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Background Clinical and molecular subcategories of inflammatory bowel disease (IBD) are needed to discover mechanisms of disease and predictors of response and disease relapse. We aimed to develop a study of a prospective adult research cohort with IBD (SPARC IBD) including longitudinal clinical and patient-reported data and biosamples. Methods We established a cohort of adults with IBD from a geographically diverse sample of patients across the United States with standardized data and biosample collection methods and sample processing techniques. At enrollment and at time of lower endoscopy, patient-reported outcomes (PRO), clinical data, and endoscopy scoring indices are captured. Patient-reported outcomes are collected quarterly. The quality of clinical data entry after the first year of the study was assessed. Results Through January 2020, 3029 patients were enrolled in SPARC, of whom 66.1% have Crohn’s disease (CD), 32.2% have ulcerative colitis (UC), and 1.7% have IBD-unclassified. Among patients enrolled, 990 underwent colonoscopy. Remission rates were 63.9% in the CD group and 80.6% in the UC group. In the quality study of the cohort, there was 96% agreement on year of diagnosis and 97% agreement on IBD subtype. There was 91% overall agreement describing UC extent as left-sided vs extensive or pancolitis. The overall agreement for CD behavior was 83%. Conclusion The SPARC IBD is an ongoing large prospective cohort with longitudinal standardized collection of clinical data, biosamples, and PROs representing a unique resource aimed to drive discovery of clinical and molecular markers that will meet the needs of precision medicine in IBD.

PURPOSE Tumor testing for microsatellite instability and/or mismatch repair-deficiency (MSI/IHC) and clinical prediction models effectively screen for Lynch syndrome (LS)–associated colorectal cancer (CRC) and endometrial cancer (EC), but they have not been assessed for their ability to identify non-LS forms of inherited risk. The aim of this study was to compare MSI/IHC and the PREMM5 prediction model to identify carriers of LS and non-LS pathogenic variants (PVs) among patients with CRC and EC. PATIENTS AND METHODS Data were retrospectively analyzed from two single-institution cohorts: 706 patients with CRC and/or EC referred for genetic evaluation/testing (high-risk cohort) and 1,058 consecutively ascertained patients with CRC (oncology clinic cohort), unselected for familial risk. All participants underwent germline multigene panel testing. PREMM5 scores were calculated from personal/family cancer history. The primary outcome was the proportion of individuals with germline PVs (LS PVs, high-penetrance PVs, and any PVs) who had abnormal MSI/IHC testing and/or PREMM5 score ≥ 2.5%. RESULTS MSI/IHC and PREMM5 had comparable sensitivity for identifying LS carriers in high-risk (89.3% v 85.7%; P = .712) and oncology clinic patients (96.6% v 96.6%; P = 1.000), although MSI/IHC had significantly superior specificity for LS (81.3% v 20.1%; P < .001; 92.3% v 24.3%; P < .001). In both cohorts, PREMM5 had superior sensitivity to MSI/IHC at identifying patients with any high-penetrance PVs and any low-, moderate-, and high-penetrance PVs. Among patients with normal MSI/IHC, PREMM5 identified 84.2% and 83.3% of high-risk patients with CRC/EC and oncology clinic CRC patients with high-penetrance PVs, respectively. CONCLUSION MSI/IHC and PREMM5 effectively identify patients with CRC and/or EC with LS, although MSI/IHC has better specificity for LS. Because PREMM5 identifies non-LS, high-penetrance germline PVs, patients with CRC and/or EC with PREMM5 score ≥ 2.5%, including those with normal MSI/IHC, should be offered multigene panel testing.

OBJECTIVE Benefit of antibiotic use in Inflammatory Bowel Disease (IBD) is unclear and has been a subject of research. This study investigated the association between antibiotic use and treatment outcomes among IBD patients using real-world data. METHODS Data from Study of a Prospective Adult Research Cohort with IBD (SPARC IBD) of Crohn’s & Colitis Foundation’s IBD Plexus program were used. Patients diagnosed with Crohn’s disease (CD) or ulcerative colitis (UC) since 2000 were included. The use of antibiotics (ciprofloxacin, metronidazole, rifaximin and vancomycin) for ≥7 days after enrollment was identified from electronic health records and case report forms. Disease activity scores were assessed at the time of enrollment (baseline) and during follow-up using 6-point Mayo score (6-pt MS) and short Clinical Disease Activity Index (sCDAI) for UC and CD, respectively. Patients’ demographic and clinical characteristics were also collected. Remission was defined as 6-pt MS of 0-1 for UC and sCDAI RESULTS A total of 2,959 IBD patients (UC=1,060; CD=1,899) were included. Mean age at diagnosis was 30±14 years (UC=32±15; CD=28±14). Forty-four percent of the patients were male (UC=49%; CD=41%) and 79% were White (UC=82%; CD=78%). Antibiotic use after enrollment was observed in 29% of the patients (UC=26%; CD=30%). About 60% of UC or CD patients were in remission at baseline. The antibiotic use group had significantly higher baseline disease activity (UC 6-pt MS: 1.7±1.8; CD sCDAI: 167±96) than patients without antibiotic use (UC 6-pt MS: 1.3±1.7; CD sCDAI: 137±89). In the subset of patients with mild, moderate or severe baseline IBD (6-pt MS>1 for UC; sCDAI≥150 for CD), the baseline disease activity scores were largely comparable between patients who used antibiotic and who did not (UC 6-pt MS: 3.6±1.3 vs 3.3±1.3, p-value=0.063; CD sCDAI: 248±83 vs 238±83, p-value=0.169), while patients who used antibiotics were less likely to experience remission during follow-up compared to those who did not use antibiotics (UC adjusted remission hazard ratio [aRHR] 0.39, 95% confidence interval [CI] 0.26-0.60; CD aRHR 0.60, 95% CI 0.46-0.79). CONCLUSION In this study, antibiotic use in patients with IBD was negatively associated with remission during follow-up. The effect of antibiotics on gut microbiome and optimal use of antibiotics in IBD patients need to be further explored.

