An Evidence Framework for Genetic Testing (2017) / Chapter Skim
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4 Evidence
4 Evidence
Pages 59-78
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From page 59... ...
Although this report emphasizes clinical utility and is designed to address issues of patient management and clinical care, as noted in the statement of task, evidence of analytic validity and clinical validity remains important in test development and is an informative element of the evidence base. The chapter begins with a brief introduction to the types of evidence and their use in evaluating genetic tests.
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From page 60... ...
. The evidence base on genetic tests is described in this chapter as it applies to the domains of analytic validity, clinical validity, and clinical utility.
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From page 61... ...
First, validating genetic tests is often challenging because of a lack of appropriately qualified samples, a lack of gold-standard reference methods, and the constantly emerging and evolving genetic techniques. Thus, data on analytic validity of genetic tests might be lacking, inconsistent, or out of date.
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From page 62... ...
information underlying testing technology that has well-established analytic validity Analytic validity is an integral element of clinical validity such that some approaches to evaluation of evidence on genetic tests assume that analytic validity has been demonstrated if clinical validity has been shown; that is, observation of a gene–disease association depends on the ability to classify people correctly as to genetic status (Teutsch et al., 2009; CDC, 2013)
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From page 63... ...
The types of studies used to generate evidence of the clinical validity of a genetic test are also described. When evaluating the clinical validity of a test, the clinical scenario is an important consideration.
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From page 64... ...
. For example, FDA approved cystic fibrosis testing by NGS for a specific panel of variants in the CFTR gene because there was good evidence of the analytic validity and clinical validity for the variants (based on statistical evidence on the frequency of the variants in patients versus controls and functional predictions)
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From page 65... ...
Pragmatically, the clinical validity of a genetic test has to depend on evidence of the association of the gene -- rather than of all the variants found in the gene -- with the disease of interest. Otherwise, nearly all genes would be excluded through usual methods of determining causality.
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From page 66... ...
. It is less important in diagnostic or prognostic genetic testing when a person already has symptoms and a test is used to establish or confirm a diagnosis.
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From page 67... ...
Without data on penetrance, the databases are useful primarily for diagnostic and prognostic tests and far less clinically useful for predictive tests. Increased submission of data on detected mutations and associated clinical information to such databases and the curation of data in the databases will help to improve the evidence base on the clinical validity of genomic tests (MacArthur et al., 2014; Brookes and Robinson, 2015)
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From page 68... ...
Thus, cohort studies are the design of choice for providing risk estimates that are necessary for predictive genetic testing. However, cohort studies can be expensive because they require continuous follow-up unless they can be constructed retrospectively.
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From page 69... ...
Evidence of clinical validity is stronger when the molecular and biologic mechanisms leading to the disease are understood than when mechanisms are not understood. Evidence on clinical validity in distinct groups or small datasets can provide proof of concept, but additional data representative of the entire range of the intended clinical population provide much stronger evidence on clinical validity (Teutsch et al., 2009)
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From page 70... ...
. For example, EGAPP examined genetic testing strategies for patients who had newly diagnosed colorectal cancer to identify cases of Lynch syndrome, thus determining clinical validity of the test.
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From page 71... ...
Finally, although the analytic validity and clinical validity of many genetic tests have been established for many genetic tests, the clinical utility of many tests in many contexts remains uncertain (Teutsch et al., 2009; Feero et al., 2013)
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From page 72... ...
One example is the companion diagnostic test of CFTR genetic testing for cystic fibrosis patients and the use of an FDA-approved medication, Ivacaftor, for the G551D variant (and nine additional variants)
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From page 73... ...
. The ideal approach to conclusions about clinical utility would be to base decisions about genetic tests on controlled trials, but in reality such decisions are routinely based on less rigorous levels of evidence.
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From page 74... ...
routinely considers evidence reviews on rare conditions that are being considered for inclusion on the screening panel. As in the case of rare conditions, such as those considered for genetic testing, the evidence base (especially from screening trials)
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From page 75... ...
However, traditional methods (systematic evidence reviews) are difficult to apply to genetic tests.
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From page 76... ...
Studies should include a broad array of potential outcomes that reflect the clinical utility of genetic testing, including ones that extend beyond clinical outcomes, such as well-being, quality of life, and impacts on family members. DoD could conduct prospective studies, such as RCTs, in its facilities or affiliated institutions or could sponsor outside research.
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From page 77... ...
of promising tests; implementing processes for data collection and analysis of its own experience with genetic testing; supporting evidence-based systematic reviews of genetic tests; contributing genetic variants and associated clinical data to public evidence repositories; and partnering with other organizations to facilitate these recommendations.
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