bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP31 Serum protein markers for early and differential IBD diagnosis validated by machine learning approaches
Authors: Verstockt S , Verplaetse N , Raimondi D , Verstockt B , Glorieus E , De Decker M , Hannes L , Ballet V , Vandeput E , Moreau Y , Ferrante M , Laukens D , Mana F , De Vos M , Vermeire S , Cleynen I 
Published: January 2020

Abstract

Background
The inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory conditions with a polygenic and multifactorial pathogenesis. Intensified treatment early in the disease course of IBD results in better outcomes. This is, however, challenged by the diagnostic delay faced in IBD, and especially in CD. Therefore, markers supporting early and differential diagnosis are needed. In this study, we aimed to discriminate IBD patients from non-IBD controls, and CD from UC patients, using serum protein profiles combined with an IBD polygenic risk score.

Methods
Patients naïve for immunosuppressives and biologicals, and without previous IBD-related surgery were prospectively included within 3 months after diagnosis, across three Belgian IBD referral centres (PANTHER study). We collected serum from 127 patients (88 CD, 39 UC) and 66 age- and gender-matched non-IBD controls. Relative serum levels of 576 unique proteins were quantified (OLINK). Proteins were ranked according to (1) adjusted (adj.) p values obtained from differential expression analysis; (2) importance scores from machine-learning feature-selection algorithms (univariate feature selection, logistic regression with L2 penalty and Random Forest). For all individuals, a weighted IBD polygenic risk score (PRS) was calculated (PRSice 2.0) for the 242 known IBD risk loci. Receiver operating characteristics (ROC) and area under the curve (AUC) analysis were performed to measure the performance of top-ranked proteins and the IBD PRS (R package ROCR).

Results
Following statistical analysis, 243 serum proteins were found to be differentially expressed (adj. p &lt; 0.05) between IBD patients and controls. Three top-ranked markers were also identified as top 10 ranked proteins by all feature-selection algorithms, and resulted in a significant AUC of 93% (95% CI: 89–97%) to distinguish IBD from controls. While adding the IBD PRS did not further contribute (AUC 93% [95% CI: 89–97%]), the top-ranked protein on its own had a strong discriminative power with an AUC of 87% (95% CI: 82–92%). When comparing UC and CD, we found 15 differentially expressed proteins. Two proteins ranked within the top 10 across all feature-selection algorithms. This two-marker panel could discriminate UC from CD with an accuracy of 88% (95% CI: 82–96%). Adding the IBD PRS did not further improve the prediction model (AUC=88% [95% CI: 81–96%]).

Conclusion
Machine learning approaches validated top differentially expressed serum proteins with diagnostic potential in IBD. We identified a three-marker panel classifying IBD patients and non-IBD controls, and a two-marker panel discriminating UC from CD.
DOP36 Family-specific host genetic and gut microbial signatures have a beneficial role in early identification of familial inflammatory bowel diseases
Authors: SHIN G Y , Park Y M , Ha E , Gu K N , Kim K , Lee C K , Kim H J 
Published: January 2020

Abstract

Background
Familial IBD may have its own signatures with respect to host genetic variants and/or gut microbiome. However, available data focussing on this topic is still limited, particularly for Asian patients with familial IBD. We aimed to investigate the possible host genetic and gut microbial signatures in familial IBD through a combined analysis of genomic and metagenomic profiles.

Methods
All patients were affiliated with a prospectively recruited cohort of patients with IBD (NCT03589183) and met the diagnostic criteria of Crohn’s disease (CD) or ulcerative colitis (UC). We constructed a unique family cohort comprising ≥2 affected individuals with familial IBD and ≥1 their unaffected, healthy first-degree relative (FDR) in each family. Whole-exome sequencing for rare variants followed by a genome-wide single-nucleotide polymorphism analysis for common variants was performed. A polygenic risk score (PRS) was calculated separately in Crohn’s disease (CD), ulcerative colitis (UC) or IBD. Gut microbial community was analysed by 16s rRNA sequencing of stool samples.

