Zinc transporter 8 autoantibody testing requires age-related cut-offs
Introduction Zinc transporter 8 autoantibodies (ZnT8A) are biomarkers of beta cell autoimmunity in type 1 diabetes that have become more widely available to clinicians in recent years. Robust control population-defined thresholds are essential to ensure high clinical specificity in islet autoantibod...
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BMJ Publishing Group
2021-03-01
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| Series: | BMJ Open Diabetes Research & Care |
| Online Access: | https://drc.bmj.com/content/9/1/e002296.full |
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| author | Timothy James McDonald Angela Cooper Sian Louise Grace |
| author_facet | Timothy James McDonald Angela Cooper Sian Louise Grace |
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| description | Introduction Zinc transporter 8 autoantibodies (ZnT8A) are biomarkers of beta cell autoimmunity in type 1 diabetes that have become more widely available to clinicians in recent years. Robust control population-defined thresholds are essential to ensure high clinical specificity in islet autoantibody testing. We aimed to determine the optimal cut-offs for ZnT8A testing.Research design and methods 97.5th and 99th centile cut-offs were determined using residual clinical sera from 1559 controls aged between 0 and 83 years with no history of diabetes and a hemoglobin A1c level of less than 6.0% (<42 mmol/mol). ZnT8A were measured by ELISA (RSR, Cardiff, UK) on a Dynex DS2 ELISA robot (Dynex, Preston, UK). We assessed the impact of age-related cut-offs in comparison with the manufacturer’s recommended threshold in a mixed cohort of young-onset (<age 30) diabetes (UNITED study (Using pharmacogeNetics to Improve Treatment in Early-onset Diabetes), n=145).Results Using the manufacturer’s limit of detection, 6 WHO U/mL, 16.2% of people in the control cohort had detectable levels of ZnT8A and those who had detectable ZnT8A were much more likely to be younger (p<0.0001). The 97.5th and 99th centile thresholds were substantially higher in younger participants: 18 and 127 WHO U/mL (tested under 30 years) in comparison with 9 and 21 WHO U/mL (tested 30 years and over). In the UNITED cohort some of those found to be ZnT8A-positive by the manufacturer’s threshold but negative using the appropriate 99% centile cut-off (127 WHO U/mL) displayed characteristics suggestive of type 2 diabetes.Conclusions Age-related thresholds are needed for ZnT8A testing. In those aged <30 years, use of manufacturers’ recommended cut-offs may result in low test specificity and potentially high rates of false positive test results in patients who do not have autoimmune diabetes. |
| format | Article |
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| language | English |
| publishDate | 2021-03-01 |
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| series | BMJ Open Diabetes Research & Care |
| spelling | doaj-art-330334f0ea52478f8ff5f685f3caba132025-08-20T02:50:22ZengBMJ Publishing GroupBMJ Open Diabetes Research & Care2052-48972021-03-019110.1136/bmjdrc-2021-002296Zinc transporter 8 autoantibody testing requires age-related cut-offsTimothy James McDonald0Angela Cooper1Sian Louise Grace2The Institute of Biomedical & Clinical Science, University of Exeter, Exeter, UKsenior research fellowThe Institute of Biomedical & Clinical Science, University of Exeter, Exeter, UKIntroduction Zinc transporter 8 autoantibodies (ZnT8A) are biomarkers of beta cell autoimmunity in type 1 diabetes that have become more widely available to clinicians in recent years. Robust control population-defined thresholds are essential to ensure high clinical specificity in islet autoantibody testing. We aimed to determine the optimal cut-offs for ZnT8A testing.Research design and methods 97.5th and 99th centile cut-offs were determined using residual clinical sera from 1559 controls aged between 0 and 83 years with no history of diabetes and a hemoglobin A1c level of less than 6.0% (<42 mmol/mol). ZnT8A were measured by ELISA (RSR, Cardiff, UK) on a Dynex DS2 ELISA robot (Dynex, Preston, UK). We assessed the impact of age-related cut-offs in comparison with the manufacturer’s recommended threshold in a mixed cohort of young-onset (<age 30) diabetes (UNITED study (Using pharmacogeNetics to Improve Treatment in Early-onset Diabetes), n=145).Results Using the manufacturer’s limit of detection, 6 WHO U/mL, 16.2% of people in the control cohort had detectable levels of ZnT8A and those who had detectable ZnT8A were much more likely to be younger (p<0.0001). The 97.5th and 99th centile thresholds were substantially higher in younger participants: 18 and 127 WHO U/mL (tested under 30 years) in comparison with 9 and 21 WHO U/mL (tested 30 years and over). In the UNITED cohort some of those found to be ZnT8A-positive by the manufacturer’s threshold but negative using the appropriate 99% centile cut-off (127 WHO U/mL) displayed characteristics suggestive of type 2 diabetes.Conclusions Age-related thresholds are needed for ZnT8A testing. In those aged <30 years, use of manufacturers’ recommended cut-offs may result in low test specificity and potentially high rates of false positive test results in patients who do not have autoimmune diabetes.https://drc.bmj.com/content/9/1/e002296.full |
| spellingShingle | Timothy James McDonald Angela Cooper Sian Louise Grace Zinc transporter 8 autoantibody testing requires age-related cut-offs BMJ Open Diabetes Research & Care |
| title | Zinc transporter 8 autoantibody testing requires age-related cut-offs |
| title_full | Zinc transporter 8 autoantibody testing requires age-related cut-offs |
| title_fullStr | Zinc transporter 8 autoantibody testing requires age-related cut-offs |
| title_full_unstemmed | Zinc transporter 8 autoantibody testing requires age-related cut-offs |
| title_short | Zinc transporter 8 autoantibody testing requires age-related cut-offs |
| title_sort | zinc transporter 8 autoantibody testing requires age related cut offs |
| url | https://drc.bmj.com/content/9/1/e002296.full |
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