Establishing the Medical Actionability of Genomic Variants

Abstract

Actionability is an important concept in medicine that does not have a well-accepted standard definition, nor is there a general consensus on how to establish it. Medical actionability is often conflated with clinical utility, a related but distinct concept. This lack of clarity contributes to practice variation and inconsistent coverage decisions in genomic medicine, leading to the potential for systematic bias in the use of evidence-based interventions. We clarify how medical actionability and clinical utility are distinct and then discuss the spectrum of actionability, including benefits for the person, the family, and society. We also describe applications across the life course, including prediction, diagnosis, and treatment. Current challenges in assessing the medical actionability of identified genomic variants include gaps in the evidence, limited contexts with practice guidelines, and subjective aspects of medical actionability. A standardized and authoritative assessment of medical actionability is critical to implementing genomic medicine in a fashion that improves population health outcomes and reduces health disparities.

Keywords: actionability; clinical utility; evidence; genomic medicine; intervention; medical actionability.

Figure 1

The spectrum of actionability, which includes benefits for the person, the family, and society.

Figure 2

The spectrum of actionability across the life course. Within each stage of life, genomic tests can be actionable for different applications, including prediction, diagnosis, and treatment.

Figure 3

An analytical framework for answering the following question: Does sequencing genes for conditions that would then be monitored by a surveillance program reduce the risk of a bad health outcome compared with having no surveillance program? In some cases, there can be direct evidence about the program’s effectiveness (top); if there is no direct evidence, then individual pieces of the program may provide indirect evidence (bottom).