Table 5.

Grading the quality of evidence for the individual components of the chain of evidence (key questions)⁵⁷

Adequacy of information to answer key questions	Analytic validity	Clinical validity	Clinical utility
Convincing	Studies that provide confident estimates of analytic sensitivity and specificity using intended sample types from representative populations	Well-designed and conducted studies in representative population(s) that measure the strength of association between a genotype or biomarker and a specific and well-defined disease or phenotype	Well-designed and conducted studies in representative population(s) that assess specified health outcomes
	Two or more Level 1 or 2 studies that are generalizable, have a sufficient number and distribution of challenges, and report consistent results	Systematic review/meta-analysis of Level 1 studies with homogeneity	Systematic review/meta-analysis of randomized controlled trials showing consistency in results
			At least one large randomized controlled trial (Level 2)
	One Level 1 or 2 study that is generalizable and has an appropriate number and distribution of challenges	Validated Clinical Decision Rule
		High quality Level 1 cohort study
Adequate	Two or more Level 1 or 2 studies that	Systematic review of lower quality studies	Systematic review with heterogeneity
	Lack the appropriate number and/or distribution of challenges	Review of Level 1 or 2 studies with heterogeneity	One or more controlled trials without randomization (Level 3)
	Are consistent, but not generalizable	Case/control study with good reference standards	Systematic review of Level 3 cohort studies with consistent results
	Modeling showing that lower quality (Level 3, 4) studies may be acceptable for a specific well- defined clinical scenario	Unvalidated Clinical Decision Rule (Level 2)
Inadequate	Combinations of higher quality studies that show important unexplained inconsistencies	Single case-control study	Systematic review of Level 3 quality studies or studies with heterogeneity
		Nonconsecutive cases
	One or more lower quality studies (Level 3 or 4)	Lacks consistently applied reference standards	Single Level 3 cohort or case-control study
	Expert opinion	Single Level 2 or 3 cohort/case-control study	Level 4 data
		Reference standard defined by the test or not used systematically
		Study not blinded
		Level 4 data