Genetics and Public Health: The Future is Now

Definitions

Analytical Validity
For DNA-based tests, analytical validity requires establishing the probability that a test will be positive when a particular sequence (analyte) is present (analytical sensitivity) and the probability that the test will be negative when the sequence is absent (analytical specificity). Another measure of analytical validity is reliability, or the probability of repeatedly getting the same result. In validating a new test analytically, the laboratory techniques should be as similar as possible to those used when the test will be performed clinically once it is validated. Analytical sensitivity and specificity of a genetic test must be determined before it is made available in clinical practice.

Clinical Validity
Clinical validation involves establishing several measures of clinical performance including 1) the probability that the test will be positive in people with the disease (clinical sensitivity), 2) the probability that the test will be negative in people without the disease (clinical specificity), and 3) the probability that people with positive test results will get the disease (positive predictive value, PPV) and that people with negative results will not get the disease (negative predictive value). Predictive value depends on the prevalence of the disease in the group or population being studied, as well as on the clinical sensitivity and specificity of the test. Data on a particular intended use of a test is needed before that use becomes generally accepted clinical practice.

Two intrinsic features of genetic diseases affect clinical validity:

  • Heterogeneity The same genetic disease might result from the presence of any of several different variants (alleles) of the same gene or of different genes. With current technology, all disease-related alleles cannot always be identified, particularly when there are many. This failure to detect all disease-related mutations reduces a test's clinical sensitivity.
  • Penetrance The probability that disease will appear when a disease-related genotype is present is the penetrance of the genotype. When penetrance is incomplete, PPV is reduced. Penetrance is incomplete when other genetic or environmental factors must be present.

Clinical Utility
To improve the benefits of testing, efforts must be made as tests are developed to investigate the safety and effectiveness of new interventions. In the absence of such interventions, studies must be mounted to ensure that testing is beneficial and, particularly, does not inflict psychological harm. The effect of testing on people with negative, as well as positive results, is important to assess. The scientists and laboratories developing genetic tests might not have the expertise to explore a number of issues related to communication and counseling. Collaboration with clinical geneticists, genetic counselors, and psychologists can improve the quality of studies looking into these aspects of test development. Before a genetic test can be generally accepted in clinical practice, data must be collected to demonstrate the benefits and risks that accrue from both positive and negative results.

From National Human Genome Research Institute