OBJECTIVE IBD Plexus is a data exchange platform that houses four cohorts, including The Study of a Prospective Adult Research Cohort with IBD (SPARC IBD). SPARC IBD is a multicentered, longitudinal cohort that follows patients through their standard of care. In IBD Plexus, patient reported data (eCRF) is linked with clinical and electronic medical record (EMR) data. Biospecimens are continuously collected and have been used to generate a myriad of molecular and biomarker data. To facilitate inflammatory bowel disease (IBD) research, we built an R package ‘ibdplexus’ (https://github.com/ccf-tfehlmann/ibdplexus), with multiple functions to load, filter and subset the data in IBD Plexus. Currently, this R package focuses primarily on SPARC IBD, with a future goal to expand to incorporate other studies. Each function is designed to help understand an IBD patient’s journey including their treatment use and disease activity over time. PRIMARY FUNCTIONS Three main functions help navigate the prescription information from the eCRF and structured EMR data. ‘Sparc_medication_filter’ filters the prescription data to generate a dataset with medication(s) of interest from eCRF and EMR data. For long-term medications including biologics, aminosalicylates, and immunomodulators, `sparc_medication_starts’ extracts the first instance of a medication start date from eCRF and EMR data. Sparc_medication_at_index’ generates a dataset with each participant and their medication at a specified time-point (e.g., enrollment, at time of biosample collection, etc.). Another set of functions map out a patient’s disease activity over the course of their enrollment. ‘Calculate_disease_scores’ creates a list of dataframes and an optional spreadsheet containing multiple tabs with disease activity and endoscopy scores for participants. Calculations include the short Crohn’s Disease activity index and the patient reported outcome (PRO) derivations PRO2 and PRO3, as well as the simple endoscopic score for Crohn’s Disease. For ulcerative colitis patients, the disease activity measures include the 6 and 9-point Mayo score and Mayo endoscopy score. ’Sparc_scores’ generates a dataset with each SPARC participant and their disease activity scores at a specified time-point. CONCLUSION The ibdplexus R package has increased the speed and efficiency with which the SPARC IBD data can utilized for research projects. Twenty domains can now be easily collapsed into one table mapped to a date of interest. These reference tables are then used to complete multiple queries, reducing the time per query from up to a day to an hour. The results from the medication functions are well aligned with a subset of patients that underwent chart review. In the few cases where the medication at index date did not align, the information was only available in progress notes or other forms of unstructured EMR data.

BackgroundMismatch repair (MMR) deficiency is the hallmark of tumors from Lynch syndrome (LS), sporadic MLH1 hypermethylated, and Lynch-like syndrome (LLS), but there is a lack of understanding of the variability in their mutational profiles based on clinical phenotypes. The aim of this study was to perform a molecular characterization to identify novel features that can impact tumor behavior and clinical management.MethodsWe tested 105 MMR-deficient colorectal cancer tumors (25 LS, 35 LLS, and 45 sporadic) for global exome microsatellite instability, cancer mutational signatures, mutational spectrum and neoepitope load.Results78% of tumors showed high contribution of MMR-deficient mutational signatures, high level of global exome microsatellite instability, loss of MLH1/PMS2 protein expression and included sporadic tumors. 22% of tumors showed weaker features of MMR deficiency, 73% lost MSH2/MSH6 expression and included half of LS and LLS tumors. Remarkably, 9% of all tumors lacked global exome microsatellite instability. Lastly, HLA-B07:02 could be triggering the neoantigen presentation in tumors that show the strongest contribution of MMR-deficient tumors.ConclusionsNext-generation sequencing approaches allow for a granular molecular characterization of MMR-deficient tumors, which can be essential to properly diagnose and treat patients with these tumors in the setting of personalized medicine.

