Longitudinal Subphenotypes of Urinary Symptoms in Type I Diabetes
Lower urinary tract symptoms (LUTS) in men and urinary incontinence (UI) in women are dynamic conditions with numerous factors contributing to risk and progression. Understanding of natural history of urinary symptoms in diabetes is limited. We describe factors influencing the long-term trajectory of LUTS in men and UI in women with type 1 diabetes (T1DM) using non-parametric statistical methods.
Longitudinal data from 565 men and 523 women in the Epidemiology of Diabetes Interventions and Complications (EDIC) study were used to define LUTS/UI annually over 5 years. Trajectories were identified using a k-means clustering approach on the American Urological Association Symptom Index (AUASI) in men and Sandvik Severity Index in women. Subphenotypes were selected based on cluster quality metrics. A multinomial random forest model was fit to predict subphenotype assignment using information from baseline. Factors associated with LUTS/UI trajectory were identified by permuting each predictor and assessing change in accuracy as compared to the non-permuted data using the fitted model.
At baseline, mean age was 51.0 (SD 6.4) and 50.1 (SD 7.0) in men and women, respectively. 27.5% of men reported moderate/severe LUTS and 28.7% of women moderate/severe UI. We identified 3 subphenotypes for UI among women and 4 for LUTS among men (Figure 1A, 1B). Subphenotypes D in men and C in women demonstrate a deterioration of function over time in contradistinction to stable patterns and low/moderate severity in other clusters. The classification model achieved a multiclass area-under-the-curve (AUC) of 0.65 for AUASI and 0.61 for Sandvik using 10-fold cross-validation. Based on permutation importance (Figure 1C, 1D), key predictors were age (p = 0.002) and autonomic dysfunction (p < 0.001) for LUTS trajectory and BMI (p = 0.02) for UI.
LUTS/UI are prevalent complications in men and women with T1DM. A limited number of factors were identified in delineating subphenotypes of LUTS/UI. These data may be relevant to future investigations of mechanisms for distinct endotypes of LUTS/UI, as well as candidates for interventions targeting metabolic factors contributing to variation in symptoms.
Funding: K12 DK111011 and R01 DK083927 from the National Institute of Diabetes and Digestive and Kidney Disease.