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



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.



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).



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.
Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Jonathan S
0000-0003-2360-2664
JS
Berg
Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Ann Katherine M
AK
Foreman
Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Julianne M
0000-0001-5843-4432
JM
O'Daniel
Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Jessica K
JK
Booker
Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Lacey
L
Boshe
Department of Social Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Timothy
T
Carey
Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Kristy R
0000-0001-8263-096X
KR
Crooks
Division of Cardiology, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Brian C
BC
Jensen
Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.|Department of Social Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.|Center for Bioethics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Eric T
ET
Juengst
Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Kristy
0000-0002-8338-7989
K
Lee
Department of Social Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Daniel K
DK
Nelson
Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Bradford C
0000-0002-2842-8645
BC
Powell
Division of Genetics and Metabolism, Department of Pediatrics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Cynthia M
0000-0002-4260-5601
CM
Powell
Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.|Department of Social Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.|Division of Genetics and Metabolism, Department of Pediatrics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Myra I
0000-0001-9680-6006
MI
Roche
Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Cecile
C
Skrzynia
Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Natasha T
0000-0001-5148-9772
NT
Strande
Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Karen E
KE
Weck
Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Kirk C
KC
Wilhelmsen
Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
James P
JP
Evans
D002874:Chromosome Mapping; D030342:Genetic Diseases, Inborn / Q000175:diagnosis* / Q000453:epidemiology / Q000473:pathology; D005820:Genetic Testing; D015894:Genome, Human; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D033162:Incidental Findings