Characterizing the pre-clinical phase of inflammatory bowel disease

Abstract

Understanding the biological changes that precede a diagnosis of inflammatory bowel disease (IBD) could facilitate pre-emptive interventions, including risk factor modification, but this pre-clinical phase of disease remains poorly characterized. Using measurements from 17 hematological and biochemical parameters taken up to 10 years before diagnosis in over 20,000 IBD patients and population controls, we address this at massive scale. We observe widespread significant changes in multiple biochemical and hematological parameters that occur up to 8 years before diagnosis of Crohn's disease (CD) and up to 3 years before diagnosis of ulcerative colitis. These changes far exceed previous expectations regarding the length of this pre-diagnostic phase, revealing an opportunity for earlier intervention, especially in CD. In summary, using a nationwide, case-control dataset-obtained from the Danish registers-we provide a comprehensive characterization of the hematological and biochemical changes that occur in the pre-clinical phase of IBD.

Keywords: Crohn's disease; Danish nationwide registers; blood tests; inflammatory bowel disease; pre-clinical; prediction models; ulcerative colitis.

Graphical abstract

Figure 1

Biochemical and hematological changes in the pre-clinical phase of IBD The dataset was divided into 1-year pre-diagnosis time intervals so that time interval −1 contains measurements from the year preceding diagnosis, etc. Left panels show results for CD, and the right panels show results for UC. Tiles are colored by the estimated beta-values of the transformed test results. A positive (red) estimate indicates that the test measurements were higher in future CD or UC patients compared to controls. Empty tiles indicate insufficient available measurements within the time interval to fit a model. Number of participants for each measure is shown in Table 1. ns, adjusted p value ≥ 0.05; ∗, adjusted p value < 0.05; ∗∗, adjusted p value < 0.01; ∗∗∗, adjusted p value < 0.001; CRP, C-reactive protein; f-cal, fecal calprotectin; ALAT, alanine-aminotransferase.

Figure 2

Biochemical and hematological values in relation to the medical references. For each test parameter in CD, UC, and respective controls, the median value was calculated and plotted for each time interval before diagnosis. If the same individual had multiple results within a time interval, the median value was used. Medical reference limits for each test are shown as horizontal dashed lines. Plots of the remaining features can be found in Figure S3B. Number of participants for each measure is shown in Table 1.

Figure 3

Prediction models of IBD based on clinical features (A) A logistic regression model to predict future CD/UC cases from controls was fitted on data from time interval −1. The resulting model was used to calculate the predicted probability of developing IBD on all data. The plot shows the mean predicted probability of developing IBD in each time interval. Shaded areas represent standard error. (B) Random forest (RF) models were fitted to separate CD/UC cases and controls using training data from time interval −1 (80% of data). The final model was applied on the validation data from time interval −1 (20% of data) and the entire datasets from other time intervals. The figure shows the resulting AUC values for the model’s ability to predict future CD/UC cases at each time interval, together with the corresponding sample size of the dataset that the model was applied to. In time interval −1, the RF model is applied to the validation dataset only. (C) ROC curves and their AUCs for each time interval for predicting CD from controls. (D) ROC curves and their AUCs for each time interval for predicting UC from controls. AUCs were evaluated for whether they differed significantly from 0.5 using a Mann-Whitney U test. Number of participants for each measure is shown in Table 2. IBD, inflammatory bowel disease; CD, Crohn's disease; UC, ulcerative colitis; FPR, false positive rate; TPR, true positive rate; AUC, area under the receiver operating characteristic curve.