Results
Eight Korean families comprising 16 with familial IBD (12 concordant IBD, 4 discordant IBD) and 9 FDRs were included for analysis. Whole-exome sequencing identified four family-specific candidate genes (LAMA5, MYO15B, TTN, and WDR66) with rare missense variants that were transmitted preferentially to the affected FDRs in at least ≥3 families (Figure 1). An in silico analysis identified the deleterious effect of the identified variants on the gene products including LAMA5 (SIFT = 0, PolyPhen-2 = 0.72). The patients with CD, but not those with UC, had a significantly higher mean PRS than controls (PRS = 2.137 vs. 0.742, p-value = 0.030). Metagenomic sequencing revealed significant differences in α- and β-diversity of gut microbiota among the patients with CD, those with UC, and unaffected FDRs (all p &lt; 0.05), showing lower microbial richness in the patients with familial IBD (p = 0.02). In various taxonomic levels, compared with unaffected FDRs, the patients with familial IBD showed the significantly differential abundance of several gut bacteria (all corrected p &lt; 0.05; Figure 2).

Conclusion
Family-specific host genetic and gut microbial signatures have a beneficial role in early-identification of familial IBD (NCT03515070).
DOP37 Neoplastic lesions outside diseased area in inflammatory bowel disease patients: A national cohort study
Authors: Cremer A , Demetter P , De Vos M , Rahier J F , Baert F , Moreels T , Macken E , Louis E , Vermeire S , Franchimont D 
Published: January 2020

Abstract

Background
Patients with inflammatory bowel diseases (IBD) are at increased risk of dysplasia and colitis-associated cancer (CAC). The presentation of (pre)neoplastic lesions (low-grade dysplasia (LGD), high-grade dysplasia (HGD) or colorectal cancer (CRC) is reported to vary depending if the lesions are located inside disease area (IDA) or outside diseased area (ODA). The primary aim was to analyse the characteristics and prognostic of IDA compared with ODA neoplastic lesions in a large cohort of IBD patients.

Methods
We performed a multicentre retrospective pathological data collection from 7 tertiary referral regional or academic IBD centres in Belgium. Clinical, endoscopic and pathological data were retrieved through retrospective electronic chart review. From the IBD pathology databases, 1183 colorectal lesions were identified in 541 IBD patients: 415 developed dysplasia (77%) and 126 CRC (23%) during their follow-up. Biopsies and surgical specimen were centrally reviewed by an expert IBD pathologist to confirm the diagnosis of dysplasia and/or CRC.

Results
Demographic and clinical variables of the study population are summarised in Table 1. More patients with IDA lesions had HGD (9%) or CAC (27%) during their follow-up compared with the group of patients with ODA lesions (3% of HGD and 11% of CRC) (p &lt; 0,0001). Mortality was higher in patients with IDA than in those with ODA lesions (p &lt; 0.05). When comparing IBD patients with IDA lesions and CAC (=111) to those with ODA lesions and sporadic CRC (n = 15), median age at IBD diagnosis was lower (29 (IQR:22–49) vs. 41(IQR:28–54) years; p = 0.0001). Characteristics of the 1183 neoplastic lesions are summarised in Table 2. IDA lesions were more frequently non-visible, non-polypoid and ≥ 1 cm than ODA lesions (p &lt; 0.0001). ODA sporadic CRC was more frequently located in the right colon compared with IDA CAC (5/16 (31%) vs. 21/133 (16%), p &lt; 0.01).

Conclusion
Neoplastic lesions outside the diseased area were more likely to be visible, polypoid, &lt; 1cm, in the right colon and diagnosed at endoscopy than inside disease area lesions. A lower prevalence of HGD and Cancer were reported with neoplastic lesions outside the diseased area.
DOP38 Prevalence of fatigue in a severe inflammatory bowel disease cohort highly exposed to biologics
Authors: Liefferinckx C , El hamdi M , Fassin M , Cremer A , Minsart C , Amininejad L , Wambacq V , Van Gossum A , Franchimont D 
Published: January 2020

Abstract

Background
In addition to physical and psychological factors, systemic inflammation, anaemia and/or malnutrition contribute to fatigue in Crohn’s disease (CD) and ulcerative colitis (UC). Despite recent advances in the management of the disease activity, fatigue is a major disabling symptom for inflammatory bowel disease (IBD) patients.

