A taxonomy of medical uncertainties in clinical genome sequencing

Abstract

PurposeClinical next generation sequencing (CNGS) is introducing new opportunities and challenges into the practice of medicine. Simultaneously, these technologies are generating uncertainties of unprecedented scale that laboratories, clinicians, and patients are required to address and manage. We describe in this report the conceptual design of a new taxonomy of uncertainties around the use of CNGS in health care.MethodsInterviews to delineate the dimensions of uncertainty in CNGS were conducted with genomics experts, and themes were extracted in order to expand upon a previously published three-dimensional taxonomy of medical uncertainty. In parallel we developed an interactive website to disseminate the CNGS taxonomy to researchers and engage them in its continued refinement.ResultsThe proposed taxonomy divides uncertainty along three axes: source, issue, and locus, and further discriminates the uncertainties into five layers with multiple domains. Using a hypothetical clinical example, we illustrate how the taxonomy can be applied to findings from CNGS and used to guide stakeholders through interpretation and implementation of variant results.ConclusionThe utility of the proposed taxonomy lies in promoting consistency in describing dimensions of uncertainty in publications and presentations, to facilitate research design and management of the uncertainties inherent in the implementation of CNGS.

A New Era, New Strategies: Education and Communication Strategies to Manage Greater Access to Genomic Information

“…The results of genome sequencing can be numerous, uncertain, and ambiguous. 1 The impact of many gene variants on a person’s health and future can be difficult to predict, especially when no symptoms have yet emerged, in part because these effects are moderated by numerous other factors, such as a person’s behaviors and environmental exposures over time. As next-generation genomic sequencing, including whole-genome sequencing information becomes more common in research, clinical, and public health contexts, there is a need for comprehensive communication strategies and education approaches to prepare patients and clinicians to manage this information and make informed decisions about its use.…”

Patients' perspectives of variants of uncertain significance and strategies for uncertainty management

“…(a) PROBABILITY (i.e., “the fundamental indeterminacy or stochastic nature of future outcomes”) (Han et al, )…”

“…Genomic medicine, especially genomic testing, is awash with uncertainties—from variant interpretation to communicating results to patients (Han et al, ). Variants of uncertain significance (VUS) are genomic variants which cannot be classified as pathogenic or benign because of inadequate or conflicting information.…”

“…Issue refers to “the specific substantive matter about which an individual lacks knowledge.” This can be subdivided into scientific (diagnostic, prognostic, causal or therapeutic), practical (“lack of knowledge about the structures of healthcare and the processes of healthcare”), and personal (psychosocial and existential issues). Locus refers to “the party in whose mind uncertainty resides.” The taxonomy identifies various stakeholders including “patients, clinicians, researchers, or other individuals including family members, regulators, payers or health policy makers.” A more extensive definition of components of the taxonomy is available in Han et al, .…”

Associations of perceived norms with intentions to learn genomic sequencing results: Roles for attitudes and ambivalence.

“…These are findings that may or may not represent pathogenic variants in the absence of further data. As such, decisions to receive genomic sequencing results are complicated by consideration of the consequences of a range of uncertainties (Han et al, in press). For patients, genetic discrimination has been a long-standing concern (Green, Lautenbach, & McGuire, 2015).…”