Fig. 6: A multi-metabolite signature for T2D risk prediction.
a, AUC for T2D risk prediction in each cohort. Yellow: the model with metabolomic signature only, acquired using a leave-one cohort-out cross-validation approach to avoid overfitting (within WHI, the signature was acquired using a leave-one-out cross-validation); blue: the model with conventional risk factors including age, sex, smoking, BMI, dyslipidemia, hypertension, lipid-lowering medication use, anti-hypertensive medication use and family history of T2D; red: the model with conventional risk factors plus the metabolomic signature. For cohorts analyzed with Cox model, we plotted AUC estimated at the median follow-up time. We compared the AUC of the conventional plus metabolomic signature model to that of the conventional model; **two-sided P < 0.01, ^two-sided P < 0.1. b,c, Two examples of ROC curves and two-sided P values from WHI (b) and Black participants from ARIC (c). d, Crude incident rate of T2D by cohort, across deciles of the metabolomic signature, with a smooth trendline and 95% CI (gray band) from locally estimated scatterplot smoothing (LOESS). e, Relative risk ratio (points) and 95% CI (lines) for incident T2D, comparing participants in higher versus the lowest deciles of the metabolomic signature. Analyses were conducted separately in NHS, NHS2, HPFS, SOL, WHI, PREDIMED and Black and white participants from ARIC, separately, adjusting for age, sex, smoking, alcohol consumption, fasting status, hypertension, dyslipidemia, lipid-lowering medication use, anti-hypertensive medication use, BMI, WHR, family history of T2D and cohort-specific variables. We plotted relative risk ratios from the meta-analysis (n = 20,930). f, In multivariable analysis, BMI, red meat intake and sugary drink consumption (purple) were associated positively with the metabolomic signature, whereas PA, and intakes of coffee/tea, whole grains and wine (green), were associated inversely with the metabolomic signature (FDR < 0.05). A Sankey plot was used to demonstrate the associations between each of the 44 metabolites constituting the final metabolomic signature with these risk factors and with T2D risk (band-width proportional to the association coefficients).