PURPOSE: Tumor testing for microsatellite instability and/or mismatch repair-deficiency (MSI/IHC) and clinical prediction models effectively screen for Lynch syndrome (LS)–associated colorectal cancer (CRC) and endometrial cancer (EC), but they have not been assessed for their ability to identify non-LS forms of inherited risk. The aim of this study was to compare MSI/IHC and the PREMM(5) prediction model to identify carriers of LS and non-LS pathogenic variants (PVs) among patients with CRC and EC. PATIENTS AND METHODS: Data were retrospectively analyzed from two single-institution cohorts: 706 patients with CRC and/or EC referred for genetic evaluation/testing (high-risk cohort) and 1,058 consecutively ascertained patients with CRC (oncology clinic cohort), unselected for familial risk. All participants underwent germline multigene panel testing. PREMM(5) scores were calculated from personal/family cancer history. The primary outcome was the proportion of individuals with germline PVs (LS PVs, high-penetrance PVs, and any PVs) who had abnormal MSI/IHC testing and/or PREMM(5) score ≥ 2.5%. RESULTS: MSI/IHC and PREMM(5) had comparable sensitivity for identifying LS carriers in high-risk (89.3% v 85.7%; P = .712) and oncology clinic patients (96.6% v 96.6%; P = 1.000), although MSI/IHC had significantly superior specificity for LS (81.3% v 20.1%; P < .001; 92.3% v 24.3%; P < .001). In both cohorts, PREMM(5) had superior sensitivity to MSI/IHC at identifying patients with any high-penetrance PVs and any low-, moderate-, and high-penetrance PVs. Among patients with normal MSI/IHC, PREMM(5) identified 84.2% and 83.3% of high-risk patients with CRC/EC and oncology clinic CRC patients with high-penetrance PVs, respectively. CONCLUSION: MSI/IHC and PREMM(5) effectively identify patients with CRC and/or EC with LS, although MSI/IHC has better specificity for LS. Because PREMM(5) identifies non-LS, high-penetrance germline PVs, patients with CRC and/or EC with PREMM(5) score ≥ 2.5%, including those with normal MSI/IHC, should be offered multigene panel testing.

BACKGROUND: Germline variants in the APC and MUTYH genes contribute to colorectal cancer (CRC) and adenoma risk, though may occur with varying frequencies in individuals of different ancestries. The aim of this study was to evaluate the prevalence of APC, monoallelic MUTYH and biallelic MUTYH germline variants in Ashkenazi Jewish (AJ) and Other Ancestry (OA) individuals with colorectal adenomas. METHODS: We studied 7,225 individuals with colorectal adenomas who had germline APC and MUTYH testing at a commercial laboratory. Cross-sectional medical history data were extracted from provider-completed test requisition forms. We performed bivariate analysis to compare the frequency of APC and MUTYH variants between AJ and OA, and examined APC p.I1307K and monoallelic MUTYH carrier phenotypes using logistic regression. RESULTS: Pathogenic APC variants occurred in 38/285 AJ (13%) and 1342/6940 OA (19%; P=0.09); biallelic MUTYH variants in 2/285 (1%) AJ and 399/6940 (6%) OA (P

1579 Background: Current clinical prediction models provide syndrome-specific numeric estimates of an individual's likelihood of having a specific hereditary cancer syndrome (e.g., PREMM5 for Lynch syndrome; BRCAPRO for BRCA1/2). With the emergence of multigene panel testing (MGPT), there is a need to evaluate individuals' risk of carrying a pathogenic variant in a diverse array of cancer susceptibility genes in parallel. This study’s aim was to develop and validate the PREMMplus clinical prediction model for multigene cancer risk assessment. Methods: PREMMplus was developed in a cohort of 7296 individuals who had undergone germline MGPT at a single center. Logistic regression models were used to examine candidate predictive variables – including age, sex, ethnicity, and personal/family history of cancer – to provide a numeric estimate of an individual’s likelihood of carrying a pathogenic/likely pathogenic germline variant in one of 18 cancer susceptibility genes (11 high- [ APC, BRCA1/2, CDH1, EPCAM, MLH1, MSH2, MSH6, biallelic MUTYH, PMS2, and TP53] and 7 moderate-penetrance [ ATM, CDKN2A, CHEK2, PALB2, PTEN, RAD51C, and RAD51D]). Model performance was validated in an independent dataset of 14845 individuals who had undergone MGPT at a commercial laboratory. Results: Using clinical characteristics, including personal/family history of 18 cancers plus colorectal adenoma burden, PREMMplus demonstrated an excellent ability to predict pathogenic variants in high penetrance genes at 90% sensitivity. PREMMplus had acceptable performance with the addition of 7 moderate penetrance genes. PREMMplus was well-calibrated and demonstrated comparable performance in the external validation dataset. Conclusions: PREMMplus is the first validated risk assessment model to quantify an individual’s likelihood of carrying pathogenic variants in a wide diversity of cancer risk genes, and can be used to select individuals who should undergo MGPT. As expected, PREMMplus’s discriminatory capacity was reduced with the inclusion of moderate penetrance cancer risk genes. [Table: see text]