Estimating overdiagnosis in giant cell arteritis diagnostic pathways using genetic data: genetic association study
Author:
Chatzigeorgiou Charikleia1ORCID, Barrett Jennifer H1, Martin Javier2, Morgan Ann W134ORCID, Mackie Sarah L13ORCID, Morgan Ann W, Mackie Sarah L, Sorensen Louise, Raashid Lubna Haroon, Martin Steve, Robinson James I, Mellen Sam, Hoggart Sarah, Barrett Jennifer H, Taylor John C, Pease Colin, Dasgupta Bhaskar, Watts Richard, Gough Andrew, Isaacs John D, Green Michael, McHugh Neil, Hordon Lesley, Kamath Sanjeet, Nisar Mohammed, Patel Yusuf, Yee Chee-Seng, Stevens Robert, Nandi Pradip, Nandagudi Anupama, Jarrett Stephen, Li Charles, Levy Sarah, Mollan Susan, Salih Abdel, Wordsworth Oliver, Gondo Prisca, Hollywood Jane, Peters Genessa, Routledge Christine, Gill Anne, Carr Lisa, Wood Rose, Williams Clare, Oakley Mandy, Sanders Emma, Mackenzie Felicity, Fong Rosanna, James Lynne, Spimpolo Jenny, Kempa Andy, Culfear Karen, Nugaliyadde Asanka, Roads Esme, Rowbotham Bridie, Masqood Zahira,
Affiliation:
1. School of Medicine, University of Leeds , Leeds, UK 2. Institute of Parasitology and Biomedicine Lopez-Neyra, CSIC , Granada, Spain 3. NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust , Leeds, UK 4. NIHR Leeds Medicines and In Vitro Diagnostics Co-operative, Leeds Teaching Hospitals NHS Trust , Leeds, UK
Abstract
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.
Funder
National Institute for Health Research Leeds Biomedical Research Centre
Publisher
Oxford University Press (OUP)
Subject
Pharmacology (medical),Rheumatology
Cited by
1 articles.
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