On the use of population-based registries in the clinical validation of genetic tests for disease susceptibility.
OBJECTIVE
Many new genetic tests for susceptibility to adult-onset diseases are developed on the basis of selected and high-risk groups. Before such tests can be used in medical practice, however, epidemiologic studies must be conducted to evaluate their clinical sensitivity, specificity, and positive predictive value in the general population. For many common adult-onset diseases, this process may take decades of follow-up.


METHODS
We illustrate how clinical validation of new predictive genetic tests can be done retrospectively using case-control studies that are derived from population-based registries of diseases. We use the examples of birth defects and cancer registries to illustrate a hypothetical process by which such tests can be clinically validated.


RESULTS
We demonstrate how such epidemiologic studies can be successfully used to derive measures of a test's sensitivity, specificity, positive predictive value, negative predictive value, and of the population attributable fraction of disease due to the disease-susceptibility genes. Under certain assumptions, data derived from population-based case-control studies provide adequate estimates of lifetime risks for disease (penetrance) among people with specified genotypes.


CONCLUSIONS
With adequate protections of human subjects, studies involving population-based registries of disease will increasingly become valuable in validating the numerous genetic tests that will emerge from advances in human genetic research and the Human Genome Project.
Yang
Q
Q
Birth Defects and Pediatric Genetrics Branch, Centers for Disease Control and Prevention, Atlanta, Georgia 30341, USA.
Khoury
M J
MJ
Coughlin
S S
SS
Sun
F
F
Flanders
W D
WD
D000328:Adult; D001943:Breast Neoplasms / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D019398:Genes, BRCA1 / Q000235:genetics; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005821:Genetic Techniques; D005820:Genetic Testing; D005828:Genetics, Population; D005838:Genotype; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008875:Middle Aged; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics; D010641:Phenotype; D011237:Predictive Value of Tests; D012042:Registries; D015203:Reproducibility of Results; D012307:Risk Factors; D012680:Sensitivity and Specificity
D005819:Genetic Markers; D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2)