“The data show that 7 (37%) of 19 laboratories correctly reported all variants for both wet and dry samples; [the FDA-approved test] also correctly reported all variants for both wet and dry samples”
Clinical Laboratory Improvement Advisory Committee (CLIAC) Next Generation Sequencing (NGS) Workgroup
“A problem for the industry is that…[the same] variant is classified as a ‘variant of unknown significance’, ‘likely benign’, and ‘pathogenic’ by different laboratories due to variations in interpretation.”
Americans Support Increased FDA Oversight to Ensure Accuracy of Diagnostic Tests
“One in 10 Americans who have received a test result report inaccuracy”
Food and Drug Administration Notification and Medical Device Reporting for Laboratory Developed Tests; Draft Guidance for Industry, Food and Drug Administration Staff, and Clinical Laboratories; Availability
“Given a changing landscape in terms of the volume, technology, and business model of IVDs offered as LDTs since 1976, in combination with the increasingly important role of diagnostic devices, including LDTs, in critical clinical treatment decisions, the FDA does not believe that generally exercising enforcement discretion with respect to the regulatory requirements for these devices remains appropriate.”
The Role of Lab-Developed Tests in the In Vitro Diagnostics Market
“The current diagnostic testing regulatory system—in which tests are regulated according to where they are developed and used, rather than the risk they pose if they are inaccurate—creates double standards and potential loopholes that undermine public health objectives.” OR “The Centers for Medicare & Medicaid Services (CMS) regulates labs but has limited insight into the quality, reliability, or usefulness of LDTs, including whether patients have been harmed as a result of their use.”
Challenges of Providing Concordant Interpretation of Somatic Variants in Non-Small Cell Lung Cancer: A Multicenter Study
“Owing to numerous reasons, the interpretation of variants differed greatly, which might in turn lead to the inappropriate clinical care of patients with NSCLC.”
In Silico Proficiency Testing for Clinical Next-Generation Sequencing
“Most current proficiency testing challenges for NGS are methods-based PT surveys that use DNA from reference samples engineered to harbor specific mutations that test both sequence generation and bioinformatics analysis. These methods-based PTs are limited by the number and types of mutations that can be physically introduced into a single DNA sample. In silico proficiency testing, which evaluates only the bioinformatics component of NGS assays, is a recently introduced PT method that allows for evaluation of numerous mutations spanning a range of variant classes.”
Identification of Misclassified ClinVar Variants via Disease Population Prevalence
“We observed up to 11.5% of genetic disorders with inflation in pathogenic variant sets and up to 92.3% for the variant set with conflicting interpretations. This improved to 7.7% and 57.7%, respectively, after filtering for disease-specific allele frequency. The patterns of inflation were replicated using public data from more than 138,000 genomes. The burden of rare variants was a main contributing factor of the observed inflation, indicating collective misclassified rare variants. We also analyzed the dynamics of re-classification of variant pathogenicity in ClinVar over time, which indicates progressive improvement in variant classification. The study shows that databases include a significant proportion of wrongly ascertained variants; however, it underscores the critical role of ClinVar to contrast claims and foster validation across submitters.”
Genetic Misdiagnoses and the Potential for Health Disparities
“Multiple patients, all of whom were of African or unspecified ancestry, received positive reports, with variants misclassified as pathogenic on the basis of the understanding at the time of testing. Subsequently, all reported variants were recategorized as benign. The mutations that were most common in the general population were significantly more common among black Americans than among white Americans (P<0.001). Simulations showed that the inclusion of even small numbers of black Americans in control cohorts probably would have prevented these misclassifications. "
Reinterpretation of common pathogenic variants in ClinVar revealed a high proportion of downgrades
“Of 326 variants retrieved, 217 variants in 173 genes were selected for curation. Overall, 87 (40%) variants were downgraded to benign, likely benign or variant of uncertain significance. Five variants (2%) were found to be more likely to be risk factors.”