Chapter 11: challenges in and principles for conducting systematic reviews of genetic tests used as predictive indicators

Abstract

In this paper, we discuss common challenges in and principles for conducting systematic reviews of genetic tests. The types of genetic tests discussed are those used to 1). determine risk or susceptibility in asymptomatic individuals; 2). reveal prognostic information to guide clinical management in those with a condition; or 3). predict response to treatments or environmental factors. This paper is not intended to provide comprehensive guidance on evaluating all genetic tests. Rather, it focuses on issues that have been of particular concern to analysts and stakeholders and on areas that are of particular relevance for the evaluation of studies of genetic tests. The key points include: The general principles that apply in evaluating genetic tests are similar to those for other prognostic or predictive tests, but there are differences in how the principles need to be applied or the degree to which certain issues are relevant. A clear definition of the clinical scenario and an analytic framework is important when evaluating any test, including genetic tests. Organizing frameworks and analytic frameworks are useful constructs for approaching the evaluation of genetic tests. In constructing an analytic framework for evaluating a genetic test, analysts should consider preanalytic, analytic, and postanalytic factors; such factors are useful when assessing analytic validity. Predictive genetic tests are generally characterized by a delayed time between testing and clinically important events. Finding published information on the analytic validity of some genetic tests may be difficult. Web sites (FDA or diagnostic companies) and gray literature may be important sources. In situations where clinical factors associated with risk are well characterized, comparative effectiveness reviews should assess the added value of using genetic testing along with known factors compared with using the known factors alone. For genome-wide association studies, reviewers should determine whether the association has been validated in multiple studies to minimize both potential confounding and publication bias. In addition, reviewers should note whether appropriate adjustments for multiple comparisons were used.

Figure 1

Generic analytic framework for evaluating predictive genetic tests.

Figure 2

Generic analytic framework for evaluating predictive genetic tests when the impact on family members is important.

Figure 3

Analytic framework for evidence gathering on CYP450 genotype testing for SSRI treatment of depression. Abbreviation: SSRI = selective serotonin reuptake inhibitor. Numbers in this figure represent the research questions addressed in the systematic review:45 1 (overarching question): Does testing for cytochrome P450 (CYP450) polymorphisms in adults entering selective serotonin reuptake inhibitor (SSRI) treatment for non-psychotic depression lead to improvement in outcomes, or are testing results useful in medical, personal, or public health decisionmaking? 2: What is the analytic validity of tests that identify key CYP450 polymorphisms? 3a: How well do particular CYP450 genotypes predict metabolism of particular SSRIs? Do factors such as race/ethnicity, diet, or other medications, affect this association? 3b: How well does CYP450 testing predict drug efficacy? Do factors such as race/ethnicity, diet, or other medications, affect this association? 3c: How well does CYP450 testing predict adverse drug reactions? Do factors such as race/ethnicity, diet, or other medications, affect this association? 4a: Does CYP450 testing influence depression management decisions by patients and providers in ways that could improve or worsen outcomes? 4b: Does the identification of the CYP450 genotypes in adults entering SSRI treatment for non-psychotic depression lead to improved clinical outcomes compared to not testing? 4c: Are the testing results useful in medical, personal or public health decisionmaking? 5: What are the harms associated with testing for CYP450 polymorphisms and subsequent management options?