A39 HEALTHY FIRST-DEGREE RELATIVES FROM MULTIPLEX FAMILIES VERSUS SIMPLEX HARBOR A HIGHER RISK OF DEVELOPING CROHN'S DISEASE AND ARE ASSOCIATED WITH SUBCLINICAL INFLAMMATION AND ALTERED MICROBIOME COMPOSITION
Bibliographic record
Abstract
Abstract Background Healthy individuals within families with multiple affected members (multiplex families) with Crohn’s disease (CD) have a notably high risk of developing CD. No large prospective pre-disease cohort has assessed differences in preclinical intestinal inflammation, permeability, fecal microbiome, and genetics in healthy at-risk subjects from multiplex families. Purpose We aimed to assess differences in subclinical gut inflammation, genetic risk, gut barrier function, and fecal microbiota composition between first-degree relatives (FDRs) from families with 2 or more affected members (multiplex) and families with only one affected member (simplex). Also, we aimed to assess the risk of future CD onset in subjects from multiplex versus simplex families. Method We utilized the GEM Project cohort of healthy FDRs of CD patients. Subclinical gut inflammation was assessed using fecal calprotectin (FCP) at recruitment. Gut barrier function was assessed using the lactulose-to-mannitol ratio (LMR). For assessment of the CD-related genetic risk, CD-polygenic risk scores (CD-PRS) were calculated. Microbiome composition was assessed by sequencing fecal 16S ribosomal RNA. Generalized estimating equations logistic regression and LEfSe (PMID: 21702898) were used to assess the associations between multiplex status and different outcomes. A Cox proportional hazards model was used to assess time-related risk of future onset of CD. Result(s) 4385 subjects were included. Median age was 17 [IQR 12-24] years, 52.9% were female, 69.4% were siblings and 30.6% were offspring. 4052 (92.4%) and 333 (7.6 %) were simplex and multiplex subjects, respectively. After adjusting for age, sex, family size, and relation to proband, multiplex status was significantly associated with higher baseline FCP (p=0.038), but was not associated with either baseline LMR or CD-PRS (p=0.19 and p=0.33, respectively). We found no significant differences in alpha diversity (Shannon index) (p=0.57) between simplex and multiplex subjects. Beta diversity analysis assessed by the Bray-Curtis dissimilarity index did not reveal significant differences (R2=3e-04, p=0.607). The genera Eisenbergiella, Eggerthellaceae uncultured, and Morganella, were significantly more abundant in multiplex subjects, whereas Lachnospira, Sutterella, Lachnospiraceae_NK4A136_group, and Lachnospiraceae_UCG_004 less abundant. The risk of CD onset was significantly higher in multiplex subjects. In multivariable analysis, multiplex status at recruitment was associated with increased risk of CD onset (adjusted HR 3.41, 95% CI 1.70-6.87, p=0.00055), after adjusting for demographics, FCP, LMR, and CD-PRS. Conclusion(s) Multiplex status compared to simplex is associated with a 3.4-fold increased risk of CD onset, a higher FCP, and fecal bacterial composition. A comprehensive assessment of environmental factors that increase CD risk in multiplex families remains to be elucidated in future studies. Disclosure of Interest None Declared
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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 | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.009 | 0.001 |
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".