Article type
Year
Abstract
Background: Spectrums of mutations in the BReast CAncer susceptibility genes BRCA1 and BRCA2 have been linked to the development of both breast and ovarian cancers. The analytical validity of molecular technologies and issues associated with BRCA1/2 genetic testing were examined in an effort to help patients, health care providers, hospitals, health regions and governments make informed decisions.
Objective: To describe and determine the analytical validity of the various molecular techniques used to identify BRCA1/2 mutations.
Method: Published and grey literature were identified from 1994 onwards by searching databases, trial registries, and the Internet, including websites of health technology assessment agencies. Primary researchers and the commercial developer were also contacted for information. Eligibility criteria were established a priori by two independent reviewers. Methodological information and test descriptions were extracted, and sensitivity and specificity values were calculated.
Results: Of 881 citations identified, 28 (27 unique studies) were included for study. High variability was found across studies in the unit of analysis, mutations tested, molecular techniques studied and the reference test used as a 'gold standard' for comparison. Although most studies used direct sequence analysis as the reference, no two tests used the same index test and unit of analysis thereby precluding comparisons of methods. As a result, it was not possible to determine the most suitable molecular technique for BRCA1/2 testing. Despite the high sensitivity and specificity scores reported in most studies, the study quality was generally poor, with evidence for selection and measurement bias (i.e., inappropriate subject selection and lack of test reliability assessment and blinded testing conditions).
Discussion: In the literature identified for this review, there was insufficient evidence to suggest that any particular molecular technique demonstrated overall superior analytical performance compared to any other, therefore, other factors should be considered in deciding the method used for testing. Results of the studies selected for this report must be interpreted with caution due to their methodological limitations. Future research should seek to overcome these limitations so that meaningful quantitative analyses can be conducted and comparisons made.
Objective: To describe and determine the analytical validity of the various molecular techniques used to identify BRCA1/2 mutations.
Method: Published and grey literature were identified from 1994 onwards by searching databases, trial registries, and the Internet, including websites of health technology assessment agencies. Primary researchers and the commercial developer were also contacted for information. Eligibility criteria were established a priori by two independent reviewers. Methodological information and test descriptions were extracted, and sensitivity and specificity values were calculated.
Results: Of 881 citations identified, 28 (27 unique studies) were included for study. High variability was found across studies in the unit of analysis, mutations tested, molecular techniques studied and the reference test used as a 'gold standard' for comparison. Although most studies used direct sequence analysis as the reference, no two tests used the same index test and unit of analysis thereby precluding comparisons of methods. As a result, it was not possible to determine the most suitable molecular technique for BRCA1/2 testing. Despite the high sensitivity and specificity scores reported in most studies, the study quality was generally poor, with evidence for selection and measurement bias (i.e., inappropriate subject selection and lack of test reliability assessment and blinded testing conditions).
Discussion: In the literature identified for this review, there was insufficient evidence to suggest that any particular molecular technique demonstrated overall superior analytical performance compared to any other, therefore, other factors should be considered in deciding the method used for testing. Results of the studies selected for this report must be interpreted with caution due to their methodological limitations. Future research should seek to overcome these limitations so that meaningful quantitative analyses can be conducted and comparisons made.