Assessing the analytic validity of molecular testing for Huntington disease using data from an external proficiency testing survey

Abstract

original research article Purpose: Documenting high analytic validity of the molecular diagnostic test for Huntington disease is important because of counseling implications. This dominantly inherited adult onset disorder (prevalence of three or more per 100,000) is characterized by chorea, ataxia, and personality changes. The molecular basis is excessive CAG repeats in the HTT gene. methods:External proficiency testing survey results for Huntington disease were extracted (2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010). Analytic interpretations and CAG repeat lengths were compared with published performance criteria.Results: Between 2008 and 2010, 33 US participating laboratories reported clinical test interpretations. Analytic validity was high (sensitivity: 99.5%, 95% confidence interval: 97.1-99.9%; specificity: 99.2%, 95% confidence interval: 97.1-99.9%). Repeat length errors occurred in 2.6% (95% confidence interval: 1.8-3.8%) of 1,060 allelic challenges, with most being minor or from a single participant. Past performance (2003)(2004)(2005)(2006)(2007) was similar. The 23 international participants had more total repeat length errors (17.5%, 95% confidence interval: 14.6-20.7%). Further analyses indicated that assessment criteria can be relaxed without jeopardizing analytic validity.conclusion: Analytic validity is high for Huntington disease testing among US laboratories. International survey participants had lower analytic validity and a higher proportion of poorly performing laboratories. The reasons for this are unclear.Genet Med 2012:14(1):69-75

Highly accurate molecular genetic testing for HFE hereditary hemochromatosis: results from 10 years of blinded proficiency surveys by the College of American Pathologists

“…Previous publications have analyzed CAP/ACMG PT data for a variety of molecular genetic tests, including microsatellite instability, Tay-Sachs disease, Canavan disease, familial dysautonomia, BRCA1/2, pharmacogenetic analytes, Huntington disease, cystic fibrosis, fragile X syndrome, and other rare inherited disorders. 14,15,[22][23][24][25][26][27] Other publications have examined cystic fibrosis molecular testing in both the United States and Italy. 28,29 All of these publications indicate that molecular genetic tests have excellent analytic performance, with an overall sensitivity greater than 95% and specificity greater than 99%.…”

A Model Study of In Silico Proficiency Testing for Clinical Next-Generation Sequencing

“…Many PT programs are based on an individual analyte, and are appropriately termed analyte-specific or disease-specific PT programs. The utility of analyte-specific approaches for DNA analysis has been well documented, [12][13][14] and laboratories that do not perform disease-specific surveys have more errors than laboratories that do. 15 However, given the number of genes that are routinely evaluated in clinical practice by NGS-based approaches, and the range of mutations for which testing is performed by NGS, it is virtually impossible for laboratories to follow an analytespecific PT approach in routine clinical practice.…”

Current Landscape and New Paradigms of Proficiency Testing and External Quality Assessment for Molecular Genetics

“…In surveys with many subscribers, such as cystic fibrosis, it is not uncommon for participants to utilize a wide variety of commercially available assays as well as laboratory developed tests. Although PT/EQA performance is usually excellent for molecular genetic tests, 52,53 analytical errors do occur. Some errors may be associated with the design of the assay.…”