Don't Take Our Word For It...
How does the lack of meaningful regulation impact patient care?
How do inaccurate results harm patients?
Why does it matter?
How do we improve an insufficiency regulated industry?
Read below from multiple thought leaders that have evaluated the inadequacies and pitfalls within the genetic and genomic industry. Through multiple studies and real world practice, gaps have been identified.
New genetic and genomic tests are entering the clinical market daily, and new labs are popping up weekly. Their test results drive patient care, yet most clinical genetic and genomic tests have not been adequately evaluated for accuracy of results.
SPOT/Dx Pilot Publication; Pfeifer JD et al. Reference Samples to Compare Next-Generation Sequencing Test Performance for Oncology Therapeutics and Diagnostics. American Journal of Clinical Pathology 2022
“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.”
"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Food and Drug Administration Notification and Medical Device Reporting for Laboratory Developed Tests; Draft Guidance for Industry, Food and Drug Administration Staff, and Clinical Laboratories; Availability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 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."
"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."
"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."
"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. "
"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."
"With the generation of genomics data continuously becoming easier and cheaper, the interpretation of the large amounts of data and the identification of the relevant disease-causing environmental factors will remain the biggest challenges of the years to come."
"A common error is to assume that the sensitivity and specificity of a test equates to diagnostic accuracy. The whole point of a diagnostic test is to use it to make a diagnosis, so we need to know the probability that the test will give the correct diagnosis. The sensitivity and specificity do not give us this information. Instead we must approach the data from the direction of the test results, using predictive values."
Orthogonal Comparison of Four Plasma NGS Tests With Tumor Suggests Technical Factors are a Major Source of Assay Discordance
"Our orthogonal approach identified false-negative (FN) and false-positive (FP) variants with high confidence and revealed substantial variability among the ctDNA assays, with a range of sensitivity (38% to 89%) and positive predictive value (36% to 80%). "
Assessment of Interlaboratory Variation in the Interpretation of Genomic Test Results in Patients With Epilepsy
"In this cross-sectional study, most interpretations of genetic variants associated with epilepsy were concordant among laboratories, but more than half of the variants with conflicting interpretations occurred in genes that have therapeutic implications."
Conflicting Interpretation of Genetic Variants and Cancer Risk by Commercial Laboratories as Assessed by the Prospective Registry of Multiplex Testing
"Among all participants, 56 of 518 (11%) had a variant with conflicting interpretations ranging from pathogenic/likely pathogenic to VUS, a discrepancy that may alter medical management."
"At times, the sheer quantity of information provided by NGS leads to more questions than answers, a concept known as the Next-Generation Sequencing Paradox:41 the more genes tested in a panel, the greater the likelihood of VUS detection and the greater the ambiguity of the test results. "
One in seven pathogenic variants can be challenging to detect by NGS: an analysis of 450,000 patients with implications for clinical sensitivity and genetic test implementation
"The analytic and clinical sensitivity of NGS workflows can vary considerably, particularly for prevalent, technically challenging variants. This can have important implications for the design and validation of tests (by laboratories) and the selection of tests (by clinicians) for a wide range of clinical indications."
"In the U.S., clinical genetic and genomic testing labs provide diagnostic, predictive, prognostic, and theragnostic tests with perceived clinical value—a perception is frequently untethered from reality. This means that many patients are inadvertently harmed when well-meaning clinicians use low-value and inaccurate tests in patient care."
"Molecular diagnostic techniques are part of the ancillary arsenal of anatomic pathologists. Advances in technology and knowledge regarding disease pathogenesis, tumorigenesis, and immune function contribute to the development of these assays. However, each technique, if applied incorrectly or in ignorance, can lead to difficulties in execution or errors in interpretation."