Since newborn screening (NBS) began in the 1960's, technological advances have resulted in its use in an increasing number of disorders. Recent developments in whole genome sequencing and its simpler corollary, whole exome sequencing (WES), now afford the opportunity to comprehensively define the variation within an individual's genome in a rapid and affordable manner. Many challenges arise with the clinical application of genome-scale sequencing and in deriving practical benefit to infants and children. Its utility in NBS has yet to be demonstrated and its application in the pediatric population requires special examination, not only for potential clinical benefits, but also for the unique ethical challenges it presents. In this proposal, we outline a highly interdisciplinary approach to identifying, confronting and overcoming the major challenges that must be met in order to implement deep sequencing technology to enhance current newborn screening in a diverse pediatric population. Overarching Aim 1 will evaluate the utility of WES as a diagnostic tool to extend the utility of current NBS. Using diverse cohorts of infants and young children with known conditions identified through NBS, we will examine the sensitivity and specificity of WES. We will also utilize WES in cohorts of children with known conditions not currently screened for as potential candidates for NBS in the future. Overarching Aim 2 will develop and assess a framework for analyzing WES in a clinically oriented framework based on principles of ethics and evidence-based medicine. We will develop strategies to guide clinicians, clinical laboratories and patients/families in their decisions regarding the inevitable incidental findings that will be detected in ways that respect the child and protect his/her future autonomy, while also respecting parental interests and rights. Overarching Aim 3 will explore ethical, legal and social issues (ELSl) involved in informed decision-making and develop best practices regarding return of results after testing. We will develop novel decision support tools and evaluate their usefulness in parental decision making, and examine the burdens placed on clinicians as this new technology is deployed in the vulnerable and special population that are newborns and their families.
Genomic medicine has tremendous potential to improve the health of children by facilitating more accurate diagnosis, deeper insight into mechanisms of disease, and individually targeted prevention and treatment. This proposal is relevant to public health because critical challenges remain to be addressed before genomic medicine can be broadly implemented in the newborn screening context.
|Lewis, Megan A; Stine, Alex; Paquin, Ryan S et al. (2018) Parental preferences toward genomic sequencing for non-medically actionable conditions in children: a discrete-choice experiment. Genet Med 20:181-189|
|Paquin, Ryan S; Peinado, Susana; Lewis, Megan A et al. (2018) A behavior-theoretic evaluation of values clarification on parental beliefs and intentions toward genomic sequencing for newborns. Soc Sci Med :|
|Ormond, Kelly E; Hallquist, Miranda L G; Buchanan, Adam H et al. (2018) Developing a conceptual, reproducible, rubric-based approach to consent and result disclosure for genetic testing by clinicians with minimal genetics background. Genet Med :|
|Strande, Natasha T; Brnich, Sarah E; Roman, Tamara S et al. (2018) Navigating the nuances of clinical sequence variant interpretation in Mendelian disease. Genet Med 20:918-926|
|Sanghvi, Rashesh V; Buhay, Christian J; Powell, Bradford C et al. (2018) Characterizing reduced coverage regions through comparison of exome and genome sequencing data across 10 centers. Genet Med 20:855-866|
|Milko, Laura V; Rini, Christine; Lewis, Megan A et al. (2018) Evaluating parents' decisions about next-generation sequencing for their child in the NC NEXUS (North Carolina Newborn Exome Sequencing for Universal Screening) study: a randomized controlled trial protocol. Trials 19:344|
|Pawliczek, Piotr; Patel, Ronak Y; Ashmore, Lillian R et al. (2018) ClinGen Allele Registry links information about genetic variants. Hum Mutat 39:1690-1701|
|Berg, Jonathan S; Agrawal, Pankaj B; Bailey Jr, Donald B et al. (2017) Newborn Sequencing in Genomic Medicine and Public Health. Pediatrics 139:|
|Berg, Jonathan S (2017) Exploring the importance of case-level clinical information for variant interpretation. Genet Med 19:3-5|
|Mollison, Lonna; Berg, Jonathan S (2017) Genetic screening: birthright or earned with age? Expert Rev Mol Diagn 17:735-738|
Showing the most recent 10 out of 16 publications