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. 2024 Aug 1;63(8):2307-2313.
doi: 10.1093/rheumatology/kead643.

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

Charikleia Chatzigeorgiou  1 , Jennifer H Barrett  1 , Javier Martin  2 , Ann W Morgan  1   3   4 , Sarah L Mackie  1   3 ; UK GCA Consortium
Collaborators, Affiliations

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

Charikleia Chatzigeorgiou et al. Rheumatology (Oxford). .

Abstract

Objectives: GCA can be confirmed by temporal artery biopsy (TAB) but false negatives can occur. GCA may be overdiagnosed in TAB-negative cases, or if neither TAB nor imaging is done. We used HLA genetic association of TAB-positive GCA as an 'unbiased umpire' test to estimate historic overdiagnosis of GCA.

Methods: Patients diagnosed with GCA between 1990 and 2014 were genotyped. During this era, vascular imaging alone was rarely used to diagnose GCA. HLA region variants were jointly imputed from genome-wide genotypic data of cases and controls. Per-allele frequencies across all HLA 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 GCA patients were compared with data from 2619 population controls. TAB-negative GCA (n = 147) and GCA without TAB result (n = 160) had variant frequencies intermediate between TAB-positive GCA (n = 356) and population controls. For example, the allele frequency of HLA-DRB1*04 was 32% for TAB-positive GCA, 29% for GCA without TAB result, 27% for TAB-negative GCA and 20% in population controls. Making several strong assumptions, we estimated that around two-thirds of TAB-negative cases and one-third of cases without TAB result may have been overdiagnosed. From these data, TAB sensitivity is estimated as 88%.

Conclusions: Conservatively assuming 95% specificity, TAB has a negative likelihood ratio of around 0.12. Our method for utilizing standard genotyping data as an 'unbiased umpire' might be used as a way of comparing the accuracy of different diagnostic pathways.

Keywords: HLA; giant cell arteritis; overdiagnosis; temporal artery biopsy.

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