An Age-Based Framework for Evaluating Genome-Scale Sequencing Results in Newborn Screening

Abstract

Objective-To assess the performance of a standardized age-based metric for scoring clinical actionability to evaluate conditions for inclusion in newborn screening (NBS), and compare it with the results from other contemporary methods. Study design-The North Carolina Newborn Exome Sequencing for Universal Screening (NC NEXUS) study developed an age-based, semi-quantitative metric (ASQM) to assess the clinical actionability of gene-disease pairs and classify them with respect to age of onset or timing of interventions. This categorization was compared with the gold standard Recommended Uniform Screening Panel (RUSP) and other methods to evaluate gene-disease pairs for newborn genomic sequencing. Results-We assessed 822 gene-disease pairs, enriched for pediatric onset of disease and suspected actionability. Of these, 466 were classified as having childhood onset and high actionability, analogous to conditions selected for the RUSP core panel. Another 245 were classified as having childhood onset and low to no actionability, 25 were classified as having adult onset and high actionability, 19 were classified as having adult onset and low to no actionability, and 67 were excluded due to controversial evidence and/or prenatal onset.

Second Tier Molecular Genetic Testing in Newborn Screening for Pompe Disease: Landscape and Challenges

“…Furthermore, tNGS based testing can avoid constraints or complicating factors associated with biochemical testing, such as the infant's gestational age at birth, transfusion status, age at sample collection, need for repeat sampling (rescreens or redraws), and metabolic and feeding states. The NIH funded NSIGHT consortium (Newborn Sequencing in Genomic Medicine and Public Health) evaluated newborn diseases using genome scale sequencing in randomized clinical trials [21,22,29]. This is an exciting time to be at the forefront of applying genomic information to rapidly identifying and treating genetic disorders such as PD.…”

Newborn Screening for Genetic Diseases: An Overview of Current and Future Applications

“…In this context, methods for the selection of appropriate conditions to be introduced as part of a NGS NBS-panel must be developed and tested. With this in mind, Milko et al recently developed an aged-based semi-quantitative scoring method for evaluating the relevance for the introduction of new genetic conditions to NBS panel using genomic sequencing [37]. Their model was mostly based on major screening criteria to evaluate clinical actionability (severity of the disease, likelihood of clinical manifestation, acceptability and efficacy of intervention, overall knowledge of the gene-disease association) [38].…”

“…As expected, the correlations were not perfect, but they reflected the lower clinical actionability of 2 ry compared to 1 ry RUSP conditions, more of the latter being classified in the high clinical actionability category. Comparisons with the BabySeq projects, which categorized their gene-disease pairs on the validity of the gene-disease association, earliest reported age of onset, and penetrance, allowed to reach to a consensus for the identification of 292 conditions to be potentially introduced to a NGS NBS-panel, and another 125 optional for disclosure [37]. Considering that the benefit of NBS for many of the 466 disease-pairs is yet to be proven, it would be wise to apply a stringent classification restricting NGS NBS only for disorders showing definitive or strong clinical validity based on the ClinGen framework [41].…”

Large Scale Next Generation Sequencing and Newborn Screening: Are We Ready?

“…The report by Milko et al in this volume of The Journal proposed an age-based framework for evaluating genome-scale sequencing results in newborn screening using an age-based semiquantitative metric (ASQM) to assess the clinical actionability of gene-disease pairs and classify them with respect to age of onset or timing of interventions. 5 This frame work was compared with the gold standard Recommended Uniform Screening Panel (RUSP). This study describes a method to help facilitate decisions about the potential use of genomic sequencing for NBS as well assisting parents and physicians in making informed decisions about the disclosure of results.…”

“…In contrast, earlier diagnosis and treatment with advanced therapies can achieve remission. 5,6 Over the last few decades, there have been significant advances in understanding the molecular and immune mechanisms involved in JIA; primarily the role of lymphocytes and proinflammatory cytokines. Because of this new knowledge, advanced biologic therapies have been developed.…”