A semiquantitative metric for evaluating clinical actionability of incidental or secondary findings from genome-scale sequencing

Abstract

Purpose: As genome-scale sequencing is increasingly applied in clinical scenarios, a wide variety of genomic findings will be discovered as secondary or incidental findings, and there is debate about how they should be handled. The clinical actionability of such findings varies, necessitating standardized frameworks for a priori decision making about their analysis.

Methods: We established a semiquantitative metric to assess five elements of actionability: severity and likelihood of the disease outcome, efficacy and burden of intervention, and knowledge base, with a total score from 0 to 15.

Results: The semiquantitative metric was applied to a list of putative actionable conditions, the list of genes recommended by the American College of Medical Genetics and Genomics (ACMG) for return when deleterious variants are discovered as secondary/incidental findings, and a random sample of 1,000 genes. Scores from the list of putative actionable conditions (median = 12) and the ACMG list (median = 11) were both statistically different than the randomly selected genes (median = 7) (P < 0.0001, two-tailed Mann-Whitney test).

Conclusion: Gene-disease pairs having a score of 11 or higher represent the top quintile of actionability. The semiquantitative metric effectively assesses clinical actionability, promotes transparency, and may facilitate assessments of clinical actionability by various groups and in diverse contexts.Genet Med 18 5, 467-475.

Figures

Figure 1

Semiquantitative metric scores. (a) Summary of overlap between the gene lists analyzed. The American College of Medical Genetics and Genomics (ACMG) genes included 26 gene–disease pairs (25 not including NTRK) that were not among the bin 1 genes. Conversely, 130 bin 1 genes were not among the ACMG genes. Of the 111 random genes with a defined disease association, 4 overlapped with the bin 1 genes (ANK2, BRIP1, COL1A2, PROC), 1 overlapped with the ACMG genes (NTRK1), and 1 gene overlapped both lists (PTEN). The Locus-Variant Binning Committee also evaluated 80 other gene–disease pairs, including alternative phenotypes for some genes, or different genes with similar disease phenotypes. One of these genes was on the ACMG list (NF2) and two were on the random list (CASQ2 and MAX). (b) Distribution of semiquantitative metric scores. Box-whisker plots showing the median, 25th–75th percentiles (box), and 5th–95th percentiles (whiskers) of the scores for the bin 1 gene list, ACMG gene list, random gene list, and other gene list. Asterisks indicate statistically significant differences (P < 0.0001, two-tailed Mann-Whitney test).