Abstract
BackgroundUsing next-generation sequencing (NGS) in newborn screening (NBS) could expand the number of genetic conditions detected pre-symptomatically, simultaneously challenging current precedents, raising ethical concerns, and extending the role of parental decision-making in NBS. The NC NEXUS (Newborn Exome Sequencing for Universal Screening) study seeks to assess the technical possibilities and limitations of NGS-NBS, devise and evaluate a framework to convey various types of genetic information, and develop best practices for incorporating NGS-NBS into clinical care. The study is enrolling both a healthy cohort and a cohort diagnosed with known disorders identified through recent routine NBS. It uses a novel age-based metric to categorize a priori the large amount of data generated by NGS-NBS and interactive online decision aids to guide parental decision-making. Primary outcomes include: (1) assessment of NGS-NBS sensitivity, (2) decision regret, and (3) parental decision-making about NGS-NBS, and, for parents randomized to have the option of requesting them, additional findings (diagnosed and healthy cohorts). Secondary outcomes assess parents’ reactions to the study and to decision-making.Methods/designParticipants are parents and children in a well-child cohort recruited from a prenatal clinic and a diagnosed cohort recruited from pediatric clinics that treat children with disorders diagnosed through traditional NBS (goal of 200 children in each cohort). In phase 1, all parent participants use an online decision aid to decide whether to accept NGS-NBS for their child and provide consent for NGS-NBS. In phase 2, parents who consent to NGS-NBS are randomized to a decision arm or control arm (2:1 allocation) and learn their child’s NGS-NBS results, which include conditions from standard (non-NGS) NBS plus other highly actionable childhood-onset conditions. Parents in the decision arm use a second decision aid to make decisions about additional results from their child’s sequencing. In phase 3, decision arm participants learn additional results they have requested. Online questionnaires are administered at up to five time points.DiscussionNC NEXUS will use a rigorous interdisciplinary approach designed to collect rich data to inform policy, practice, and future research.Trial registrationclinicaltrials.gov, NCT02826694. Registered on 11 July, 2016.
Highlights
Using next-generation sequencing (NGS) in newborn screening (NBS) could expand the number of genetic conditions detected pre-symptomatically, simultaneously challenging current precedents, raising ethical concerns, and extending the role of parental decision-making in NBS
This paper summarizes the NC NEXUS protocol, which is designed to achieve the foregoing aims
Decision aid To help parents make informed decisions about whether to accept genomic sequencing for their child and about their preferences for additional information, we developed a web-based decision aid grounded in principles of informed decision-making
Summary
The NC NEXUS study is led by an interdisciplinary team and is examining the technical, clinical, and ethical issues associated with utilizing genome-scale sequencing technology to screen newborns. Commercial laboratories currently market direct-to-consumer genomic sequencing of newborns [41, 42], heightening concerns about the clinical validity and long-term impact of returning different types of genetic information to parents of newborns These concerns, coupled with the likelihood that genomic screening technology will eventually be adopted into neonatal public health screening, emphasize the need for a practical and ethical infrastructure, including validated decision-support materials and an evidence-based process, by which to apply genomic sequencing to NBS for the tangible benefit of parents and children. A broader understanding of several aspects is needed to facilitate incorporation of NGS into newborn public health screening and inform development of important future NBS policy guidelines These include how parents understand NGS-NBS, the decisions that they make, the role of a decision aid and the supporting clinical interactions in influencing parents’ decisions, and the ramifications of disclosure for family adaptation.
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