Methods
The aim of this prospective study is to evaluate the prevalence of IBD patients suffering from fatigue in a tertiary IBD referral centre and delineate its contributing factors. All patients with a confirmed IBD diagnosis were eligible. A given written consent has been obtained for each patient (P2019/053). Fatigue evaluation was assessed by FACIT-F. Self-report questionnaires were used to assess different factors related to fatigue: disease activity was assessed by patient-reported outcomes (PRO), anxiety by State and Trait Spielberger scores, depression by Beck score (BDI-II), sleep quality by Insomnia severity index (ISI) and Epworth scale, and quality of life by the Short Inflammatory Bowel Disease Questionnaire (SIBDQ). Biological values including haemoglobin, C-reactive protein (CRP), thyroid-stimulating hormone (TSH), folic acid and B12 vitamin were collected when available.

Results
Demographic data of the 128 included patients are presented in Table 1. This cohort was characterised by a high prevalence of CD complicated behaviours and UC pancolitis. 84.4% of patients (n = 108) were exposed to biologics at the time of completion of the questionnaire.

The prevalence of fatigue was 65.6% stratified as severe (FACIT-F &lt;20) and moderate (FACIT-F 20–40) in 21.1% and 44.5%, respectively. Fatigue was clearly associated with active disease in CD, anxiety, depression, poor quality of life, insomnia and somnolence but not with active disease in UC. All biological values were within normal ranges and did not influence fatigue. Older age at diagnosis was associated with lower FACIT-F score while disease duration was not (Table 2). No correlation was found between fatigue and any specific biologics (p = 0.08).

Conclusion
This prospective study reported a fatigue prevalence of 65.6% in a severe IBD cohort highly exposed to biologics. Beyond disease activity in CD, psychological factors (whether they are causes or consequences) such as anxiety, depression, poor quality of life and insomnia were associated with fatigue.
DOP45 Increased prevalence but not incidence of myocardial infarction and stroke in patients with inflammatory bowel diseases in Quebec in 1996–2015
Authors: Verdon C , Reinglas J , Filliter C , Coulombe J , Gonczi L , Afif W , Wild G , Seidman E , Bitton A , Bessissow T , Brassard P , Lakatos P L 
Published: January 2020

Abstract

Background
Chronic inflammatory diseases have been linked to increased risk of atherothrombotic events, but the risk associated with inflammatory bowel disease (IBD) is conflictive. We, therefore, examined the risk of and risk factors for myocardial infarction (MI) and stroke in patients with IBD in Quebec.

Methods
We used the public health administrative database from the Province of Québec to identify newly diagnosed IBD patients between 1996 and 2015 with established case ascertainment algorithm. Incidence and prevalence of stroke and myocardial infarction were defined using ICD codes found in primary, secondary care visits or admission. Comorbidity analysis was performed by both using a logistic regression or a Poisson model with outcome rates for 1000 person-years adjusted for age and sex along with one comorbidity of interest, or with medical therapy as a time-varying variable. Significant variables (p &lt; 0.05) were added to a multivariable models along with age and sex. Analyses were run overall and stratified by disease type. Incidence rate ratios, 95% CIs and p-values were computed.

Results
In total, 34 644 newly diagnosed IBD patients (CD: 59.5%) were identified. The prevalence but not incidence rates of MI was higher in IBD (prevalence at the end on 2013: 3.98%, OR:2.03 95% CI: 1.92–2.15, incidence: 0.234 per 1000 patient-years) compared with the background Canadian rates (prevalence in 2012–2013: 2.0%, incidence: 0.220 per 1000 patient-years), while the prevalence and incidence rates of stroke were not significantly higher in IBD (prevalence in 2012–2013: 2.98%, OR: 1.15 95% CI:1.08–1.23, incidence: 0.122 per 1000 patient-years vs Canadian rates: (prevalence in 2012–2013: 2.60%, incidence: 0.297 per 1000 patient-years). We identified age, sex, hyperlipidaemia and hypertension (p &lt; 0.001 for each) as risk factors for developing MI and stroke in both CD and UC. Diabetes was identified as an additional risk factor for MI in CD and stroke in UC. Exposure to biologicals was associated with a higher incidence of MI compared with the non-treatment group (IRR: 1.51, 95% CI: 0.82–2.76, p = 0.07) in the insured IBD population.

