Estimating overdiagnosis in giant cell arteritis diagnostic pathways using genetic data: genetic association study

Objectives Prompt diagnosis of giant cell arteritis (GCA) is important to avert visual loss. False-negative temporal artery biopsy (TAB) can occur. Without vascular imaging, GCA may be overdiagnosed in TAB-negative cases, but it is unclear how often this occurs. An unbiased test is a way to address an imperfect reference standard. We used the known Human Leukocyte Antigen (HLA) region genetic association of TAB-positive GCA to estimate the extent of overdiagnosis before widespread adoption of temporal artery ultrasound as a first-line test. Methods Patients diagnosed with GCA between 1990-2014 consented to the UKGCA Consortium study. HLA region variants were jointly imputed from genome-wide genotypic data of cases and controls. Per-allele frequencies across all variants with p<1.0×10 −5 were compared with population control data to estimate overdiagnosis rates in cases without a positive TAB. Results Genetic data from 663 patients diagnosed with GCA were compared with data from 2619 population controls. TAB-negative GCA (n=147) and GCA without a TAB result (n=160) had variant frequencies intermediate between those of TAB-positive GCA and population controls. Making several strong assumptions, we estimated that around two-thirds of TAB-negative cases and around one-third of cases without TAB result may have been overdiagnosed. From these data, TAB sensitivity is estimated at around 88%. Conclusions Conservatively assuming 95% specificity, TAB has a negative likelihood ratio of around 0.12. Genotyping alone cannot diagnose GCA at the individual level. Group-level HLA variant genotyping might be used to compare the overall accuracy of different diagnostic pathways or different classification criteria sets. Key messages Under certain conditions and assumptions, overdiagnosis can be estimated using genetic data. The specificity of temporal artery biopsy was estimated as about 88%. Without vascular imaging, giant cell arteritis may often be overdiagnosed in biopsy-negative patients.