Development and validation of Risk Equations for Complications Of type 2 Diabetes (RECODe) using individual participant data from randomised trials

Abstract

Background: In view of substantial mis-estimation of risks of diabetes complications using existing equations, we sought to develop updated Risk Equations for Complications Of type 2 Diabetes (RECODe).

Methods: To develop and validate these risk equations, we used data from the Action to Control Cardiovascular Risk in Diabetes study (ACCORD, n=9635; 2001-09) and validated the equations for microvascular events using data from the Diabetes Prevention Program Outcomes Study (DPPOS, n=1018; 1996-2001), and for cardiovascular events using data from the Action for Health in Diabetes (Look AHEAD, n=4760; 2001-12). Microvascular outcomes were nephropathy, retinopathy, and neuropathy. Cardiovascular outcomes were myocardial infarction, stroke, congestive heart failure, and cardiovascular mortality. We also included all-cause mortality as an outcome. We used a cross-validating machine learning method to select predictor variables from demographic characteristics, clinical variables, comorbidities, medications, and biomarkers into Cox proportional hazards models for each outcome. The new equations were compared to older risk equations by assessing model discrimination, calibration, and the net reclassification index.

Findings: All equations had moderate internal and external discrimination (C-statistics 0·55-0·84 internally, 0·57-0·79 externally) and high internal and external calibration (slopes 0·71-1·31 between observed and estimated risk). Our equations had better discrimination and calibration than the UK Prospective Diabetes Study Outcomes Model 2 (for microvascular and cardiovascular outcomes, C-statistics 0·54-0·62, slopes 0·06-1·12) and the American College of Cardiology/American Heart Association Pooled Cohort Equations (for fatal or non-fatal myocardial infarction or stroke, C-statistics 0·61-0·66, slopes 0·30-0·39).

Interpretation: RECODe might improve estimation of risk of complications for patients with type 2 diabetes.

Funding: National Institute for Diabetes and Digestive and Kidney Disease, National Heart, Lung and Blood Institute, and National Institute on Minority Health and Health Disparities, National Institutes of Health, and US Department of Veterans Affairs.

Figure 1. Calibration plots

Kaplan-Meier event rates over 10 years predicted by RECODe versus observed rates in the ACCORD study (n=9635, 2001–09), DPPOS (n=1018, 1996–2001), and Look AHEAD study (n=4760, 2001–12). Predictions using UKPDS OM2 and the ACC/AHA PCEs for atherosclerotic cardiovascular disease (non-fatal or fatal myocardial infarction or stroke) are presented if available. Points are displayed for deciles of predicted and observed Kaplan-Meier event rates, with fewer centiles than deciles used if fewer than 5 events were observed per group or to prevent unstable inferences per guidelines. ACCORD=Action to Control Cardiovascular Risk in Diabetes study. ACC/AHA PCEs=American College of Cardiology/American Heart Association Pooled Cohort Equations. DPPOS=Diabetes Prevention Program Outcomes Study. Look AHEAD=Action for Health in Diabetes study. ESRD=end-stage renal disease. MNSI=Michigan Neuropathy Screening Instrument. RECODe=Risk Equations for Complications Of type 2 Diabetes. UKPDS OM2=United Kingdom Prospective Diabetes Study Outcomes Model 2.

Figure 2. Outcome classification by RECODe versus UKPDS OM2

Number of people correctly classified or misclassified as high risk or low risk using RECODe versus UKPDS OM2 in (A) ACCORD and (B) Look AHEAD. RECODe=Risk Equations for Complications Of type 2 Diabetes. ACCORD=Action to Control Cardiovascular Risk in Diabetes. Look AHEAD=Action for Health in Diabetes.