Conclusion
Increased prevalence but not incidence of MI and no increased risk of stroke was identified in this population-based IBD cohort from Quebec. Risk factors for both MI and stroke included age, sex, hyperlipidaemia, hypertension and diabetes in IBD. Exposure to biologicals, reflecting disease severity in administrative databases, was associated with a higher incidence rate ratio for MI in IBD.
DOP46 Impact of a genetic burden on familial aggregation of inflammatory bowel disease
Authors: Lee H S , Hannes L , Vancamelbeke M , Ballet V , Ferrante M , Vermeire S , Cleynen I 
Published: January 2020

Abstract

Background
Family history of inflammatory bowel disease (IBD) is the strongest risk factor for IBD. There currently, however, is limited understanding of the contribution of genetic risk to familial aggregation of IBD. We aimed to evaluate the association between the IBD polygenic risk score (PRS) and familial IBD, and determine its contribution to familial IBD.

Methods
We included 54 multiple-affected families (≥3 first-degree relatives affected) of European ancestry, including 189 affected IBD patients (156 Crohn’s disease; 33 ulcerative colitis), and 133 unaffected relatives. For all individuals, Immunochip genotypes were available. Weighted PRSs with estimates derived from literature were calculated using PRSice-2.0, including clumping and different p-value thresholds (pT) to select which variants to include in the score. Explained variance (Nagelkerke pseudo-R²) was calculated across different pTs. To account for possible intra-familial correlations, the association between PRS and familial IBD was evaluated in age- and sex-adjusted generalised mixed regression models including family as random effects. Sporadic cases (n = 1768) and non-IBD controls (n = 868) with Immunochip genotypes were used for comparison.

Results
Using pT = 0.05 for PRS calculation, we found that affected relatives had a higher PRS than unaffected relatives (p = 1.00 × 10−2), sporadic cases (p = 4.58 × 10−2), and non-IBD controls (p &lt; 2.20 × 10−16) (Figure 1a and b). The risk of disease in families increased by 1.23-fold (95% confidence interval (CI) 1.21–1.24) for every incremental standard deviation in PRS. Individuals in the highest quartile had a 3.45 times higher risk of IBD (95% CI 1.77–6.72) than those in the lowest quartile. However, the proportion of the explained variance between affected and unaffected family members was smaller than that of sporadic IBD and non-IBD controls; and the best pT was different for familial or sporadic IBD. In familial IBD, the best-fit PRS was at pT = 6.90 × 10−3 and explained 5.3% (Figure 1c, p = 3.07 × 10−4) of variance, whereas, in sporadic IBD, the best-fit PRS was at pT = 0.08 and explained 16.7% (Figure 1d, p = 8.48 × 10−63). For sporadic IBD, a typical increase in the proportion of variance explained was seen with more liberal p-value thresholds and levelling off at ~pT = 0.1 (Figure 1d). What was striking, however, was that in familial IBD this additive genetic variance was only observed until pT = 0.01, after which explained variance dropped dramatically (Figure 1c).

Conclusion
Higher IBD polygenic risk increases the risk for familial IBD as it does for sporadic IBD. In sporadic IBD, the increased risk is defined by variants of all p-value levels (until ~pT = 0.1). In familial IBD, the difference between those affected or not is in the higher-effect variants (p &lt; 0.01).
DOP50 The landscape of somatic mutations in non-neoplastic IBD-affected colon
Authors: Olafsson S , McIntyre R E , Coorens T , Butler T , Robinson P , Lee-Six H , Sanders M , Arestang K , Dawson C , Tripathi M , Strongili K , Hooks Y , Stratton M R , Parkes M , Martincorena I , Raine T , Campbell P J , Anderson C A 
Published: January 2020

Abstract

Background
Under normal physiological conditions, colonic crypts accrue ~40 somatic mutations for every year of life. That somatic mutations contribute to the development of cancer is well established, but their patterns, burden and functional consequences in diseases other than cancer have not been extensively studied and our understanding of the effects of chronic inflammation on the mutational profile and clonal structure of the colon is limited. Here, we investigated how the recurrent cycles of inflammation, ulceration and regeneration seen in IBD impact the mutational and clonal structure of intestinal epithelia.

Methods
We isolated and whole-genome sequenced ~400 individual colonic crypts from 46 IBD patients and compared these to ~400 crypts from 41 non-IBD controls. We compared the mutation burden, mutational signature exposure, clonal structure and cancer driver mutation landscape in crypts from actively and previously inflamed regions with crypts dissected from controls.

