Building and validating a prediction model for paediatric type 1 diabetes risk using next generation targeted sequencing of class II HLA genes

Building and validating a prediction model for paediatric type 1 diabetes risk using next generation targeted sequencing of class II HLA genes

Diabetes/Metabolism Research and Reviews, September 2017

28755385

Lue Ping Zhao, Annelie Carlsson, Helena Elding Larsson, Gun Forsander, Sten A. Ivarsson, Ingrid Kockum, Johnny Ludvigsson, Claude Marcus, Martina Persson, Ulf Samuelsson, Eva Örtqvist, Chul‐Woo Pyo, Hamid Bolouri, Michael Zhao, Wyatt C. Nelson, Daniel E. Geraghty, Åke Lernmark, The Better Diabetes Diagnosis Study Group

It is of interest to predict possible lifetime risk of type diabetes (T1D) in young children for recruiting high-risk subjects into longitudinal studies of effective prevention strategies. Utilizing a case-control study in Sweden, we applied a recently developed next generation targeted sequencing (NGTS) technology to genotype class II genes, and applied an object-oriented regression (OOR) to build and validate a prediction model for T1D. In the training set, estimated risk scores were significantly different between patients and controls (P=8.12*10(-92) ), and the area under the curve (AUC) from the receiver operating characteristic (ROC) analysis was 0.917. Using the validation data set, we validated the result with AUC of 0.886. Combining both training and validation data resulted in a predictive model with AUC of 0.903. Further, we performed a 'biological validation' by correlating risk scores with six islet autoantibodies, and found that the risk score was significantly correlated with IA-2A (Z-score=3.628, P<0.001). When applying this prediction model to the Swedish population, where the lifetime T1D risk ranges from 0.5% to 2%, we anticipate identifying about 20,000 highrisk subjects after testing all newborns, and this calculation would identify about 80% of all patients expected to develop T1D in their lifetime. Through both empirical and biological validation, we have established a prediction model for estimating lifetime T1D risk, using class II HLA. This prediction model should prove useful for future investigations to identify high-risk subjects for prevention research in high-risk populations.