C.C.: PhD was supported by a Emma and Leslie Reid Scholarship from the University of Leeds. J.H.B.: received salary support from the National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC). A.W.M.: 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. S.L.M.: 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.

UK GCA Consortium: Ann W Morgan, Sarah L Mackie, Louise Sorensen, Lubna Haroon Raashid, Steve Martin, James I Robinson, Sam Mellen, Sarah Hoggart, Jennifer H Barrett, John C Taylor, Colin Pease, Bhaskar Dasgupta, Richard Watts, Andrew Gough, John D Isaacs, Michael Green, Neil McHugh, Lesley Hordon, Sanjeet Kamath, Mohammed Nisar, Yusuf Patel, Chee-Seng Yee, Robert Stevens, Pradip Nandi, Anupama Nandagudi, Stephen Jarrett, Charles Li, Sarah Levy, Susan Mollan, Abdel Salih, Oliver Wordsworth, Prisca Gondo, Jane Hollywood, Genessa Peters, Christine Routledge, Anne Gill, Lisa Carr, Rose Wood, Clare Williams, Mandy Oakley, Emma Sanders, Felicity Mackenzie, Rosanna Fong, Lynne James, Jenny Spimpolo, Andy Kempa, Karen Culfear, Asanka Nugaliyadde, Esme Roads, Bridie Rowbotham, Zahira Masqood.

[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%.

[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.

[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.

[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.

Peer reviewed