to the vicious circle (the “rare disease conundrum”) that prevents the acceleration of rare disease clinical trials, overall R&D, and better outcome for PLWRD.

Strategies implemented by S4C to break this loop are also represented in the figure. Abbreviations: NBS, Newborn screening; RD, Rare Diseases; R&D, Research and Development.

Fig 2. The S4C pillars with multi-pronged dual strategy to shorten RD diagnosis.

Abbreviations: NBS newborn screening, HCP health care provider, EHR, Electronic Health Records, RD research & development.

Fig 3. Schematic representation of the multi-layered structure of S4C and its governance and board composition to ensure appropriate levels of cooperation, scientific exchange, multi-stakeholder engagement, dialogue, and cooperation with other initiatives (as IMI2-JU).

Abbreviations: ELST, Ethical, Legal and Safety Team; CWG, Communication Working Group; DWG, Dissemination Working Group; IB, Innovative Board; CT, Coordinating Team; PMO, Project Management Office; EPMT, Executive Project Management Team; WP, Work Packages; PAB, Patient Advisory Board; SAB, Scientific Advisory Board; MSEB, Multi-Stakeholder Engagement Board; IMI2-JU, Innovative Medicine Initiative 2 Joint Undertaking, WP workpackage.

Fig 4. Different strategies adopted to drive gNBS.

Option 1) Currently treatable RDs (TREAT-panel-approach); Option 2) Actionable RDs (ACT-panel-approach); Option 3) Whole Genome Sequencing (WGS) for early symptomatic infants, tested negatively during panel-based gNBS, to recognize known NBS targeted sequencing based-escaped RDs and/or novel genes/phenotypes. On the right panel, the comparison and proportion of the final number (#) of genes screened using the three different approaches is shown. Robust criteria will be applied to select and prioritize genes to be included in TREAT and/or ACT panels. Abbreviations: NGS next generation sequencing, NBS newborn screening.