Results
We estimated the base substitution rate of affected colonic epithelial cells to be doubled after IBD onset. This change was primarily driven by acceleration of mutational processes ubiquitously observed in normal colon (Figure 1), and we did not detect an IBD-specific mutational process. In contrast to the normal colon, where clonal expansions outside the confines of the crypt are rare, we observed widespread millimetre-scale clonal expansions, even in the absence of mutations in KRAS, TP53 and APC (Figure 2). We discovered that mutations in ARID1A, PIGR and ZC3H12A, and genes in the interleukin 17 and Toll-like receptor pathways, were under positive selection in colonic crypts from IBD patients (Figure 3). With the exception of ARID1A, these genes and pathways have not been previously associated with cancer risk. A previously published mouse model of ZC3H12A suggests that LoF mutations in this gene may facilitate healing of affected mucosa without promoting tumorigenesis. This could make the encoded protein an attractive drug target. The observed enrichment of mutations in PIGR and IL17 and TLR pathways suggests that somatic mutations may initiate, maintain or perpetuate IBD pathogenesis through disruption of microbe-epithelial homeostasis.

Conclusion
Our results provide new insights into the consequences of chronic intestinal inflammation on the mutational profile and clonal structure of colonic epithelia. We identify the mutagens driving the increase in mutation burden and mutations which are under positive selection in the context of inflammation. Our results suggest that studying somatic mutations in the colon can reveal putative drug targets and pathogenic mechanisms for IBD.
DOP55 A real-world comparison of the effectiveness and safety of vedolizumab and anti-TNF therapies in early treatment initiation with first-line biologic therapy in ulcerative colitis: Results from EVOLVE
Authors: Mantzaris G , Bressler B , Kopylov U , Bassel M , Brett N , Colby C , Lopez C , Saha S , Kifnidi C , Agboton C , Adsul S , Demuth D , Luo M , Wang S , Yarur A 
Published: January 2020

Abstract

Background
Evidence suggests that early treatment (Tx) with biologic agents in Crohn’s disease improves long-term clinical outcomes. However, there is less evidence in ulcerative colitis (UC), and data comparing early Tx with first-line biologic vedolizumab (VDZ) to anti-tumour necrosis factor (anti-TNF) in real-world settings is needed. This study compared the clinical effectiveness and safety of UC patients who initiated VDZ or an anti-TNF as a first-line biologic within 2 years following diagnosis.

Methods
This was a real-world, multi-country, retrospective chart review study in Canada, Greece and the United States where biologic-naïve UC patients (≥18 years old) were treated with VDZ or an anti-TNF (adalimumab, infliximab, golimumab) agent within 2 years following diagnosis (initiated Tx May 2014–March 2018). Clinical effectiveness and safety data were collected from Tx initiation to earliest of chart abstraction date, death, or 6 months post-Tx discontinuation (Canada only). Tx persistence was defined as the duration of time from treatment initiation to discontinuation. Analyses of cumulative rates of Tx persistence, clinical response, clinical remission and mucosal healing over 24 months were estimated using Kaplan–Meier analyses. Clinical response, remission and mucosal healing were assessed using pre-defined hierarchical algorithms of standard disease measures reported in the medical records. Analyses of incidence rates (per 100 person-years [PYs]) of disease exacerbations, disease-related surgeries, serious adverse events (SAEs) and serious infections (SIs) were performed. Adjusted analyses used inverse probability weighting to balance cohorts.

Results
This analysis included 176 UC patients (VDZ: 86; anti-TNF: 90) from 37 sites. Mean (SD) age at index date: VDZ, 41.4 (18.9); anti-TNF, 36.8 (15.6) years (p = 0.20) and the proportion male: VDZ, 58.1%; anti-TNF, 56.7% (p = 0.84). At 12 months, 72.9% and 58.1% continued VDZ and anti-TNF respectively (p = 0.03) (Figure 1A). Though there were no differences in clinical response, clinical remission or mucosal healing between VDZ and anti-TNF groups; VDZ patients were significantly less likely to experience disease exacerbations (HR = 0.47 [95% CI: 0.32–0.69]) and SAEs (HR = 0.37 [95% CI: 0.19–0.72]) (Figure 2). Adjusted outcomes (Figures 1C and D, and 2B) were similar to unadjusted outcomes.

Conclusion
EVOLVE is one of the first studies that compared early VDZ Tx to early anti-TNF Tx in biologic-naïve UC patients. Results showed VDZ was associated with higher persistence, lower likelihood of experiencing disease exacerbations and a more favourable safety profile. Thus, in early UC, Tx with VDZ may improve long-term clinical outcomes. Sample size limitations warrant further study.