P321 Development and validation of an Integrated Risk Score for future risk of Crohn’s disease in healthy first-degree relatives: The CCC-GEM Project, a multicentre prospective cohort study
Bibliographic record
Abstract
Abstract Background Although the cause of Crohn’s disease (CD) is unknown, recent studies have identified a number of biomarkers associated with the risk of developing CD in healthy at-risk individuals. Establishing a combined prediction model that stratifies the future risk of CD in healthy at-risk individuals is the first step towards disease prevention and a better understanding of the preclinical phase of CD. Methods We recruited healthy first-degree relatives (FDRs) of persons with CD from 2008-2017 as part of the global multicenter prospective Crohn’s and Colitis Canada Genetic Environmental Microbial (CCC-GEM) Project. After collecting demographic information, blood, urine, and stool samples at recruitment, participants were followed for the development of CD. A GEM-integrative risk score (GEM-IRS), using random survival forest modeling that combined the baseline variables (demographics, measures of gut inflammation – fecal calprotectin, intestinal barrier function – urinary fractional excretion ratio of lactulose to mannitol, and fecal microbiome composition and predicted functional capacities – based upon 16S rDNA sequencing and PICRUSt2) to estimate time-to-CD onset, was derived and subsequently validated in two independent testing cohorts. Results Among 2,619 FDRs followed for a median of 6.8 years, 61 (2.3%) developed CD. The GEM-IRS, developed on the training cohort (n= 1,170), upon validation, showed a c-statistic of 0.789 in the pooled-testing cohorts (0.786 in the North American Testing cohort (n=1,141) and 0.804 in the Israeli Cohort (n=308)). The 4th quartile group compared to the rest had significantly increased risk of CD (hazard ratio [HR] 6.42, 95% confidence interval [CI], 3.10-13.30) in the pooled-testing cohorts (HR 5.89, 95% CI, 2.70-12.85 in North American Testing cohort; HR 10.7, 95% CI 1.24-92.65 in Israeli cohort). Furthermore, the GEM-IRS predicted CD in pre-specified subgroups of FDRs with minimal subclinical inflammation (fecal calprotectin<50 ug/g) or normal barrier function measures (lactulose/mannitol ratio<0.025), and up to 7 years before diagnosis in the pooled-testing cohort. Conclusion The GEM-IRS, which includes biomarkers of gut inflammation, intestinal barrier function, and the gut microbiome, is a valid risk stratification tool for predicting future development of CD in healthy first-degree relatives of persons with CD. The score may be used to guide preventative care for healthy first-degree relatives.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.006 | 0.010 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".