Genomic Newborn Screening: Public Health Policy Considerations and Recommendations Martina C. Cornel, J.M. Friedman, A.J. Goldenberg, K.J. Lister, K. Sénécal, D.F. Vears, the Global Alliance for Genomics and Health Regulatory and Ethics Working Group Paediatric Task Team

I have no conflicts of interest

The Global Alliance for Genomics and Health is an international collaboration of more than 370 healthcare, research, disease advocacy, life science, and information technology institutions formed to promote human health through sharing of genomic and clinical data [http://genomicsandhealth.org/]. Within this remit, the Paediatric Task Team of the Global Alliance’s Regulatory and Ethics Working Group [http://genomicsandhealth.org/working-groups/regulatory-and-ethics-working-group] was established to address issues of particular relevance to child health.

Regulatory and Ethics Working Group Leadership Bartha Maria Knoppers, McGill University Kazuto Kato, Osaka University Focuses on ethics and the legal and social implications of the Global Alliance, including harmonizing policies and standards, and developing forward-looking consent, privacy procedures, and best-practices in data governance and transparency. Contact: Adrian Thorogood (REWG Coordinator) adrian.thorogood@genomicsandhealth.org

Framework for Responsible Sharing of Genomic and Health-Related Data Aims Foster responsible data sharing; Protect and promote the welfare, rights, and interests of groups and individuals who donate their data; Provide benchmarks for accountability; Establish a framework for greater international data sharing cooperation, collaboration, and good governance; and, Serve as a dynamic instrument. Foundational Principles Respect Individuals, Families and Communities; Advance Research and Scientific Knowledge; Promote Health, Wellbeing and the Fair Distribution of Benefits; and, Foster Trust, Integrity and Reciprocity.

GA4GH Regulatory and Ethics Initiatives Accountability Ethics Review Equivalency Ageing and Dementia Participant Values BRCA Challenge Ethico-Legal Machine Readable Consent Mobile Health Consent Participant Unique Identifiers Data Protection Regulation Paediatric Data Sharing Lexicon Registered Access

Standard newborn screening Public Health Intervention Offered to all newborn infants Goal: to identify infants with conditions for which effective therapy is available Early treatment can prevent or ameliorate the disease, so that affected children can live healthier lives

Mainly genetic conditions (PKU, CF, MCADD) Diversity between jurisdictions Criteria (Wilson & Jungner 1968) to determine whether pros>cons Important health problem, treatment available, “good test”, (=sensitive & specific) agreed policy on whom to treat as patients, cost… economically balanced in relation to possible expenditure on medical care as a whole

(Whole Genome) Sequencing technologies Can identify genetic causes of rare paediatric diseases much more effectively than conventional clinical and laboratory methods Authors suggest that WGS could, at least in theory, be used in newborn screening to identify many more serious health conditions than is possible today [Levy, 2014; Landau et al., 2014; Berg & Powell, 2015; Bhattacharjee et al., 2015]

RECOMMENDATIONS (N=8) for clinicians, clinical laboratory scientists, and policy makers regarding the use of genomic technologies for population-based newborn screening:

Recommendations Only use next generation sequencing as an add-on to current screening at the present time Current newborn screening by another method should not be replaced by next generation sequencing or other genomic methods for any disease unless the genomic technology has been shown to have equal or better sensitivity and specificity for the disease.

Positive predictive value 3/9 Specificity 100,000/100,006>99.99% OBJECTIVE>25% Specificity 100,000/100,006>99.99% OBJECTIVE >99.99% (per condition) OBJECTIVE >99.5% (programme of many conditions) Test + Test - Total PKU 3 No PKU 6 100,000 100,006 9 100,009

Data sharing is needed for interpretation of variants. Equal availability and accessibility to every infant born in the jurisdiction should be guaranteed. In NL 80€ per infant currently, from public funding WGS 1000€ and interpretation…, from research (often) or health insurance (rare) Data sharing is needed for interpretation of variants. Have we seen all variants of a gene, do we know genotype-phenotype correlation for thousands of variants? PPV? Which treatment for which gene variant? Is protocol agreed?

Publicly-funded universal newborn screening by genomic methods should be limited to diseases that can be effectively treated or prevented early in life. A program should guarantee treatment and follow up. We conclude we are not yet ready to implement sequencing large multigene panels in NBS.

Thank you This work was supported by Genome Canada; Genome Quebec; Genome British Columbia; the National Human Genome Research Institute, National Institutes of Health (USA), 2P50-HG-003390-06; Research Fund Flanders (Belgium); Ministère de l'Économie, de l'Innovation et des Eportations du Québec, PSR-SIIRI-850 (Canada); and the Brocher Foundation (Switzerland). Acknowledgements: members of the Paediatric task team & Bartha Knoppers (McGill University) and Heidi Howard (Uppsala University), who provided helpful comments on the policy considerations and recommendations