Test Indications and Clinical Utility

Test indications and clinical utility concern the question of whether a genetic test should be done at all and whether its result can change anything that matters. An indication is the clinical reason that justifies testing; clinical utility is the degree to which the result improves a health outcome or decision. A test can be analytically accurate and still lack utility if its result does not alter management.

Definition

A test indication is the clinical question or condition that justifies ordering a genetic test, and clinical utility is the extent to which the test result meaningfully informs a health decision or improves an outcome, beyond merely being analytically and clinically valid.

Scope

The topic distinguishes the several layers on which a genetic test is judged: analytic validity (does the assay measure the genotype correctly), clinical validity (does the genotype relate to the phenotype or disease), and clinical utility (does using the result improve outcomes or decisions). It also covers diagnostic, predictive, carrier, and pharmacogenomic indications, and how choice of testing strategy follows from the indication. It is a reference treatment of how appropriateness is reasoned about, not a list of when to test individual patients.

Core questions

• What clinical question is the test intended to answer?
• Does a positive or negative result change management or decisions?
• How do analytic validity, clinical validity, and clinical utility differ?
• Which testing strategy best matches the indication?

Key concepts

• Analytic validity
• Clinical validity
• Clinical utility
• Diagnostic versus predictive testing
• Pharmacogenomic indication
• Pre-test probability and phenotype fit
• Testing strategy selection

Mechanisms

Selecting a test starts from the indication, which sets the pre-test probability and the relevant genes; this in turn determines whether a targeted assay, a phenotype-driven panel, or broad exome/genome sequencing is appropriate (Schwarze et al., 2018). Utility is layered onto validity: a result must first be analytically and clinically valid, and then must be actionable for the decision at hand. Pharmacogenomic testing is a clear example of a utility chain, where a genotype is linked through an established gene-drug relationship to a downstream clinical consequence (Wang et al., 2011). The interpretive framework that a laboratory applies to the result, in turn, presupposes that the variants found are evaluated against standardized evidence (Richards et al., 2015).

Clinical relevance

Reasoning about indications and utility is core to appraising whether genetic testing adds value and to counseling about what a test can and cannot accomplish. The topic describes how appropriateness and value are evaluated; it does not prescribe which tests to order for an individual or constitute diagnostic advice.

Epidemiology

As sequencing costs have declined, the range of indications for which genetic testing is considered has widened, but systematic review of broad sequencing strategies shows heterogeneous and context-dependent cost-effectiveness, underscoring that wider availability does not automatically translate into utility (Schwarze et al., 2018).

History

Frameworks for evaluating genetic tests evolved from general principles of diagnostic test evaluation toward genetics-specific models that separate analytic validity, clinical validity, clinical utility, and associated ethical, legal, and social implications. The maturation of variant-interpretation standards (Richards et al., 2015) and the accumulation of pharmacogenomic evidence (Wang et al., 2011) sharpened the distinction between a test being accurate and a test being useful.

Debates

How should clinical utility be defined and measured?

Whether utility should be restricted to changes in clinical management and outcomes or should also include broader personal and reproductive value is contested, and the evidence base for many tests' utility, especially broad sequencing, remains incomplete.

Key figures

• Heidi Rehm
• Howard McLeod

Seminal works

• richards-2015
• schwarze-2018
• wang-2011

Frequently asked questions

What is the difference between clinical validity and clinical utility?

Clinical validity is whether the genotype reliably relates to the disease or phenotype; clinical utility is whether using the test result actually improves a decision or outcome. A test can be valid yet lack utility if nothing changes as a result.

Why does the indication drive the choice of test?

The indication sets which genes are relevant and the pre-test probability, which determines whether a targeted assay, a panel, or broad sequencing is the appropriate strategy and how its costs and uncertainties trade off.