Using polygenic risk scores to aid diagnosis of patients with early inflammatory arthritis: Results from the Norfolk Arthritis Register

Ryan M. Hum, Seema D. Sharma, Michael Stadler, Sebastien Viatte, Pauline Ho, Nisha Nair, Chenfu Shi, Chuan Fu Yap, Mehreen Soomro, Darren Plant, Jenny H. Humphreys, Alexander MacGregor, Max Yates, Suzanne Verstappen, Anne Barton, John Bowes, on behalf of all NOAR collaborators

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Objective: There is growing evidence that genetic data are of benefit in the rheumatology outpatient setting by aiding early diagnosis. A genetic probability tool (G-PROB) has been developed to aid diagnosis has not yet been tested in a real-world setting. Our aim was to assess whether G-PROB could aid diagnosis in the rheumatology outpatient setting using data from the Norfolk Arthritis Register (NOAR), a prospective observational cohort of patients presenting with early inflammatory arthritis.

Methods: Genotypes and clinician diagnoses were obtained from patients from NOAR. Six G-probabilities (0%–100%) were created for each patient based on known disease-associated odds ratios of published genetic risk variants, each corresponding to one disease of rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, spondyloarthropathy, gout, or “other diseases.” Performance of the G-probabilities compared with clinician diagnosis was assessed.

Results: We tested G-PROB on 1,047 patients. Calibration of G-probabilities with clinician diagnosis was high, with regression coefficients of 1.047, where 1.00 is ideal. G-probabilities discriminated clinician diagnosis with pooled areas under the curve (95% confidence interval) of 0.85 (0.84–0.86). G-probabilities <5% corresponded to a negative predictive value of 96.0%, for which it was possible to suggest >2 unlikely diseases for 94% of patients and >3 for 53.7% of patients. G-probabilities >50% corresponded to a positive predictive value of 70.4%. In 55.7% of patients, the disease with the highest G-probability corresponded to clinician diagnosis.

Conclusion: G-PROB converts complex genetic information into meaningful and interpretable conditional probabilities, which may be especially helpful at eliminating unlikely diagnoses in the rheumatology outpatient setting.
Original languageEnglish
JournalArthritis & Rheumatology
Early online date27 Nov 2023
Publication statusE-pub ahead of print - 27 Nov 2023

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