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<1.0x10-5 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.

Chatzigeorgiou:None, Barrett: None, Martin: None, Morgan reports: consultancy fees payable to her institution from Roche/Chugai, Sanofi/Regeneron, Glazo Smith Kline and AstraZeneca, outside the submitted work. Reports research and/or educational funding were received from Roche/Chugai and Kiniksa Pharmaceuticals, outside the submitted work. Mackie reports: Consultancy on behalf of her institution for Roche/Chugai, Sanofi, AbbVie, AstraZeneca; Investigator on clinical trials for Sanofi, GSK, Sparrow; speaking/lecturing on behalf of her institution for Roche/Chugai, Vifor and Pfizer; patron of the charity PMRGCAuk. No personal remuneration was received for any of the above activities. Support from Roche/Chugai to attend EULAR2019 in person and from Pfizer to attend ACR Convergence 2021 virtually.

Chatzigeorgiou: PhD was supported by a Emma and Leslie Reid Scholarship from the University of Leeds Barrett: received salary support from the National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC) Morgan: received salary support from the Medical Research Council (MRC) TARGET Partnership Grant, MR/N011775/1, NIHR Leeds BRC, NIHR Leeds Medtech and in vitro Diagnostics Co-operative (MIC) and NIHR Senior Investigator Award Mackie: received salary support from NIHR Clinician Scientist Fellowship NIHR-CS-012-016 and NIHR Leeds BRC. The UKGCA Consortium study received funding from the NIHR Leeds BRC, MRC TARGET Partnership Grant, MR/N011775/1, Academy of Medical Sciences/Wellcome Trust (AMS-SGCL4-Mackie), Mason Medical Research Foundation and Leeds Teaching Hospitals Charitable Trustees. This study was supported in part by the NIHR Leeds BRC and the NIHR Leeds MIC. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.

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The UK GCA Consortium was designed as a genetic epidemiology study. Ethical approval was received from the Yorkshire and Humber-Leeds West Research Ethics Committee (REC Ref. 05/Q1108/28)

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