Development and validation of multivariable clinical diagnostic models to identify type 1 diabetes requiring rapid insulin therapy in adults aged 18-50 years

Abstract

Objective: To develop and validate multivariable clinical diagnostic models to assist distinguishing between type 1 and type 2 diabetes in adults aged 18-50.

Design: Multivariable logistic regression analysis was used to develop classification models integrating five pre-specified predictor variables, including clinical features (age of diagnosis, body mass index) and clinical biomarkers (GADA and Islet Antigen 2 islet autoantibodies, Type 1 Diabetes Genetic Risk Score), to identify type 1 diabetes with rapid insulin requirement using data from existing cohorts.

Setting: UK cohorts recruited from primary and secondary care.

Participants: 1352 (model development) and 582 (external validation) participants diagnosed with diabetes between the age of 18 and 50 years of white European origin.

Main outcome measures: Type 1 diabetes was defined by rapid insulin requirement (within 3 years of diagnosis) and severe endogenous insulin deficiency (C-peptide <200 pmol/L). Type 2 diabetes was defined by either a lack of rapid insulin requirement or, where insulin treated within 3 years, retained endogenous insulin secretion (C-peptide >600 pmol/L at ≥5 years diabetes duration). Model performance was assessed using area under the receiver operating characteristic curve (ROC AUC), and internal and external validation.

Results: Type 1 diabetes was present in 13% of participants in the development cohort. All five predictor variables were discriminative and independent predictors of type 1 diabetes (p<0.001 for all) with individual ROC AUC ranging from 0.82 to 0.85. Model performance was high: ROC AUC range 0.90 (95% CI 0.88 to 0.93) (clinical features only) to 0.97 (95% CI 0.96 to 0.98) (all predictors) with low prediction error. Results were consistent in external validation (clinical features and GADA ROC AUC 0.93 (0.90 to 0.96)).

Conclusions: Clinical diagnostic models integrating clinical features with biomarkers have high accuracy for identifying type 1 diabetes with rapid insulin requirement, and could assist clinicians and researchers in accurately identifying patients with type 1 diabetes.

Keywords: C-peptide; Classification; GADA; IA-2A; Type 1 Diabetes Genetic Risk Score; Type 1 diabetes; Type 2 diabetes.