Interpretable machine learning identifies metabolites associated with glomerular filtration rate in type 2 diabetes patients.

Objective: The co-occurrence of kidney disease in patients with type 2 diabetes (T2D) is a major public health challenge. Although early detection and intervention can prevent or slow down the progression, the commonly used estimated glomerular filtration rate (eGFR) based on serum creatinine may be influenced by factors unrelated to kidney function. Therefore, there is a need to identify novel biomarkers that can more accurately assess renal function in T2D patients. In this study, we employed an interpretable machine-learning framework to identify plasma metabolomic features associated with GFR in T2D patients. Methods: We retrieved 1626 patients with type 2 diabetes (T2D) in Liaoning Medical University First Affiliated Hospital (LMUFAH) as a development cohort and 716 T2D patients in Second Affiliated Hospital of Dalian Medical University (SAHDMU) as an external validation cohort. The metabolite features were screened by the orthogonal partial least squares discriminant analysis (OPLS-DA). We compared machine learning prediction methods, including logistic regression (LR), support vector machine (SVM), random forest (RF), and eXtreme Gradient Boosting (XGBoost). The Shapley Additive exPlanations (SHAP) were used to explain the optimal model. Results: For T2D patients, compared with the normal or elevated eGFR group, glutarylcarnitine (C5DC) and decanoylcarnitine (C10) were significantly elevated in GFR mild reduction group, and citrulline and 9 acylcarnitines were also elevated significantly (FDR<0.05, FC > 1.2 and VIP > 1) in moderate or severe reduction group. The XGBoost model with metabolites had the best performance: in the internal validate dataset (AUROC=0.90, AUPRC=0.65, BS=0.064) and external validate cohort (AUROC=0.970, AUPRC=0.857, BS=0.046). Through the SHAP method, we found that C5DC higher than 0.1µmol/L, Cit higher than 26 µmol/L, triglyceride higher than 2 mmol/L, age greater than 65 years old, and duration of T2D more than 10 years were associated with reduced GFR. Conclusion: Elevated plasma levels of citrulline and a panel of acylcarnitines were associated with reduced GFR in T2D patients, independent of other conventional risk factors.

Explainable Machine Learning-Based Prediction Model for Diabetic Nephropathy.

The aim of this study is to analyze the effect of serum metabolites on diabetic nephropathy (DN) and predict the prevalence of DN through a machine learning approach. The dataset consists of 548 patients from April 2018 to April 2019 in the Second Affiliated Hospital of Dalian Medical University (SAHDMU). We select the optimal 38 features through a least absolute shrinkage and selection operator (LASSO) regression model and a 10-fold cross-validation. We compare four machine learning algorithms, including extreme gradient boosting (XGB), random forest, decision tree, and logistic regression, by AUC-ROC curves, decision curves, and calibration curves. We quantify feature importance and interaction effects in the optimal predictive model by Shapley additive explanation (SHAP) method. The XGB model has the best performance to screen for DN with the highest AUC value of 0.966. The XGB model also gains more clinical net benefits than others, and the fitting degree is better. In addition, there are significant interactions between serum metabolites and duration of diabetes. We develop a predictive model by XGB algorithm to screen for DN. C2, C5DC, Tyr, Ser, Met, C24, C4DC, and Cys have great contribution in the model and can possibly be biomarkers for DN.

A Metabolism-Based Interpretable Machine Learning Prediction Model for Diabetic Retinopathy Risk: A Cross-Sectional Study in Chinese Patients with Type 2 Diabetes.

The burden of diabetic retinopathy (DR) is increasing, and the sensitive biomarkers of the disease were not enough. Studies have found that the metabolic profile, such as amino acid (AA) and acylcarnitine (AcylCN), in the early stages of DR patients might have changed, indicating the potential of metabolites to become new biomarkers. We are amid to construct a metabolite-based prediction model for DR risk. This study was conducted on type 2 diabetes (T2D) patients with or without DR. Logistic regression and extreme gradient boosting (XGBoost) prediction models were constructed using the traditional clinical features and the screening features, respectively. Assessing the predictive power of the models in terms of both discrimination and calibration, the optimal model was interpreted using the Shapley Additive exPlanations (SHAP) to quantify the effect of features on prediction. Finally, the XGBoost model incorporating AA and AcylCN variables had the best comprehensive evaluation (ROCAUC = 0.82, PRAUC = 0.44, Brier score = 0.09). C18 : 1OH lower than 0.04 µmol/L, C18 : 1 lower than 0.70 µmol/L, threonine higher than 27.0 µmol/L, and tyrosine lower than 36.0 µmol/L were associated with an increased risk of developing DR. Phenylalanine higher than 52.0 µmol/L was associated with a decreased risk of developing DR. In conclusion, our study mainly used AAs and AcylCNs to construct an interpretable XGBoost model to predict the risk of developing DR in T2D patients which is beneficial in identifying high-risk groups and preventing or delaying the onset of DR. In addition, our study proposed possible risk cut-off values for DR of C18 : 1OH, C18 : 1, threonine, tyrosine, and phenylalanine.