High-Affinity ZnT8 Autoantibodies by Electrochemiluminescence Assay Improve Risk Prediction for Type 1 Diabetes

Jia, Xiaofan; He, Lin; Miao, Dongmei; Waugh, Kathleen; Rasmussen, Cristy Geno; Dong, Fran; Steck, Andrea K.; Rewers, Marian; Yu, Liping

doi:10.1210/clinem/dgab575

Cited by 11 publications

(11 citation statements)

References 27 publications

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“…Four papers assessed differences between traditional radiobinding (RBA) assays and newer electrochemiluminescent (ECL) assays. Overall, ECL assays had higher positive predictive value, were more sensitive, and defined seroconversion earlier than traditional RBA assays (45)(46)(47). This association was most pronounced in single autoantibody positive populations (46).…”

Section: Specific Autoantibody Assay Methods Impact Risk Stratificationmentioning

confidence: 95%

Precision Diagnostics: Using Islet Autoantibodies to Characterize Heterogeneity in Type 1 Diabetes

Felton

Redondo

Oram

et al. 2023

Preprint

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Background Heterogeneity exists in type 1 diabetes (T1D) development and presentation. Islet autoantibodies form the foundation for T1D diagnostic and staging efforts. We hypothesized that autoantibodies can be used to identify heterogeneity in T1D before, at, and after diagnosis, and in response to disease modifying therapies. at clinically relevant timepoints throughout T1D progression. Methods We performed a systematic review assessing 10 years of original research studies examining relationships between autoantibodies and heterogeneity during disease progression, at the time of diagnosis, after diagnosis, and in response to disease modifying therapies in individuals at risk for T1D or within 1 year of T1D diagnosis. Results 10,067 papers were screened. Out of 151 that met data extraction criteria, 90 studies characterized heterogeneity before clinical diagnosis. Autoantibody type/target was most commonly examined, followed by autoantibody number, titer, order of seroconversion, affinity, and novel islet autoantibodies/epitopes. Recurring themes included positive relationships of autoantibody number and specific types and titers with disease progression, differing clinical phenotypes based on the order of autoantibody seroconversion, and interactions with age and genetics. Overall, reporting of autoantibody assay performance was commonly included; however, only 43% (65/151) included information about autoantibody assay standardization efforts. Populations studied were almost exclusively of European ancestry. Conclusions Current evidence most strongly supports the application of autoantibody features to more precisely define T1D before clinical diagnosis. Our findings support continued use of pre-clinical staging paradigms based on autoantibody number and suggest that additional autoantibody features, particularly when considered in relation to age and genetic risk, could offer more precise stratification. Increased participation in autoantibody standardization efforts is a critical step to improving future applicability of autoantibody-based precision medicine in T1D.

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Section: Specific Autoantibody Assay Methods Impact Risk Stratificationmentioning

confidence: 95%

Precision Diagnostics: Using Islet Autoantibodies to Characterize Heterogeneity in Type 1 Diabetes

Felton

Redondo

Oram

et al. 2023

Preprint

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“…15 For example, the anti-zinc transporter 8 (ZnT8A) antibody is widely used as a biomarker for predicting T1D, but only those with high-affinity anti-ZnT8A have predictive value. 16 Similarly, not all ACPAs have the same predictive value for RA. The variable domain glycosylation (VDG) of ACPA IgG is increased before RA onset, and increased VDG positively correlates with ACPA IgG levels and the binding breadth of citrullinated protein epitopes.…”

Section: Preventing Rheumatoid Arthritis: Lessons From That Of Type 1...mentioning

confidence: 99%

“…Second, it is important to thoroughly investigate the binding activity and daynamically follow‐up on levels of autoantibodies 15 . For example, the anti‐zinc transporter 8 (ZnT8A) antibody is widely used as a biomarker for predicting T1D, but only those with high‐affinity anti‐ZnT8A have predictive value 16 . Similarly, not all ACPAs have the same predictive value for RA.…”

mentioning

confidence: 99%

Preventing rheumatoid arthritis: Lessons from that of type 1 diabetes

Chu

2023

Rheumatology & Autoimmunity

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“…In individuals with adult-onset diabetes, presence of t-GADA is associated with the clinical phenotype of T1D and predicts insulin therapy ( 45 ). Consistently, the ECL assay for IAbs has demonstrated its unique high-affinity antibody binding feature with effectively removing those low-affinity IAbs, leading to significantly higher predictive values for IAbs detected in multiple clinical trials like TrialNet-T1D Pathway to Prevention, TEDDY, Daisy and ASK ( 38 – 41 ). In DAISY, over 50% of the children, whose single IAb in RBA was confirmed by high-affinity ECL assay (n = 83), progressed to T1D in 10 years.…”

mentioning

confidence: 93%

“…A large proportion of IAbs detected by RBA in initial screening, mainly in those individuals positive for a single IAb, were found to be low affinity. It is well documented in multiple studies that low-affinity IAbs are low risk and often not associated with disease (36)(37)(38)(39)(40)(41). Most of them disappear during the longitudinal follow-up behaving as 'transient' positivity.…”

mentioning

confidence: 99%

Effective assay technologies fit for large-scale population screening of type 1 diabetes

Jia

2023

Front. Clin. Diabetes Healthc.

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While worldwide prevention efforts for type 1 diabetes (T1D) are underway to abrogate or slow progression to diabetes, mass screening of islet autoantibodies (IAbs) in the general population is urgently needed. IAbs, the most reliable biomarkers, play an essential role in prediction and clinical diagnosis of T1D. Through laboratory proficiency programs and harmonization efforts, a radio-binding assay (RBA) has been well established as the current ‘gold’ standard assay for all four IAbs. However, in view of the need for large-scale screening in the non-diabetic population, RBA consistently faces two fundamental challenges, cost-efficiency and disease specificity. While all four IAbs are important for disease prediction, the RBA platform, with a separate IAb test format is laborious, inefficient and expensive. Furthermore, the majority of IAb positivity in screening, especially from individuals with single IAb were found to be low risk with low affinity. It is well documented from multiple clinical studies that IAbs with low affinity are low risk with less or no disease relevance. At present, two non-radioactive multiplex assays, a 3-assay ELISA combining three IAbs and a multiplex ECL assay combining all four IAbs, have been successfully used as the primary methods for general population screenings in Germany and the US, respectively. Recently, the TrialNet Pathway to Prevention study has been organizing an IAb workshop which aims to analyze the 5-year T1D predictive values of IAbs. A T1D-specific assay with high efficiency, low cost and requiring low volume of sample will definitely be necessary to benefit general population screening.

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High-Affinity ZnT8 Autoantibodies by Electrochemiluminescence Assay Improve Risk Prediction for Type 1 Diabetes

Cited by 11 publications

References 27 publications

Precision Diagnostics: Using Islet Autoantibodies to Characterize Heterogeneity in Type 1 Diabetes

Precision Diagnostics: Using Islet Autoantibodies to Characterize Heterogeneity in Type 1 Diabetes

Preventing rheumatoid arthritis: Lessons from that of type 1 diabetes

Effective assay technologies fit for large-scale population screening of type 1 diabetes

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