Application of Pediatric AWG Framework to Gene-Condition Topics

The Pediatric AWG began to apply this framework to gene-condition topics in 2017, including some genes and conditions recommended for return as a secondary finding by the ACMG (ACMG SF v3.0). To represent the degree of actionability for the topics assessed through September 2021, we summarized the actionability scores across topics. For each topic, we computed a summary score for each outcome and intervention pair by adding scores across the four domains of actionability. Because topics can involve multiple outcome-intervention pairs, we focus for comparison on the highest-scoring outcome-intervention pair for each gene-condition topic. When multiple outcome–intervention pairs tied for the highest summary score, we considered the individual domains to choose a pair, as follows. If the individual domains of the outcome–intervention pairs differed, we prioritized the pair with the highest score in the following domains as tie breakers: effectiveness, followed by severity, followed by likelihood. If the individual domains of the outcome-intervention pairs were the same, the score was included in the analysis once and attributed to more than one outcome-intervention pair. For situations where the Pediatric AWG scored topics separately by categories defined by gene (e.g., SCN5A was scored separately from KCNQ1 and KCNH2 for Long QT Syndrome) or zygosity (e.g., familial hypercholesterolemia), we present one pair for each category.